Journal of Controlled Release 170 (2013) 365–372

Contents lists available at ScienceDirect

Journal of Controlled Release

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

Review

nab-Paclitaxel mechanisms of action and delivery

Denise A. Yardley ⁎
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 100, Nashville, TN 37203, USA

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

Article history: Taxanes are a key chemotherapy component for several malignancies, including metastatic breast cancer
Received 20 November 2012 (MBC), ovarian cancer, and advanced non-small cell lung cancer (NSCLC). Despite the clinical benefit
Accepted 16 May 2013 achieved with solvent-based (sb) taxanes, these agents can be associated with significant and severe toxic-
Available online 11 June 2013
ities. Albumin-bound paclitaxel (Abraxane; nab®-Paclitaxel), a novel solvent-free taxane, has demonstrated
higher response rates and improved tolerability when compared with solvent-based formulations in patients
Keywords:
nab-Paclitaxel
with advanced MBC and NSCLC. The technology used to create nab-paclitaxel utilizes albumin to deliver
Mechanism of action paclitaxel, resulting in an advantageous pharmacokinetic (PK) profile. This review discusses the proposed
Mechanism of delivery mechanism of delivery of nab-paclitaxel, including an examination into a hypothesized greater ability to
Taxane leverage albumin-based transport relative to sb-paclitaxel. An advantageous PK profile and the more efficient
Cancer use of albumin-based transport may contribute to the preclinical finding that nab-paclitaxel achieves a 33%
higher tumor uptake relative to sb-paclitaxel. Another possible contributing factor to the tumor accumulation
of nab-paclitaxel is the binding of albumin to secreted protein acidic and rich in cysteine (SPARC), although
the data supporting this relationship between SPARC and nab-paclitaxel remain largely correlative at this
point. Recent data also suggest that nab-paclitaxel may enhance tumor accumulation of gemcitabine in pan-
creatic cancer treated with both agents. Additionally, a possible mechanistic synergy between nab-paclitaxel
and capecitabine has been cited as the rationale to combine the two agents for MBC treatment. Thus,
nab-paclitaxel appears to interact with tumors in a number of interesting, but not fully understood, ways.
Continued preclinical and clinical research across a range of tumor types is warranted to answer the
questions that remain on the mechanisms of delivery and antitumor activity of nab-paclitaxel.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Taxanes: an introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

2. The development of nab-paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
3. Mechanism of delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
4. Tumor accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
5. Clinical experience with nab-paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

1. Taxanes: an introduction breakthrough for the treatment of a wide range of cancers. The
first publication on the isolation of Taxol from the extracts of Pacific
Taxane development over the past 40 years, from the isolation of yew trees took place in 1971 [1]. Subsequent work to understand the
paclitaxel to the development of next-generation taxanes, such as antileukemic and tumor inhibitory properties of paclitaxel established
albumin-bound paclitaxel (nab-paclitaxel), has served as a major the agent's mechanism of action of as an inhibitor of mitosis [2,3]. Pac-
litaxel was found to inhibit the depolymerization of microtubules, a
process necessary for normal cell division [2–4]. Specifically, microtu-
⁎ Tel.: +1 615 329 7272. bule stabilization blocks cells in G2 and M phases of the cell cycle
E-mail address: [email protected]. resulting in cell death [4]. This effect on cells undergoing mitosis likely

0168-3659/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jconrel.2013.05.041
366 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372

