Advanced Drug Delivery Reviews 121 (2017) 101–116

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Drug targeting to myofibroblasts: Implications for fibrosis and cancer☆

Saleh Yazdani a, Ruchi Bansal a, Jai Prakash a,b,⁎
a
Targeted Therapeutics Division, Department of Biomaterials, Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The
Netherlands
b
ScarTec Therapeutics BV, Enschede, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devas-
Received 27 February 2017 tating fibrotic diseases. Not only in organ fibrosis, but also the pivotal role of myofibroblasts in tumor progression,
Received in revised form 20 June 2017 invasion and metastasis has recently been highlighted. Myofibroblast targeting has gained tremendous attention
Accepted 12 July 2017
in order to inhibit the progression of incurable fibrotic diseases, or to limit the myofibroblast-induced tumor pro-
Available online 16 July 2017
gression and metastasis. In this review, we outline the origin of myofibroblasts, their general characteristics and
Keywords:
functions during fibrosis progression in three major organs: liver, kidneys and lungs as well as in cancer. We will
Myofibroblast then discuss the state-of-the art drug targeting technologies to myofibroblasts in context of the above-mentioned
Drug targeting organs and tumor microenvironment. The overall objective of this review is therefore to advance our under-
Fibrosis standing in drug targeting to myofibroblasts, and concurrently identify opportunities and challenges for design-
Tumor microenvironment ing new strategies to develop novel diagnostics and therapeutics against fibrosis and cancer.
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).

Contents

1. Myofibroblast: biology and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

1.1. Origin and heterogeneity of myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
1.1.1. Myofibroblasts in organ fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
1.1.2. Myofibroblasts in tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1.2. Functions of myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1.2.1. Myofibroblasts' functions in organ fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
1.2.2. Myofibroblasts' functions in the tumor microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2. Concept of drug targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3. Biological barriers for drug delivery to myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.1. Liver myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.2. Renal myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.3. Lung myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.4. Tumor myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4. Potential targets in myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.1. Platelet-derived growth factor (PDGF) receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.2. Integrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.3. Mannose-6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.4. Fibroblast activation protein (FAP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.5. Retinol binding protein (RBP) receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5. Targeting systems for myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
5.1. Modified albumin-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
5.2. Peptide-modified cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.3. Nanoparticle-based systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Fibroblasts and extracellular matrix: Targeting and therapeutic tools in fibrosis and cancer".
⁎ Corresponding author at: Targeted Therapeutics, Department of Biomaterials, Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of
Twente, Enschede, The Netherlands.
E-mail address: [email protected] (J. Prakash).

http://dx.doi.org/10.1016/j.addr.2017.07.010
0169-409X/© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
102 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116

5.4. Antibody-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

5.5. Polymer-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.6. Aptamer-based systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
6. Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

1. Myofibroblast: biology and function discuss the heterogeneous origin of myofibroblasts in different organs
during organ fibrosis and tumors.
The wound healing process, in response to an injury, results in the
infiltration of inflammatory immune cells to the local tissue. Subse-
quently, the inflammatory phase progresses to the pro-fibrotic phase 1.1.1. Myofibroblasts in organ fibrosis
leading to release of cytokines and growth factors by infiltrated immune Lately, a lineage tracing study demonstrated that perivascular Gli1+
cells which cause the activation and transdifferentiation of quiescent fi- mesenchymal stem cell (MSC)-like cells markedly give rise to
broblasts into contractile myofibroblasts. Myofibroblasts secrete vast myofibroblasts in heart, lung, kidney and liver fibrosis models in vivo
amounts of extracellular matrix (ECM) proteins mainly collagens to re- [12]. Targeting perivascular Gli1 + MSC-like cells by genetic ablation
pair the wound [1,2]. These cells are predominantly identified by the ex- strategy markedly prevented the progression of fibrosis in solid organ
pression of alpha-smooth muscle actin (α-SMA), a cytoskeletal protein fibrotic models, suggesting these cells as promising target for therapy
[1]. During resolution phase, most myofibroblasts undergo apoptosis, in fibrotic diseases (Fig. 2). In line with that, recent animal experiment
while a few revert to quiescent fibroblasts, at the end of the wound by the same group showed that pharmacological targeting of Gli1 +
healing process. In case of a chronic injury that leads to chronic inflam- MSCs by Gli antagonist 61 (GANT61) attenuated the severity of bone
mation, however, myofibroblasts continue producing ECM, resulting in marrow fibrosis [13]. In liver, the primary source of myofibroblasts is
excessive scar tissue deposition, a process known as fibrosis (Fig. 1). Fi- the endogenous liver mesenchymal cells which consist of hepatic stel-
brosis not only occurs as a result of chronic injury, but also after a genet- late cells (HSCs) [14] and portal fibroblasts [15]. HSCs, vitamin A and
ic insult to epithelial cells i.e. tumorigenesis. Tumors are generally lipid droplets containing cells which are quiescent in the steady-state
considered as “wounds that do not heal” [3] and certain tumor types condition, located in the space of Disse between endothelial cells and
generate abundant fibrotic tissue (so called tumor stroma). Tumor-as- hepatocytes [16,17]. Upon injury, they lose their vitamin A and lipid
sociated myofibroblasts are the key fibrogenic cells aggravating tumor droplets and acquire myofibroblast-like phenotype. Portal fibroblasts
growth and progression. Intervening into myofibroblast-induced pro-fi- are normally present in low numbers in the connective tissue of portal
brotic and pro-tumorigenic activities using drug targeting technologies zones around portal vein(s), portal artery(ies) and bile duct(s) to main-
can be an interesting approach for developing novel therapeutics tain the integrity of portal tract. Upon chronic injury, portal fibroblasts
against fibrosis and cancer. Moreover, these technologies can be applied have been shown to proliferate and differentiate into myofibroblasts
to diagnose fibrosis progression in different diseases and tumor. In this [18,19]. In addition to HSCs and portal fibroblasts, other sources of he-
review, we discuss the biology of myofibroblasts in relation to liver, kid- patic myofibroblasts are BM-derived cells (i.e. fibrocytes and MSCs)
neys, lungs and tumor and elaborate on drug targeting strategies to [20,21] and mesothelial cells via MMT [22] (Fig. 2). Although EMT of ep-
modulate myofibroblasts. ithelial cells (hepatocytes and cholangiocytes) has also been suggested
to actively participate in liver fibrosis [23,24], recent in vivo cell fate-
mapping studies negated these findings [25–27]. Hence, the presence
1.1. Origin and heterogeneity of myofibroblasts and contribution of EMT in liver fibrogenesis seems to be context-de-
pendent and remains a matter of debate [28,29].
Since myofibroblasts are the key players in the pathogenesis of In kidneys, the origin of myofibroblasts has also been studied exten-
organ fibrosis and tumor, considerable research is still focused on un- sively in the past years. Humphreys et al. [30] through cell-fate tracing
derstanding the biology of myofibroblasts such as their origin and phe- experiments showed that myofibroblasts in kidneys originate primarily
notypic differences. In addition, exploration of different regulatory from endogenous stromal cells (pericytes and interstitial fibroblasts)
pathways involved in maintenance of their phenotype is crucial for de- but not from epithelial cells. Also, mesothelial cells have been proposed
veloping new therapeutic interventions. to transdifferentiate into mesenchymal cells via MMT [31], but further
To date, the major well-characterized origins of myofibroblasts are investigations are warranted to confirm these findings. Furthermore,
tissue-resident fibroblasts, pericytes, and bone marrow (BM)-derived glomerular mesangial cells are shown to acquire the myofibroblast phe-
mesenchymal stem/stromal cells (MSCs). Other proposed precursors notype and produce ECM in renal diseases [32]. LeBleu et al. [33] con-
of myofibroblasts are epithelial, endothelial and mesothelial cells, ducted a comprehensive analysis in genetically engineered mice to
which undergo epithelial–mesenchymal transition (EMT), endotheli- track the origin of myofibroblasts in kidney fibrosis. They showed that
al–mesenchymal transition (EndMT) and mesothelial–mesenchymal 50% of the total pool of myofibroblasts arise from resident interstitial fi-
transition (MMT), respectively [1,2,4–6]. Origin of myofibroblasts in broblasts through proliferation, while the non-proliferating
organ fibrosis and tumors is highly diverse and is largely dependent myofibroblasts derived through transdifferentiation of BM-MSCs
on the pathological site [7–9]. Despite different diseased states and or- (35%), EndMT (10%) and tubular EMT (5%). They also suggested that
gans, transforming growth factor β (TGF-β) remains the main growth pericytes probably do not contribute to the emergence of
factor causing fibroblasts differentiation. Other growth factors and cyto- myofibroblasts. In lungs, several candidates have also been identified
kines stimulating myofibroblasts differentiation are platelet-derived as potential cell-of-origin of myofibroblasts in pulmonary fibrosis like
growth factor (PDGF), connective tissue growth factor (CTGF), mono- interstitial fibroblasts [34], circulating BM-derived fibrocytes [35,36], al-
cyte chemotactic protein 1 (MCP1 or CCL2), tumor necrosis factor α veolar epithelial cells via EMT [37,38], mesothelial cells [39], capillary
(TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) [4]. In addition, endothelial cells through EndMT [40] and pericytes [41] (Fig. 2).
different mechanical forces e.g. matrix stiffness, mechanical tension/ Nevertheless, despite many exciting progress, yet there is no univer-
shear stress, vascular and interstitial flow, are the important contribut- sal consensus on the origin of myofibroblasts in different tissue fibrosis
ing factors regulating myofibroblastic differentiation [10,11]. Herein we but at the same time it is clear that the proportion of cell sources
 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116 103