explains the selectivity of paclitaxel for proliferating cells over quiescent in some patients [5]. Because of the risk of hypersensitivity, patients
cells. receiving either sb-paclitaxel or docetaxel are pretreated with corti-
Difficulties with formulation slowed the clinical development of costeroids, and patients receiving sb-paclitaxel are also routinely
paclitaxel. A key component of this challenge was the high insolubility pretreated with antihistamines [7,8].
of paclitaxel in water [5,6]. However, after an exhaustive search for nab-Paclitaxel was initially developed to avoid the toxicities typi-
excipients that could allow parenteral administration, researchers cally associated with Cremophor EL in sb-paclitaxel [19]. In contrast
considered the most viable option to be a castor oil derivative known to sb-paclitaxel and docetaxel, nab-paclitaxel does not utilize non-
as Cremophor® EL (BASF SE) [5]. The current formulation of paclitaxel ionic surfactants to solubilize paclitaxel, which are known to con-
solubilizes paclitaxel in a 1:1 solution of Cremophor EL and dehydrated tribute to toxicity and entrap paclitaxel within solvent based
ethanol to arrive at solvent-based (sb-) paclitaxel (Taxol®, Bristol- micelles [5]. nab-Paclitaxel is formulated with human serum albu-
Myers Squibb) [5]. Docetaxel, a semisynthetic analogue of paclitaxel min at a concentration similar to the concentration of albumin in
shares a similar mechanism of action and is also highly insoluble; the the blood [20]. Formulation of nab-paclitaxel takes place through
current clinical formulation of docetaxel uses polysorbate 80 (Tween® high-pressure homogenization in which albumin and paclitaxel are
80, Sigma-Aldrich) to allow administration [5,7]. combined to create particles with a mean diameter of 130 nm
Encouraging results from a number of clinical trials has led to the [20,21]. This process does not covalently link albumin to paclitaxel
approvals of sb-paclitaxel and docetaxel as a treatment component in [22]. Upon injection, the nab-paclitaxel particles dissolve into sol-
numerous cancer types [7,8]. Taxanes are now considered a corner- uble albumin–paclitaxel complexes, and paclitaxel may bind and
stone of therapy for many disease states, in part due to the results unbind albumin (injected or endogenous) or other biomolecules,
of trials showing that superior clinical benefit with respect to overall or it may exist in a free/unbound state (see Mechanism of
response rate (ORR), progression-free survival (PFS), and overall Delivery section) [21,23]. Formulation with albumin allows nab-
survival (OS) can be achieved with taxane-based therapy [9–15]. paclitaxel to be reconstituted with a simple saline solution [21].
As such, nab-paclitaxel is administered without steroid or antihis-
2. The development of nab-paclitaxel tamine prophylaxis for hypersensitivity reactions [21]. Perhaps
because nab-paclitaxel delivery is not complicated by solvents, a
While the development of docetaxel led to promising efficacy higher dose can be administered relative to sb-paclitaxel. In a
results relative to sb-paclitaxel in a phase III metastatic breast cancer pivotal phase III MBC trial of nab-paclitaxel and sb-paclitaxel at
(MBC) trial (both agents delivered once every 3 weeks [q3w]) [16], the label-indicated doses as ≥ first-line therapy in patients with
the less favorable toxicity profile of docetaxel—(significantly higher MBC, the dose of paclitaxel delivered was 49% higher for patients
rates of grade ≥ 3 neutropenia, febrile neutropenia, asthenia, periph- receiving nab-paclitaxel vs sb-paclitaxel, suggesting that higher
eral edema, sensory neuropathy, nausea, stomatitis, diarrhea, infec- dose intensity is feasible with nab-paclitaxel [19].
tion, motor neuropathy, skin disorders, and vomiting)—suggested
that the need to improve taxane-based therapy had not been entirely 3. Mechanism of delivery
met. Indeed, both sb-paclitaxel and docetaxel are associated with
a number of adverse events, including hypersensitivity reactions, Classic thought on drug distribution holds that the free, or un-
peripheral neuropathy, and neutropenia (Table 1) [7,8,16]. Weekly bound, fraction of drug is the active fraction because drug bound to
sb-paclitaxel has emerged as the preferred schedule because of the proteins or other macromolecules might be unable to cross cell
OS advantage and lower incidence of serious toxicity compared membranes [24]. In clinical studies, sb-paclitaxel has been shown to
with q3w in patients with MBC [17]. However, neurotoxicity remains be highly protein bound in plasma, with Cremophor EL further
an important treatment-limiting toxicity for weekly paclitaxel [18]. In decreasing the free/unbound fraction of drug [24,25]. To examine
a phase III trial, the weekly schedule of sb-paclitaxel resulted in a sig- the effect that formulation has on the pharmacokinetics (PK) of pac-
nificantly higher rate of grade 3 neuropathy compared with the q3w litaxel, a randomized crossover PK study was carried out in patients
schedule (Table 2; 24% vs. 12%; p = 0.0003) [18]. The solvents used in with cancer receiving either sb-paclitaxel at 175 mg/m2 q3w over
the commercial formulations of both sb-paclitaxel and docetaxel can a 3-hour infusion or nab-paclitaxel at 260 mg/m2 q3w over a
increase the risk for both hypersensitivity and peripheral neuropathy 30-minute infusion [23]. In this study, mass spectrometry was used
to identify whether circulating paclitaxel was free/unbound or not.
In this report, paclitaxel associated with Cremophor EL would not
Table 1 have been identified as unbound drug. The key finding of the study
Toxicities and treatment exposure of sb-paclitaxel and docetaxel in a head-to-head
was that the formulation of nab-paclitaxel allowed a much higher frac-
single-agent trial of greater than first-line MBC [16].
tion of unbound paclitaxel for nab-paclitaxel vs. sb-paclitaxel (6.3% vs.
sb-Paclitaxel Docetaxel p value 2.4%, p b 0.001). Furthermore, the maximal concentration of unbound
175 mg/m2 q3w 100 mg/m2 q3w
(n = 222) (n = 222)
Table 2
Grade ≥3 adverse events occurring in ≥10% of patients in either arm, n (%)a
Toxicities of sb-paclitaxel delivered weekly or q3w in a head-to-head trial of first-line
Neutropenia 121 (54.5) 207 (93.2) b0.0001
MBC [18].
Febrile neutropenia 4 (1.8) 33 (14.9) b0.001
Anemia 16 (7.2) 23 (10.4) NS Most frequent grade ≥3 sb-Paclitaxel q3w sb-Paclitaxel qw p value
Asthenia 11 (5.0) 46 (20.7) b0.001 adverse events occurring 175 mg/m2 80 mg/m2
Stomatitis 0 24 (10.8) b0.001 in either arm, %a (n = 225)b (n = 346)b