Fig. 1. Schematic diagram showing the general fibrogenesis in different organs and tumor. Injury to epithelial cells instigate inflammation i.e. infiltration of immune cells (e.g.
macrophages, lymphocytes). The inflammatory cells secrete cytokines and growth factors which activate local fibroblasts and infiltrated mesenchymal cells into myofibroblasts.
Eventually, myofibroblasts secrete extracellular matrix (ECM) leading to scarring of the tissue.

contributing to myofibroblasts pool is very much dependent on the heterogeneity in CAF population which is largely depending on their or-
pathological site, and probably also disease etiology. igin, microenvironmental stimulus, and epigenetic alterations. For de-
tailed information on fibroblasts in cancer, we refer the readers to the
1.1.2. Myofibroblasts in tumors comprehensive review of Kalluri R [79].
Solid tumors are not only consisted of malignant cancer cells but also
contain non-malignant cells so-called stromal cells such as
1.2. Functions of myofibroblasts
myofibroblasts, infiltrated immune cells, adipocytes, pericytes and en-
dothelial cells as well as ECM [42,43]. Dynamic crosstalk between cancer
Although myofibroblasts are the master producers of ECM compo-
cells and stromal cells stimulate each other and make the tumor micro-
nents, they perform number of diverse functions in organ fibrosis and
environment permissive for supporting tumor growth [44,45].
tumor by interacting with other cells in the microenvironment (Fig.
Myofibroblasts in tumor are generally referred as tumor-associated fi-
3). Herein, we discuss the role of myofibroblasts in organ fibrosis and
broblasts or cancer-associated fibroblasts (CAFs) [46], whose recruit-
in tumor.
ment and activation is mainly governed by the cytokines released by
cancer cells and infiltrated immune cells. For example, IL-1β secreted
by immune cells stimulates CAFs to produce pro-tumorigenic secretome 1.2.1. Myofibroblasts' functions in organ fibrosis
in early neoplastic lesions through NF-κB pathway [47]. Evidence from Myofibroblast activation occurs in both physiological and patholog-
both human and rodent studies indicates the complexity and heteroge- ical conditions, however, persistent activation due to ongoing injury
neity of CAFs, hence their exact molecular identification is an area of leads to pathological scar formation [1,2]. When activated in response
current controversy and remains to be clarified [46,48]. This lack of pre- to microenvironmental alterations in injured tissues, myofibroblasts
cise definition of CAFs is attributed to their various cellular origins and produce several fibrogenic and inflammatory mediators, and ECM pro-
the diversity of markers. Myofibroblasts within tumor stroma are both teins such as collagens, laminin, fibronectin, and tenascin.
BM-derived and non-BM-derived myofibroblasts [46,48–51]. BM-de- Myofibroblasts not only secrete ECM, but are also capable of remodeling
rived myofibroblasts originate from BM-MSCs and BM-derived circulat- ECM by producing matrix metalloproteinases (MMPs) and tissue inhib-
ing fibrocytes. Non-BM-derived myofibroblasts may arise from smooth itors of metalloproteinases (TIMPs) [80]. They also acquire specialized
muscle cells (SMCs), stellate cells, epithelial cells via EMT, endothelial contractile features, which result in reorganization and contraction of
cell via EndMT, pericytes, mesothelial cells via MMT, and adipose tis- ECM in wound healing and fibrotic conditions [11]. ECM itself is also a
sue-derived stem cells [46,52–67] (Fig. 2). reservoir of growth factors which create a bioactive microenvironment,
To identify CAFs, similar to other non-tumoral myofibroblasts, α- affecting many cellular behaviors such as cell adhesion, migration, and
SMA is the most commonly used marker [46]. Other CAF markers are fi- proliferation [81,82]. Furthermore, the cell cytoskeleton components
broblast-specific protein-1 (FSP-1, S100A4), vimentin, fibroblast-activa- can modulate transdifferentiation to myofibroblasts as well as affecting
tion protein-alpha (FAP-α), platelet-derived growth factor receptor- myofibroblasts' reactions to extracellular growth factors and cytokines
beta (PDGFR-β), natriuretic peptide B (NPPB), podoplanin, discoidin do- and biomechanical stimuli/signals from ECM [83].
main-containing receptor 2 (DDR2) and prolyl 4-hydroxylase (P4H), Myofibroblasts interact actively with the surrounding cells within
and loss of caveolin 1 (CAV-1) and PTEN (phosphatase and tensin ho- their fibrotic microenvironment [4] (Fig. 3). They are reported to pos-
molog). However, none of them are exclusive to specific CAFs and pres- sess a cytotoxic phenotype that causes apoptosis of epithelial cells in
ent in all CAFs, rather the expression of some of these markers is highly lung fibrosis [84]. Many studies have highlighted the dynamic and mu-
dependent on their tissue of origin [48,52,53,68–74]. The same degree tualistic interaction between myofibroblasts and immune cells [85,86].
of diversity is also observed in the gene signature of CAFs in tumor mi- On one hand, myofibroblasts can be activated by components of the in-
croenvironment [75–77]. Furthermore, recent studies suggest that epi- nate and adaptive immunity, while on the other hand, they are capable
genetic alterations may induce irreversible activation of CAFs. For of modifying immune cells' behavior by altering the microenvironment.
example, an epigenetic switch in the regulation of leukemia inhibitory Collectively, these myofibroblastic morphological and functional alter-
factor may result in pro-invasive function of CAFs via JAK-STAT pathway ations lead to an excessive ECM production and remodeling, which
activation [78]. Overall, the existing data suggest that there is a high eventually form nonfunctional fibrotic tissue in several vital organs.
104 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116

Fig. 2. Localization and cell-of-origin of myofibroblasts. The schematic figure shows the origin of myofibroblasts and their localization in lung, kidney, liver and tumor microenvironment.
Upon injury, and based on disease etiology, any of these cells can give rise to myofibroblast, and therefore are attractive and potent target for therapy in both fibrosis and cancer. However,
for some of them (with question mark), there is both in favor and against evidence, which suggest their importance and contribution as a myofibroblast pool is very much depended on the
disease etiology.

1.2.2. Myofibroblasts' functions in the tumor microenvironment There is a reciprocal interaction between CAFs and other cells in
Myofibroblasts are not merely chief actors as ECM-producing cells in tumor microenvironment. When recruited in the microenvironmental
fibrotic diseases, but also are strategic effector cells in tumor progres- milieu, fibroblasts transdifferentiation and activation are stimulated
sion. Tissue fibrosis can be predisposing factor for the development of via a large variety of growth factors and mediators secreted by both im-
cancer [87], stressing myofibroblasts as an actual link between fibrosis mune and cancer cells. One of the most well-characterized regulators of
and cancer. Myofibroblasts are salient promoter of metastasis and inva- CAFs activation is TGF-β [90]. However, other mediators, cytokines or
sion in tumor microenvironment [46,88,89] while retaining many sim- mechanisms are also shown to have an effect on CAF activation such
ilar characteristics of myofibroblasts in other organs. The unique as PDGF, basic fibroblast growth factor (bFGF), IL-6, IL-1α, EGF,
tumor microenvironmental condition such as loss of TGF-β cytostatic lysophosphatidic acid (LPA), hypoxia and ROS, cancer-derived
effect on stromal epithelial cells upon their mutations, broader variety exosomes, and NF-κB [46,48,91–94]. When activated, CAFs promote tu-
of cellular differentiation routes, and high levels of reactive oxygen spe- morigenesis and metastasis through several phenomena such as meta-
cies (ROS) promote CAF functions [88]. These CAF functions result in bolic reprogramming of the tumor microenvironment, regulating tumor
chronic repair response in tumor microenvironment, known as cancer immunity, and inducing resistance to therapy [79,95]. Moreover, CAFs
fibrosis or stroma [79]. In addition to ECM remodeling, CAFs are capable increase intratumoral interstitial fluid pressure through ECM remodel-
of secreting a wide range of mediators including TGF-β1, hepatocyte ing and contraction, which results in inefficient uptake of anti-cancer
growth factor (HGF), epidermal growth factor (EGF), vascular endothe- drugs [96]. It is therefore tempting to speculate that targeting
lial growth factor (VEGF), stromal cell-derived factor 1 (SDF1), fibro- myofibroblasts is an effective strategy not only for preventing organ fi-
blast growth factor (FGF), CTGF, the pro-inflammatory chemokine (C- brosis, but also in hampering tumor progression [46].
X-C motif) ligand 14 (CXCL14), IL-1, IL-6 and IL-8, MMPs and TIMPs, col- Interestingly, recent independent studies have revealed contrasting
lagens, tenascin-C, fibronectin and elastin [89]. These secreted media- findings that CAFs are also capable of inhibiting tumor progression in
tors are ligands for receptors overexpressed by other cell types in the mouse pancreatic tumor models. They have shown that depletion of
microenvironment which initiate the cellular crosstalk, leading to α-SMA + myofibroblasts or hedgehog deletion in pancreatic tumor
tumor progression and metastasis (Fig. 3). stroma induced tumor progression instead of tumor suppression [97,
 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116 105

Fig. 3. Function and crosstalk of myofibroblasts in fibrotic microenvironment. Myofibroblasts secrete a wide range of mediators such as extracellular matrix (ECM), cytokines and growth
factors, which either directly influence tissues (ECM production and remodeling), or act on other cells in a paracrine fashion. This results in a number of effects, such as tumor growth and
metastasis, epithelial cell activation and dedifferentiation (e.g. EMT), immune-suppression or activation, angiogenesis and vascular remodeling, and fibrosis. This vast array of effects
highlights myofibroblast as a paramount target in preventing not only organ damage and loss of function, but also tumor growth, invasion and metastasis.

98]. However, one needs to consider that these studies were performed behavior [100]. Active targeting benefits from interactions and commu-
with genetic depletion of all myofibroblasts rather than inhibiting their nications between the imposed ligand properties on the drug and phys-
activity. Besides, these observations were only related to pancreatic icochemical features of targeted cell surface/receptor. In this approach,
tumor and the outcome might be different for other cancer types. Con- therapeutic compounds are incorporated into a drug carrier which is
sidering the complexity and plasticity of the tumor stroma, further stud- decorated with a ligand against a targeting receptor or biomolecule
ies are therefore warranted to elucidate and delineate the deleterious expressed by the target cells. The targeted drug-carrier therefore recog-
and beneficial aspects of stroma within tumor. nizes and internalizes into the target cells and induces its therapeutic ef-
ficacy intracellularly. In addition to the ligand-based targeting which is
2. Concept of drug targeting actively evolving especially in the field of cancer therapy [101], active
targeting can also be achieved via modifying the physical properties of
Targeted delivery of specific therapeutic agents holds great promises the drug (e.g. size, charge, shape) for improved tissue penetration and
due to enhanced therapeutic efficacy of the drugs at lower doses, while cellular uptake [99,102]. On the other hand, most of the solid tumors
preventing or reducing the undesirable off-target effects; these benefits possess leaky and highly permeable blood vasculatures with poor/no
are also largely applicable to develop theranostic agents [99]. Drug lymphatic drainage which allow particles or macromolecules with
targeting strategies are generally categorized as passive or active b200 nm hydrodynamic diameter to extravasate through the tumor
targeting. Passive targeting is based on the fact that drugs can accumu- blood vasculature and retain within tumors. This phenomenon is com-
late into specific organs due to the blood flow, the pathophysiological monly known as Enhanced Permeability and Retention (EPR) effect
characteristics of the organ and physicochemical properties of the [99,102–104].
drug. For example, liver and spleen (reticuloendothelial organs) are ac-
tively capable of taking up foreign particles by their resident phagocytic
cells. To achieve therapeutic levels via passive targeting, targeted drugs 3. Biological barriers for drug delivery to myofibroblasts
should possess extended blood circulation time and have modifications
to avoid uptake and elimination by the reticuloendothelial system Since myofibroblasts derivation is a result of an injury to parenchy-
(RES). In both drug delivery and imaging applications, the addition of ma, they are localized adjacent to injured epithelial cells and embedded
water-soluble polymers such as polyethylene glycol (PEG) reduces into self-formed complex matrix. Their anatomical localization, howev-
RES uptake, increases circulation time, diminish aggregation and associ- er, is largely dependent on the anatomy of the injured organ, site of the
ation with non-targeted serum and tissue proteins resulting in ‘stealth’ injury within the organ and the source of myofibroblasts.
106 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116