Treatment exposure Leukopenia 9 8 NR

Treatment cycles received, 4 (35) 6 (32) NR Granulocytopenia 15 8 .017
median (maximum) Lymphopenia 12 19 NR
Relative dose intensity, 1 (0.72–1.00) 1 (0.62–1.00) NR Sensory neuropathyc 12 24 .0003
median (range)
NR, not reported.
Discontinuation due to 8 26 0.001 a
Adverse event data were listed only for the patients accrued to CALGB 9840, not
adverse events, %
the combined population that included patients combined from trial CALGB 9342.
b
NR, not reported. The paper lists these numbers as the limited set, which was the set evaluated for
a
Grade ≥3 sensory neuropathy occurred in 9 (4.1%) and 16 (7.2%) patients in the safety.
c
sb-paclitaxel and docetaxel arms, respectively. All cases were grade 3.
 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372 367

paclitaxel was about 10-fold higher for nab-paclitaxel (1284 ng/mL vs. of albumin-bound paclitaxel, which may explain the greater efficiency
122 ng/mL, p b 0.000001), and the systemic exposure (AUCINF) of of transcytosis across endothelial cells [23,37].
unbound paclitaxel was about 3-fold higher for nab-paclitaxel
(1159 h*ng/mL vs. 410 h*ng/mL, p b 0.000005). A likely explanation 4. Tumor accumulation
for these differences lies in the entrapment of paclitaxel in Cremophor
EL-based micelles in the solvent-based formulation of paclitaxel Studies have shown that a large fraction of injected albumin-
[24,26,27]. Consistent with the effect of micellar entrapment on pacli- conjugated molecules accumulate in proximity to tumors [39,40]. As
taxel distribution, Sparreboom et al. found that nab-paclitaxel achieves discussed above, albumin may reach tumors by receptor-mediated
a higher plasma clearance and a larger volume of distribution vs. transport mechanisms or by the EPR effect. It has been hypothesized
sb-paclitaxel in preclinical studies [28]. It has been suggested that that cancer cells may consume albumin from the tumor microenvi-
micellar entrapment could affect the PK linearity of sb-paclitaxel ronment and then metabolize it, possibly enhancing tumor growth
[24,26]. Table 3 lists selected PK studies on sb-paclitaxel and nab- [22,41]. Desai et al. conducted experiments in mice bearing xenograft
paclitaxel and gives the authors' characterizations of PK linearity for tumors from injected human breast cancer cells to determine wheth-
the two agents [21,24,26,29–31]. er formulation played a role in the tumor uptake of paclitaxel [37]. In
Although investigations into the distribution of unbound drug are these experiments, paclitaxel in both formulations was radioactively
important, it is also critical to consider that in human blood, paclitaxel labeled and the amount of labeled paclitaxel that eventually reached
is highly bound to proteins and other biomolecules. As stated previ- tumors was quantified. When equal amounts were injected, the re-
ously, Kumar et al. demonstrated that when sb-paclitaxel is adminis- searchers found that a third more paclitaxel from the nab-paclitaxel
tered to humans, approximately 95% of paclitaxel binds to other formulation was taken up by tumors. The authors suggested that nab-
molecules [25]. Albumin and alpha-1-acid glycoprotein contributed paclitaxel reached a higher tumor accumulation vs. sb-paclitaxel due
equally to this binding, with a minor fraction of paclitaxel bound to li- to both the lack of drug-sequestering solvent micelles and enhanced
poproteins. Furthermore, albumin is known to be a ubiquitous carrier albumin-mediated transcytosis. A subsequent report of similar experi-
of biomolecules in the blood [32], which prompts the consideration of ments suggested that nab-paclitaxel may achieve some degree of tumor
how albumin may influence the transport of nab-paclitaxel to tumors. selectivity relative to sb-paclitaxel, although the mechanisms responsi-
Circulating albumin must cross endothelial cells to reach tumors, and ble for this possibility were not characterized [42].
albumin has been reported to accomplish this in at least 2 ways Another molecular mechanism proposed to play a potential role in
(Fig. 1): receptor-mediated transcytosis and the enhanced perme- the tumor accumulation of nab-paclitaxel is the prevalence of albumin-
ation and retention (EPR) effect [33–36]. It has been hypothesized binding proteins such as secreted protein acidic and rich in cysteine