3.1. Liver myofibroblasts tubulointerstitial myofibroblasts in the kidney fibrosis remains a chal-
lenge. Considering the biological barriers in kidney (peritubular capil-
For cell-specific targeted delivery strategies against myofibroblasts, lary endothelium, the tubulointerstitium that includes interstitial cells
the targeted drugs circumvent several biological barriers to achieve ef- and ECM components), the physicochemical properties of the drug car-
fective drug concentration in the liver. Nevertheless, many of the riers are crucial for targeting renal interstitial myofibroblasts.
targeted drug delivery systems do not necessarily be accumulated suffi- Based on physicochemical properties and design of a drug-carrier
ciently in the intrahepatic target cell-type such as myofibroblasts, be- conjugate, it may pass through glomerular basement membrane and
cause of high non-specific uptake by hepatocytes and Kupffer cells reaches urinary space. Glomerular basement membrane is a specialized
that are mostly active in the uptake of (nano)particulates. In the liver, extracellular matrix of about 300 to 350 nm thickness, constituting a so-
the drug first enters via blood circulation to sinusoids and then reaches phisticated network of glycosaminoglycans and fibrous proteins, which
perisinusoidal space, where hepatocytes are located. Hepatocytes, com- together with podocytes and endothelial cells form glomerular filtration
prises of about 80% of the total resident hepatic cells in healthy liver, are barrier in the kidney glomerulus, a critical element in glomerular per-
strategic key cells in a wide range of liver diseases and are actively in- meability. Glomerular filtration barrier works as a size- and charge-se-
volved in the metabolism of numerous drugs entering the liver. In addi- lective barrier against molecules/particles, and should be considered
tion to hepatocytes, Kupffer cells (sinusoidal macrophages) accounts for in designing drug-carrier for kidney drug delivery [117]. After successful
15% of total healthy liver cell population and constitutes 80–90% of the passage across of glomerular filtration barrier, the designed drug-conju-
tissue-resident macrophages in the whole body. They are active in im- gate enters the lumen of proximal epithelial tubules. By accessing the
mune defenses by removing not only dangerous foreign compounds, tubular cells, the conjugate can bind to specific receptor (e.g. megalin
but also many large molecular-weight drugs entering the liver via circu- receptor) expressed at the luminal side (apical) of proximal tubules
lation [105]. Rapid uptake and complete degradation of many biological [118]. Then, the carrier system can either be degraded or transported
compounds by Kupffer cells make them challenging barriers to systemic to the basolateral side via transcytosis process and thereby enters into
delivery of therapeutics [106]. Also, liver sinusoidal endothelial cells the tubulointerstitial space. When the targeted delivery system is not
(LSECs), present close to hepatocytes within the space of Disse, like filtered in the glomerulus due to its large size or highly negative surface
Kupffer cells have high phagocytic ability which has a fundamental charge, and then alternative route to reach tubulointerstitial
role in immune system and host defense. As already mentioned, HSCs myofibroblasts is via the peritubular capillaries. The drug delivery carri-
are the important fibrogenic cells of liver, playing major role in liver fi- er should pass across the vascular capillary wall to end up at the
brosis/cirrhosis. However, the drugs that enter the liver will not neces- tubulointerstitial area. It has been reported that the endothelial cells
sarily reach the intended target cell type. Since HSCs are located in the of peritubular capillaries contain fenestrations (60–70 nm) [119], al-
space of Disse between endothelial cells and hepatocytes, the (targeted) though the effect of ECM deposition on the diameter and availability
drug-conjugates should pass sinusoidal endothelial barriers, and escape of these fenestrations in renal fibrotic condition remains unclear. Anoth-
Kupffer cells and hepatocytes uptake to be accumulated selectively in er barrier is the tubulointerstitial space itself which contains remodeled
HSCs for therapeutic efficacy [107]. During the pathological condition ECM and several cell types such as immune cells, fibroblasts, fibrillar
such as liver fibrosis, HSCs proliferate and secrete ECM proteins which collagen, as well as interstitial fluid. The scar tissue, particularly in ad-
altogether can occupy up to 90% of the fibrotic liver. Additionally, in- vanced form of kidney fibrosis, is the biggest challenge in delivering car-
creased ECM deposition and remodeling impose extra barriers against riers to myofibroblasts. Direct injection in the subcapsular area of
successful drug delivery in liver fibrosis. For instance, remodeling and kidney has been also utilized as another drug delivery method [120],
capillarization of sinusoidal cells due to ECM deposition in the space of however, whether this strategy is effective in cell-targeted therapies
Disse decrease vascular permeability [108,109] which result in marked in kidney diseases such as renal fibrotic conditions is currently un-
reduction in delivery of potent therapeutic to activated HSCs/ known and warrants further investigations.
myofibroblasts. Excessive ECM deposition ultimately results in deterio-
ration of hepatic parenchyma, increased intrahepatic vascular resis- 3.3. Lung myofibroblasts
tance to blood flow and portal hypertension development [16]. Due to
these alterations, portal blood flow into the liver may significantly de- The lung is also an interesting organ for non-invasive systemic deliv-
crease and compensated by arterial supply, which can compromise ery of drugs because of its anatomical and physiological characteristics
the effective drug delivery to diseased/fibrotic liver. Consequently, care- such as large absorptive surface area, high epithelial permeability and
ful and smart drug delivery strategies are desired to effectively target thin blood-alveolar barrier, rich vascularization and blood supply, and
myofibroblasts or their cell-of-origin in fibrotic liver diseases. lower drug-metabolizing enzymes [121,122]. Nevertheless, the com-
plex morphology of respiratory tract with around 40 different cell
3.2. Renal myofibroblasts types put forward several challenges for successful lung drug delivery,
e.g. targeting lung myofibroblasts. In addition to cellular barriers, there
Because of the unique anatomical structure and diversity of cells, are also non-cellular barriers such as mucus and surfactant. The conduc-
targeting to myofibroblasts in kidneys is an attractive but challenging tive regions (trachea, bronchi, and bronchiole) largely consist of ciliated
task. Renal myofibroblasts are mainly located in kidney interstitium monolayer epithelium covered by a thick mucus layer with an aqueous
(the intertubular area between nephrons, ureteric epithelial and renal hypophase constituting a highly efficient system for fast removal of det-
vasculature) in fibrotic conditions, and originate from local fibroblasts, rimental trapped pathogens and pollutants [123,124]. Surfactant, a sur-
pericytes or infiltrated BM-derived fibrocytes [110]. The first region of face-active lipid-protein material, synthesizes by type-II pneumocytes
kidney exposing to body circulation is the glomerulus which is com- and covers the alveolar surface. Pulmonary surfactant plays a crucial
posed of capillary network, renal capsule, endothelial cells, glomerular role in decreasing the surface tension at the air-liquid interface,
basement membrane, podocytes, parietal epithelial cells and mesangial preventing pulmonary collapse during expiration and lowering the
cells. During kidney diseases, the components of glomeruli are shown to workload required for inhalation. Despite their vital protective roles,
be important in inducing kidney injury and damage, and therefore pos- both viscous mucus secretion and surfactant layer are the most impor-
sible potential therapeutic targets in renal diseases [111–114]. Specific tant hindrances in drug delivery to the respiratory airways. The local
targeting to mesangial cells and podocytes have been shown to be a immune system has also a key role in maintaining the normal function
promising approach in both in vitro and in vivo animal models to treat of pulmonary system. However, regarding pulmonary drug delivery,
glomerular injury, and consequently hampering the progression of both cellular immune components consisting of macrophages, dendritic
many renal diseases [115,116]. However, drug targeting to and mast cells, and the humoral components like lactoferrins, surfactant
 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116 107

proteins, defensins, mannose binding lectin and lysozyme, are other drugs pharmacodynamically active [136]. Despite that, emerging evi-
types of barriers [124–126]. Lung myofibroblasts are usually located in dence highlights the complexity and heterogeneity of tumor microenvi-
the alveolar interstitium in the healthy lung, but presence of distinct ronment milieu. This underlines the pressing need for further detailed
subset so-called ‘subepithelial myofibroblasts’ has also been reported knowledge on cancer biology to allow for designing new therapeutic
in the alveolar septa of lung adenocarcinomas beneath or around agents to selectively target not only tumor cells, but also stromal cells
tumor cells [127]. Delivery of potent drug to the lung myofibroblasts such as CAFs.
(or their precursor cells), which normally accumulate in the lung inter-
stitium in fibrotic conditions, via intravenous systemic route is also chal- 4. Potential targets in myofibroblasts
lenging. While in the blood circulation, the designed drug-carrier
conjugate should pass endothelial cells to end up in interstitial area of The most important part of the targeted therapy development is to
the lung. However, in pathological conditions such as lung fibrotic dis- identify potential molecular targets that are involved in the pathological
eases, the permeability of blood vasculature within pathological lesions processes that, upon alternation, can lead to the disease resolution/re-
may change due to the injury to endothelial cells and vascular remodel- version. The therapeutic targeting strategies to inhibit myofibroblasts
ing. This blood capillary permeability is essential for proper accumula- functions can be categorized into (i) small molecule drugs/inhibitors
tion of systemically administered drug-conjugate, especially for e.g. receptor tyrosine kinases inhibitors such as RhoA kinase, ERK, JNK
nanoparticles drug delivery to target cells (myofibroblasts) in lung stro- etc.; signaling pathways inhibitors such as TGF-β, PDGFR-β, Hedgehog,
ma [128]. In addition, the dense fibrotic tissues due to collagen deposi- Notch, Wnt, endothelin-1, and siRNA and microRNA (for details, refer
tion and remodeled ECM in chronic conditions may cause low diffusion to reviews [137–143]). (ii) Monoclonal antibodies that can identify
of the drugs. Due to unique pulmonary blood circulation, large particles and bind to the targets on the cell surface or outside the cells. (iii)
(micrometer size) can be entrapped within lung capillaries. This proper- Targeted delivery systems consisting of the targeting moiety such a de-
ty has been used to not only deliver passively large particles to the lung, livery vehicle or protein carrying therapeutic agent conjugated to
but also to enhance the pulmonary retention of designed microparticles targeting ligands. Also, increasing investigations substantiate the ad-
[129,130]. This passive delivery strategy might be applied also for vantage of applying dual-targeting strategy, especially for simultaneous
targeting lung myofibroblasts. targeting of different cells/components in tumor microenvironment
Overall, for targeted delivery of potential therapeutic compounds to using nanomedicine [144].
myofibroblasts in pulmonary fibrosis, the intended delivery system Many efforts have gone into unraveling the detailed mechanisms in-
should be designed to overcome all the significant barriers while volved in transdifferentiation of precursors to myofibroblasts as well as
retaining its therapeutic activity. determining the potential targets expressed on activated
myofibroblasts. However, most of these proposed targets have been
3.4. Tumor myofibroblasts identified based on in vitro experiments, and therefore their expression
profile and therapeutic value in in vivo situation need to be further val-
Highly complex and heterogonous pathophysiology of tumors poses idated. Moreover, the majority of those candidate targets are also
many limitations on delivering proper and effective dose of drugs to the expressed in other cells in the body, and even their extent and pattern
site of tumor microenvironment to CAFs. The physiologically abnormal of expression alter much among different disease pathology. Further-
structure of tumor microenvironment compromises the major and more, more specific targets are needed that are universally expressed
most important routes of molecular transports which are highly effi- on myofibroblasts, as some targets are present on certain precursors
cient in healthy organs: vascular, trans vascular and interstitial trans- of myofibroblasts. Hence, non-targeted systemic therapies to treat
port, and cellular uptake [131]. The major abnormalities in tumor myofibroblasts may not be a successful approach and exerts unwanted
microenvironment are: solid stress, which is induced by tumor growth, side effects in off-target tissues or cells. It would be desirable to define
can effect vascular and interstitial transport and consequently increase moieties that are exclusively expressed or over-expressed by
interstitial fluid pressure; tortuous and leaky blood vessel networks myofibroblasts during pathological conditions such as fibrosis and carci-
which hamper the normal blood flow in tumor microenvironment; col- nogenesis. Consequently, we elaborate herein on cell surface targets
lapsed and nonfunctional lymphatic vessels that in combination with which have been used in vivo as well as potential candidates for in
leaky and heterogeneous blood vessels give rise to interstitial fluid re- vivo drug delivery to myofibroblasts, considering the translational po-
tention leading to further increase in interstitial pressure; and finally tential of the target/delivery strategy towards clinical practice.
highly dense ECM accumulation that makes additional barrier to inter-
stitial transport [132]. Because of these transport barriers, most drugs 4.1. Platelet-derived growth factor (PDGF) receptors
exhibit low efficacy in cancer therapy as they have poor penetration
and distribution into tumors [133], hence present unique challenges PDGF receptors are the tyrosine kinase receptors (PDGFR-α and
against targeted delivery to CAFs. PDGFR-β) with common domain structures, including five extracellular
For targeted delivery of potent drug-conjugates to CAFs, the first immunoglobulin (Ig) loops and an intracellular tyrosine kinase (TK) do-
challenge is to overcome the substantial barrier of morphologically ab- main. PDGFR-α and -β exist in homo- or hetero-dimeric forms and bind
normal blood vessels' basement membrane in tumors [134]. The specif- to PDGF dimeric subunits [145]. Until now, PDGF-AA, -BB, -AB, -CC, and
ic characteristics of remodeled basement membrane in tumor -DD forms are reported to exist [146]. Binding of the PDGF to their re-
vasculature can affect/limit the extravasation of the designed drug-car- ceptors leads to autophosphorylation of tyrosine residues that activate
rier (e.g. nanoparticles) from intratumoral blood vessels into the inter- several signaling molecules regulating cell growth, proliferation, differ-
stitium, where CAFs are localized. In addition, infiltrated immune cells entiation, and development in many diseases including fibrosis and can-
accumulated in perivascular area can be another significant barrier for cer [145]. The expression of PDGF receptors on myofibroblasts has been
efficient delivery of the drugs to CAFs due to their high phagocytic ca- shown to be tissue specific in different fibrotic diseases. For example,
pacity, especially for nanoparticle-drug delivery systems [135]. PDGFR-α expression on lung myofibroblasts can be induced or sup-
Several approaches have been proposed to improve the delivery and pressed by different stimuli in pulmonary diseases, while they express
therefore the potency of therapeutics to tumor microenvironment like PDGFR-β constitutively. In contrast, PDGFR-β expression on liver
solid stress attenuation, improving the function of tumor vasculatures, myofibroblasts is extremely inducible and upregulated during liver in-
dampening the interstitial fluid pressure, and improving the physico- jury, and is a hallmark of early HSCs activation [147]. PDGF expression
chemical properties of therapeutic agents [132,136]. These strategies has also been correlated with myofibroblasts differentiation and prolif-
improve the pharmacokinetic of the drugs, and concurrently keep the eration, and subsequent ECM deposition, both in experimental models
108 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116

and human diseases [147]. PDGF antagonism and pharmacological inhi- ligands are IGF-II and retinoic acid [172]. This receptor is highly efficient
bition of PDGFR-β has shown to be a promising therapeutic approach for intracellular delivery as it rapidly internalizes after binding to its li-
and is therefore a potential target in organ fibrosis as well as in tumor gands. M6P/IGF-IIR is particularly expressed on activated HSCs during
growth and metastasis [147–152]. We and others have utilized the liver fibrosis [173], and was explored for HSC-specific drug delivery
myofibroblasts' PDGF receptors for targeted delivery of compounds to [174,175]. This receptor is also shown to be selectively expressed by
treat organ fibrosis or tumor growth [153–156], demonstrating the po- various cancer cells and fibroblasts in vitro and in B16 and C26 tumor
tential of targeting PDGF receptors as clinically feasible therapeutic ap- models in vivo [176]. Apart from liver, M6P/IGF-IIR expression was
proach in fibrosis and cancer [157]. demonstrated in arteries, glomeruli and tubular epithelial cells of
TGR(mRen2)27 rat kidneys, but not specifically on renal fibroblasts/
4.2. Integrins myofibroblasts [177]. Collectively, these data suggest that M6P/IGF-IIR
is a suitable target for drug targeting to HSCs, but more studies are war-
Integrins are 90 to 160 kDa transmembrane heterodimeric receptor ranted to establish it as a pan-myofibroblast target.
proteins that bridge the ECM to the intracellular cytoskeleton, playing a
crucial role in ECM-cell adhesion and also cell-cell adhesion [158]. They
exist in α/β non-covalently associated heterodimeric forms consist of 4.4. Fibroblast activation protein (FAP)
18 α and 8 β subunits, that assemble into 24 different receptors with
different binding properties and distinct tissue and cellular distribution. FAP is a type II membrane serine protease with an extracellular cat-
Integrins mediate the crosstalk between the epithelia, tissue alytic domain with dipeptidyl peptidase IV (DPPIV)-like fold. FAP ex-
myofibroblasts and immune cells and thereby are involved in the initi- pression is shown to be mainly restricted to the reactive stroma of
ation and progression of tissue fibrosis. Integrin receptors are reported many tumors including breast, colorectal, skin and pancreatic tumors,
to be overexpressed on the myofibroblasts in different fibrotic diseases while no expression was seen in the neighboring healthy cells. FAP ex-
and tumor stroma [159]. Recently, a crucial role of αv integrins in tissue pression has been also observed in non-tumoral diseases such as liver
fibrosis in multiple organs has been highlighted [160]. An extensive cirrhosis and arthritis [178–180]. Brennen et al. [181] generated a
study by Henderson et al. [161] has demonstrated that HSCs express thapsigargin (TG)-based FAP-activated prodrugs which after CAF inter-
several αv-containing integrins (αvβ1, αvβ3, αvβ5 and αvβ8) and action became proteolytically activated by FAP and releasing TG analog
their expressions are markedly increased in fibrotic livers, as shown in in the tumor microenvironment, resulting in significant inhibition of
mice models and human patients. Furthermore, using Pdgfrb-Cre mu- tumor growth in breast and prostate xenograft cancer models. FAP has
rine model, they demonstrated that selective αv integrin depletion in also been used for disassembling cleavable amphiphilic peptide
PDGFR-β-expressing myofibroblasts significantly inhibited the progres- (CAP)-based nanoparticles or activating promelittin-containing FAP-
sion of hepatic, pulmonary and renal fibrosis. These interesting findings cleavable sequences attached to phospholipid and reduced graphene
suggest that strategies to manipulate αv integrins could be potentially oxide nanosheets for efficient and rapid release of encapsulated drugs
attractive therapeutic targets to prevent the progression of fibrosis. at the tumor sites [182,183]. Using transgenic lung and xenograft CT26
Integrin αv is well-reported to be overexpressed in angiogenic blood colon cancer mouse models, Santos et al. [184] showed that genetic de-
vasculature and has been targeted using RGD sequence-containing pep- letion and pharmacologic inhibition of FAP inhibited tumor growth
tides to tumors [162,163]. Lately, Chen et al. [164] reported higher ex- which attributed to an indirect inhibition of tumor cell proliferation,
pression of α6 integrin in lung myofibroblasts both in vitro and in marked reduction of myofibroblasts content, and tumor angiogenesis.
vivo. Genetic ablation and pharmacological inhibition of α6 integrin at- These findings highlight FAP as a promising therapeutic cell surface tar-
tenuated bleomycin-induced experimental lung fibrosis. Also, integrin get for designing drug delivery strategies.
α11 has been also identified to be overexpressed by CAFs of non-
small-cell lung carcinoma (NSCLC), and head and neck cancer [165,
166]. Earlier findings have indicated that stromal integrin α11 has a cru- 4.5. Retinol binding protein (RBP) receptor
cial role in both primary tumor growth and in the metastatic process,
highlighting integrin α11 as a unique therapeutic target in tumor stro- Retinol (vitamin A) receptor, also known as “stimulated by retinoic
ma [167,168]. We have recently identified α11 as a key target acid 6” (STRA6) or RBP receptor, is a membrane-bound cell surface re-
overexpressed on myofibroblasts within different fibrotic tissues in- ceptor which acts as a transporter for retinol. Retinol binds to RBP in
cluding liver, kidneys, and lungs, while its expression is very low in nor- the blood, and the complex is transported into HSCs through STRA6
mal organs [169], and showed that α11 knockdown in myofibroblasts and stored as retinyl palmitate in cytoplasmic lipid droplets [185].
inhibited their differentiation and pro-fibrotic functions. These data STRA6 is highly expressed by HSCs and plays an important role in up-
highlight α11 integrin as both cell surface and therapeutic target in take and storage of retinol, and used as a promising target for HSCs-spe-
myofibroblasts. In addition to integrin α subunits, recently Martin et cific drug delivery as shown in experimental models of liver fibrosis
al. [170] has illustrated upregulation of integrin β1 in myofibroblasts [186,187]. However, more studies in other fibrotic diseases and cancer
and its important role in liver fibrogenesis. Integrin β1 interacts with are warranted to establish RBP receptor as pan-myofibroblasts target.
several α subunits and is broadly expressed on number of cells and tis-
sues which makes it less interesting cell-specific target. Nevertheless,
targeting β1 integrin or its downstream intracellular pathways in 5. Targeting systems for myofibroblasts
myofibroblasts still remains a promising therapeutic approach.
Herein we describe the drug targeting systems for delivering thera-
4.3. Mannose-6-phosphate/insulin-like growth factor-II receptor (M6P/ peutic agents to myofibroblasts, which utilize the cell surface targets,
IGF-IIR) described in Section 4. As a general targeting strategy, ligands such as
peptides, antibodies, aptamers or other moieties are designed against
M6P/IGF-IIR is a multifunctional receptor, also known as cation-in- receptors overexpressed by myofibroblasts. These ligands are either di-
dependent M6P receptor, involved in the transport of cellular proteins rectly conjugated to the therapeutic molecule or to a (nano)carrier in-
from the cell surface or trans Golgi network to lysosomes [171]. This re- corporating a therapeutic agent. If a ligand is therapeutically active by
ceptor has four distinct binding sites for M6P-containing molecules and itself, then such strategy may act as “dual targeting”. The major
other sites for non-M6P-containing ligands. M6P-containing ligands are targeting systems reported in literature are summarized in Fig. 4 and
latent TGF-β and lysosomal enzymes, whereas non-M6P-containing described as follows.
 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116 109

Fig. 4. Schematic illustration showing receptors or proteins expressed by myofibroblasts and carriers to target myofibroblasts. The surface targets on myofibroblasts are dependent on their
origin and location. For example, fibroblast activation protein (FAP), a protease enzyme, is shown to be widely expressed on cancer-associated fibroblasts (CAFs) and shown to be targeted
with either peptide or antibody (e.g. Doxorubicin-loaded nanoparticles (PNP-D-mAb). On the other hand, platelet-derived growth factor receptor beta (PDGFR-β) is the most common
receptor which is shown to be expressed on myofibroblasts in liver fibrosis, kidney fibrosis and tumor stroma. A cyclic peptide so called PPB has been used to target this receptor after
conjugating to albumin or a nanocarrier, as illustrated here. For example, (1) PPB-modified sterically-stabilized liposome (SSL) loaded with IFNγ (PPB-SSL-IFNγ); (2) PDGFR-β-specific
IFNγ construct (PPB-PEG-IFNγ) and (3) PPB-modified human serum albumin (PPB-HSA). Another receptor mannose-6-phosphate (M6P)/insulin like growth factor-II receptor (M6P/
IGF-IIR), which is overexpressed specifically on HSCs but not reported on general myofibroblasts, was targeted with M6P(28)-HSA (albumin chemically modified with 28 M6P
moieties) or M6P-HSA conjugated liposomes. Furthermore, retinol binding protein (RBP) receptor, expressed by HSCs, has the main role in vitamin A uptake and storage. To target RBP
receptor, vitamin A-coupled liposomes have been designed and used to deliver siRNA against heat-shock protein 47 to HSCs in liver fibrotic models. Integrin αv receptor which is
available in various forms (e.g. αvβ3, αvβ5, αvβ6, αvβ8) has been shown to be expressed on myofibroblast in different organ fibrosis which makes it a potential candidate for
targeting. “?” indicates that there is a lack of integrin targeting approaches to target myofibroblasts.

5.1. Modified albumin-based systems HSC-specific accumulation and anti-fibrotic effects in vitro and in vivo
in bile duct ligation (BDL) rat model [189,190].
Since during liver fibrogenesis myofibroblasts largely originate from Subsequently, apoptotic drug 15-deoxy-D12,14-prostaglandin J2
HSCs, the differentiated forms of HSCs become the key target cells. (15d-PGJ2) was delivered using two carriers: M6P-HSA, and peptide-
Therefore, several targeted drug delivery systems have been designed modified albumin (PPB-HSA) that has affinity for PDGFR-β [175]. It
against HSCs to inactivate them using ligand modified albumin [188]. was shown that 86% of 15dPGJ2-M6P-HSA and 63% of 15dPGJ2-PPB-
In this system, human serum albumin (HSA) was modified by conjugat- HSA accumulated predominantly in the HSCs (64%) and Kupffer cells
ing targeting ligands such as sugar molecules or peptides which have (39%) in the BDL rat fibrotic liver 15 min post-intravenous injection
specific binding to a cell surface target receptor on the differentiated [175]. Gliotoxin (GTX), another pro-apoptotic drug, was also delivered
HSCs. In addition, therapeutic drug molecules or imaging agents could to HSCs using M6P-HSA delivery carrier and M6P-HSA-GTX construct
be conjugated to HSA for therapeutic efficacy or diagnosis, or both. induced apoptosis of activated HSCs in vitro, in vivo and in fibrotic
Use of HSA has several benefits as a carrier: (i) high liver slices [191]. These results showed the potential of both carriers
immunocompatibility being the most abundant blood protein; (ii) the for delivering pro-apoptotic agents to the myofibroblasts in the fibrotic
presence of many functional groups (e.g. 44 lysines, free cysteine) pro- liver.
viding enormous possibilities for modification; (iii) long circulating Angiotensin II inhibitors and several other kinase inhibitors, e.g. rho-
half-life; (iv) optimal molecular size preventing renal filtration but kinase inhibitor, impede key signaling pathways in HSCs and
avoiding recognition by the RES. For targeting HSCs, albumin has been myofibroblasts. Thus, attempts were made to deliver these inhibitors
modified with mannose-6-phosphate and PDGFR-β-binding peptide. (Losartan, Angiotensin II inhibitor and Y27632, rho-kinase inhibitor)
M6P/IGF-IIR, overexpressed on HSCs, was explored for HSC-specific specifically to HSCs using previously tested M6P-HSA carrier. The results
drug delivery using M6P-HSA (albumin chemically modified with 28 showed HSC-specific accumulation, and improved therapeutic efficacy
M6P moieties) [174] (Fig. 4). Using in vitro cell culture, animal models with reduced off-target effects in several models of liver fibrosis. Both
of liver fibrosis and liver slices from normal and cirrhotic human livers, carrier-coupled inhibitors lowered portal pressure without affecting
it was demonstrated that M6P-HSA construct was effectively taken up mean arterial pressure, while free untargeted drugs induced severe sys-
and internalized in activated HSCs via receptor-mediated endocytosis. temic hypotension [192–195]. Similarly, ALK5 inhibitor LY-364947
Two cytostatic and anti-proliferative drugs: doxorubicin (DOX) and (TGF-β signaling pathway inhibitor) was also delivered via M6P-HSA,
pentoxifylline (PTX) were coupled to M6P-HSA carrier and showed and conclusively showed HSC-specific uptake and inhibited ECM
110 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116

deposition in acute liver fibrosis model while prevented unwanted ad- established therapeutics and successively increased the therapeutic
verse effects in other cells [196]. index of drugs, both via ‘site-specific’ and/or ‘site-avoidance’ drug deliv-
Beljaars et al. [197] showed HSC-specific delivery using HSA-conju- ery [204,205].
gated RGD-sequence containing cyclic peptides which selectively Targeting peroxisome proliferator-activated receptor-γ ligand
binds to collagen type VI receptor (via integrins), the receptor that is (rosiglitazone) using M6P-HSA conjugated liposomes showed promis-
eminently expressed on activated HSCs. Both in vitro and in vivo results ing therapeutic results in CCl4-induced rat model of liver fibrosis [206]
verified that this carrier can be used for the targeted delivery of potent (Fig. 4). Also, Li et al. [207] by using M6P-modified bovine serum albu-
anti-fibrotic drugs to HSCs, and simultaneously it can also be utilized min nanoparticles encapsulating anti-fibrotic drug sodium ferulate
as receptor antagonists while delivering the drugs to target cells (dual demonstrated HSC-specific uptake and improved efficacy as compared
targeting) [198]. to free drug both in vitro and in vivo. Similar studies illustrated im-
proved anti-fibrotic property with reduced systemic effects by using a
5.2. Peptide-modified cytokines targeted PPB-modified sterically-stabilized liposome (SSL) loaded with
IFNγ [208,209].
Knowing the central importance of PDGFR-β in liver fibrosis [199, Another promising target is the retinol binding protein receptor
200], novel peptide-based targeting approaches were developed for (RBP receptor or STRA6) expressed by HSCs. Vitamin A-coupled lipo-
the delivery of anti-fibrotic cytokine IFNγ to PDGFR-β-expressing somes loaded with siRNA against heat-shock protein 47 that acts as a
HSCs in fibrotic liver [201]. IFNγ was coupled to PDGFR-β-recognizing collagen-specific chaperone, were shown to inhibit hepatic fibrosis in
peptides (either monocyclic PPB or bicyclic dimeric BiPPB) via bifunc- different experimental fibrotic models [186]. Duong et al. [187] showed
tional PEG linkers or HSA drug-delivery carrier (Fig. 4). Targeted IFNγ promising results by using vitamin A-nanoparticles to deliver nitric
showed HSC-specific uptake and improved therapeutic efficacy, while oxide (NO) into HSCs that attenuated the progression of liver fibrosis
reducing systemic side effects as compared to untargeted free or and portal hypertension.
PEGylated IFNγ using different targeting approaches in carbon tetra- Recently, Zhang et al. [210] aimed at examining the effectiveness of
chloride (CCl4)-induced liver fibrosis mouse models. These results dem- nanoparticle carrier which assists corona formation in drug delivery to
onstrate the impact of cell-specific targeted therapies as compared to HSCs. They meticulously validated retinol-conjugated polyetherimine
untargeted free biologicals. For clinical translation, targeted IFNγ was (RcP) nanoparticles that could attract plasma proteins such as the reti-
further miniaturized by synthesizing a chimeric molecule (mimγ- nol binding protein 4 (RBP4), and thus formed corona on the surface
BiPPB) composed of mimetic IFNγ (IFNγ signaling domain) and of nanoparticles. Usually the corona formation poses a negative effect
PDGFR-β-binding bicyclic peptide either chemically (via chemical con- on the modified ligands and may impede the targeting properties of
jugations) or biotechnologically (in E.coli) [202]. This designed IFNγ the designed conjugate by interfering in ligand-receptor interaction.
peptidomimetic conjugate (mimγ-BiPPB) substantially prevented the This modified corona formation composed of RBP/retinol complex was
progression of fibrosis in CCl4-induced mouse models of liver fibrosis, able to be directed to HSCs as a retinol-storing cells. Using this delivery
offering novel therapeutic approaches not only for the treatment of system, they delivered antisense oligonucleotide (ASO)-loaded RcP car-
liver fibrosis, but also in curing other fibrotic diseases. rier to activated HSCs in CCl4 and BDL models of liver fibrosis [210]. By
In another study, we reported the beneficial effects of targeted IFNγ this strategy, they could effectively increase the therapeutic potential
delivery to kidney myofibroblasts to halt fibrosis both in vitro and in of the compound in treating the disease. This study highlights the prac-
vivo [154]. By conjugating the PEGylated IFNγ to PDGFR-β-recognizing tical importance of modifying corona formation as a new promising ap-
peptides (PPB-PEG-IFNγ) (Fig. 4), myofibroblasts-selective PPB-PEG- proach for targeted delivery, which needs to be further evaluated for its
IFNγ construct inhibited the progression of renal fibrosis in unilateral clinical translation. Du et al. [211] designed IFN-α1b-encapsulated RGD-
ureter obstruction (UUO) mouse models, while at the same time coupled sterically stable liposomes that specifically bind to HSC-ex-
prevented the unwanted systemic side effects of untargeted IFNγ. This pressing collagen VI receptor. cRGD-liposomes showed increased HSCs
novel targeted delivery approach, by increasing the efficacy and reduc- accumulation (10-times higher than unlabeled liposomes) and im-
ing the off-target systemic side effects of IFNγ, holds a great promise for proved therapeutic efficacy in BDL model of liver fibrosis. Also, Thomas
the future of drug targeting to renal myofibroblasts. These studies high- et al. [212] by means of hyaluronic acid (HA) micelles delivered angio-
light the potential of myofibroblasts targeted therapeutics in the treat- tensin type I receptor blocker losartan to activated HSCs which marked-
ment of renal fibrosis. ly reduced the development of liver fibrosis. These studies highlight the
In addition, we have also shown the specific stromal targeting of potential of drug delivery strategies in targeting myofibroblasts by tak-
IFNγ using PDGFR-β expressed on pericytes and CAFs. We synthesized ing advantage of effective and potent drugs or biologicals for the treat-
PDGFR-β-specific IFNγ construct (PPB-HSA-IFNγ) and revealed that ment of fibrotic diseases, though mainly in hepatic fibrosis.
specific PDGFR-β-binding cyclic peptides can be used to deliver IFNγ Increasing evidence indicate that nanoparticles are capable of com-
to pericytes and fibroblasts to inhibit angiogenesis and tumor growth bating several barriers and difficulties faced using conventional drugs.
[203]. In another study, we examined the effect of conjugated doxorubi- Various studies have shown potential applications of nanoparticles es-
cin to PPB-HSA in targeting PDGFR-β expressing cells in C26-tumor pecially in drug delivery and targeting, as well as in diagnostic field
bearing mice (Fig. 4) which markedly diminished the C26 tumor such as imaging in kidney diseases [213]. A well-designed study by
growth, compared to non-conjugated, free doxorubicin treated mice Choi et al. [214] examined the renal distribution of 10 to 150 nm nano-
[156]. particles by intravenous injection. They showed the intra-renal distribu-
tion and size-dependent deposition of gold-loaded nanoparticles, with
5.3. Nanoparticle-based systems 80 to 100 nm preferentially accumulated in mesangium, while smaller
particles were able to reach the peritubular capillaries of the kidney.
Although some conventional drugs have good therapeutic index, The data emerged from this and other studies offers the possibility of
their systemic delivery at effective dose may induce severe side effects developing targeted nanoparticles for effective treatment of glomerular
in healthy cells. To avoid these unwanted effects, while simultaneously disease [215]. In addition to therapeutic options, the non-invasive imag-
increasing the concentration of the drugs at specific location or target ing techniques using nanoparticles for kidney diseases have been devel-
cell, and overcoming many of the inadequacies in drug development oped [213]. Recent advances in MRI-detectable magnetic nanoparticles
and delivery, e.g. difficulties in crossing biological barriers, nano-carriers revealed very promising results in order to monitor functional and his-
systems for drug delivery purposes have been advanced technologically. tological parameters of the kidney. For example, in patients progressing
This pronounced advancement substantially improved the efficacy of to chronic kidney disease (CKD) as an early detection approach such as
 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116 111

measuring/evaluating the numbers and the function of glomeruli/neph- 5.6. Aptamer-based systems
ron and/or in assessing renal inflammation [117,216].
In a recent study, Ji et al. [217] designed a dual-mode nanomaterial Due to the capacity of these single-stranded oligonucleotides to bind
which enhanced the efficacy of anti-cancer drug doxorubicin. Doxorubi- to their targets with high specificity and affinity, both RNA- and DNA-
cin-loaded nanoparticles (PNP-D) were synthesized via encapsulation based aptamers have been shown to possess enormous potential for
by peptide nanoparticles (PNP). PNP-D-mAb construct was then therapeutic applications [229]. The specific characteristic features of
engineered through electrostatic binding of monoclonal mouse anti- the aptamers make them also favorable candidates for drug delivery
body (mAb), which recognizes FAP-α on CAFs. These modifications en- strategies such as aptamer drug conjugates [230]. Aptamers are also
abled PNP-D-mAb construct to bind FAP-α-expressing CAFs (Fig. 4), called chemical antibodies on account of their functional similarities
resulting in release of cell-penetrating peptide (CPP) in tumor microen- with antibodies. However, because of several unique properties such
vironment for increased cellular uptake and therapeutic efficacy of DOX. as specificity, stability, penetration efficiency, etc., aptamer
Ernsting et al. [218] benefitted from taxane nanoparticles in order to nanomedicines have great potential and more advantages compare to
target stroma in an animal model of pancreatic tumor. They prepared a common antibody-based therapeutics, particularly in oncology field
construct (Cellax-DTX polymer) consisting of docetaxel (DTX), PEG, and [231,232].
acetylated carboxymethylcellulose. By injecting this compound, they Using osteopontin-directed RNA aptamer (OPN-R3), Hunter et al.
showed that these nanoparticles accumulated in CAFs and subsequently [233] could significantly block the osteopontin-induced signaling activ-
reduced metastatic potential of the tumor and increased the survival in ity in human dermal fibroblasts in vitro, suggesting the potential possi-
mice bearing pancreatic cancer. bility of this aptamer as an anti-fibrotic therapeutic. In a rat model of
glaucoma filtration surgery, administration of aptamer S58 (which tar-
gets TGF-βRII) in conjugation with chitosan-based hydrogel (CS/S58)
5.4. Antibody-based systems showed superior anti-fibrotic effects than chitosan alone [234]. In a re-
cent well-conducted study, Kato et al. [235] convincingly demonstrated
Antibody-mediated delivery of therapeutic modalities to selective the beneficial effects of modified anti-ATX DNA aptamer RB014 in re-
antigens has caught growing interest mainly in cancer therapy as an ef- ducing markers of lung fibrosis in an experimental mouse model of
fective strategy. The encouraging results and emerging evidences of e.g. bleomycin-induced pulmonary fibrosis. Although, to best of our knowl-
antibody-drug conjugates in tumor filed hold lots of promise for edge, there is no published study yet available using aptamer-based de-
treating patients [219,220]. Schuster et al. [221] developed FAP anti- livery strategy to specifically target myofibroblasts in vivo, the
body-modified immunoliposomes encapsulating antifibrotic drug de- encouraging findings of recent investigations using aptamers pose as
feroxamine and showed substantial attenuation of collagen deposition promising clinically feasible approach in treating fibrotic diseases.
in activated fibroblasts in vitro. In another study, targeted lipid-coated The promising therapeutic concepts emerging from these recent ad-
nanoparticles were designed using TNF nanocytes (tumor necrosis vancements in the field, although awaiting further validation in future,
factor was covalently attached to the surface of polymeric nanopar- suggest that novel drug delivery strategies have potential to open a
ticles) which incorporated with a single-chain Fv (scFv) molecule new era in treating patients suffering from cancer. However, there are
targeted to FAP-expressing cells [222]. Although the in vivo practical several challenges before such advanced therapies can be advanced to
applicability of this approach awaits future studies, these results clinic. For example, for drug delivery to the fibrotic microenvironment
showed the potential of this multifunctional lipid-nanoparticle com- the challenges are: (i) Physiological challenges: crossing different bio-
posite system in targeting FAP-expressing cells, which may have fu- logical barriers including extravasation and penetration through the
ture applications in treating fibrotic conditions and tumor. Also complex fibrotic tissue; (ii) Formulation challenges: the complexity of
recently, biphasic immunoliposomes which target concomitantly the formulation (combining different components such as ligand, carri-
endoglin (CD105) and FAP were designed, and tested in vitro with er and drug), multiple products within a formulation, batch-to-batch
promising results [223]. variations, physicochemical characterization and scale up issues; (iii)
The role of PDGF system in fibrotic condition and tumor stroma, par- Translational challenges: a regulatory roadmap, lack of clinically rele-
ticularly liver fibrosis, has been well-documented. There are several vant animal models leading to clinical failures despite strong preclinical
promising therapeutic antibodies and aptamers for targeting the PDGF data, clinical study designs and lack of defined clinical endpoints for
receptors in liver fibrosis which are currently in advanced preclinical chronic fibrotic diseases.
studies or clinical trials [224]. Despite the above-mentioned challenges, recent advancements in
the targeted drug delivery approaches and nanomedicines have deliv-
ered promising results and have achieved many preclinical and clinical
5.5. Polymer-based systems successes in the field of cancer therapy. Because of the ample available
information, reader is referred to some comprehensive reviews [236–
The recent advancements in polymer-based drug delivery under- 240] for further details on the topic.
score the great potential of this technology in targeted delivery of
both therapeutics and theranostics [225,226]. The polymer-drug conju- 6. Conclusion and future perspectives
gates gained significant attention especially in cancer therapy in order
to improve the efficiency of targeted delivery to tumor microenviron- Emerging studies underline the central role of myofibroblasts in
ment [227]. However, the application of this delivery system in the organ fibrosis and tumorigenesis much beyond their traditional ECM
field of organ fibrosis is still very limited. Yang et al. [228] constructed producing role. There are increasing efforts towards unmasking the
a polymer-based compound by conjugating collagen type I specific tri- complexity of myofibroblast phenotypes revealing that myofibroblasts
plex forming oligonucleotide (TFO) to HPMA, as polymer carrier, ac- are not a single cell population but a mixture of different cell popula-
commodated with M6P and GFLG peptidyl linkers. These conjugates tions with contrasting functions. These new insights on the diverse ori-
markedly increased the delivery of TFO to HSCs in rat model of liver fi- gin and multitudinal functions of myofibroblasts will help in
brosis, underling the potential of this polymer-based delivery strategy discovering the novel therapeutic targets to design new interventions.
in treating liver (or possibly other) fibrotic diseases. Future investiga- At the same time, many developed therapeutic agents resulted in a
tions are indeed warranted to confirm the advantages of the polymer- lack of efficacy in vivo due to their premature degradation or inability
based drug delivery over other delivery strategies in organ fibrosis and to enter cells such as the cases of siRNA and miRNA. Drug targeting tech-
tumor. nologies have demonstrated great potential by protecting their
112 S. Yazdani et al. / Advanced Drug Delivery Reviews 121 (2017) 101–116

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