that nab-paclitaxel may take advantage of each of these mechanisms (SPARC) in proximity to tumors [38]. According to this theory, proteins
to reach the tumor microenvironment [37,38]. such as SPARC may exist at higher-than-normal levels in the tumor
To initiate transcytosis, albumin binds to an albumin-specific re- interstitium. Thus, these proteins could sequester paclitaxel bound to al-
ceptor, such as glycoprotein 60 (gp60). This effects a process of cell bumin in tumors at levels higher than those in healthy tissues. High
membrane invagination to form vesicles, which are then transported SPARC expression correlates with disease progression across a range of
through the endothelial cell before fusing with the membrane of the tumor types [43–56]; however, some clinical data have suggested a
other side of the cell thereby releasing the vesicle contents to the correlation between SPARC expression in the tumor and/or tumor
interstitial space [33,34]. microenvironment and positive clinical outcomes in patients receiv-
Experiments designed to characterize the level of transport of nab- ing nab-paclitaxel [38,57–59]. Other studies have failed to show
paclitaxel vs sb-paclitaxel across a layer of endothelial cells in culture such a correlation [60,61]. Thus, further studies delineating the molecu-
found that more than 4-fold more nab-paclitaxel was transported lar relationship between SPARC and nab-paclitaxel are warranted.
across the cells compared with sb-paclitaxel (Fig. 2) [37]. Furthermore, In a phase I/II advanced pancreatic cancer trial, Von Hoff et al.
a mixture of Cremophor EL and ethanol well below clinically relevant reported promising efficacy of nab-paclitaxel plus gemcitabine in the
levels inhibited the binding of paclitaxel to both albumin and endothe- form of an ORR of 48% and a median OS of 12.2 months [57]. An analysis
lial cells. This suggests that Cremophor EL may hinder the capacity of of the relationship between median OS and SPARC expression found
paclitaxel to use albumin-based transport mechanisms to the tumor that patients with high SPARC expression demonstrated a median OS
microenvironment (Fig. 2). of 17.8 months, whereas patients with low SPARC expression had a
The EPR effect posits that the vasculature around tumors is leaky, median OS of 8.1 months (p = 0.0431). The activity of nab-paclitaxel
allowing molecules below a certain size to escape the circulation through plus gemcitabine was further evaluated in preclinical studies reported
gaps between endothelial cells [35,36]. The second facet of the EPR effect alongside the clinical findings described above [57]. These experiments
is that lymphatic drainage to return leaked molecules to the circulatory were carried out in mice bearing xenograft tumors of human pancreatic
system is compromised around tumors, leading to the collection of cancer origin. A 2.8-fold enrichment of gemcitabine in xenograft tumors
molecules such as albumin in the tumor microenvironment. was conferred by combination treatment with nab-paclitaxel relative to
Considering the effects of formulation on unbound drug concentra- tumors in mice treated with gemcitabine only. The authors postulated
tion and albumin-bound drug, it appears that nab-paclitaxel holds 2 that at least one underlying mechanism for this effect was that nab-
biodistribution advantages over sb-paclitaxel. First, it results in a greater paclitaxel may have depleted the stromal barrier in the tumor microen-
fraction of unbound paclitaxel; second, it may result in a higher fraction vironment and thus augmented circulation to the tumor, thereby
allowing gemcitabine greater access to tumors. In further support of
this were the observations of decreased numbers of collagen fibers
Table 3 and an approximate 3-fold increase in the staining for mNestin, a marker
Pharmacokinetic linearity of sb-paclitaxel and nab-paclitaxel. of endothelial cells. However, the exact mechanism by which nab-
Primary author Year of publication sb-Paclitaxel nab-Paclitaxel paclitaxel leads to this stromal reduction remains unclear. To date,
experiments to test the effect of sb-paclitaxel on tumor stroma have
Gianni 1995 Not linear NA
Van Tellingen 1999 Not linear NA not been performed.
Brouwer 2000 Not linear NA A separate preclinical study investigating the mechanisms of
Gelderblom 2002 Linear 3-compartment NA antitumor activity of nab-paclitaxel plus gemcitabine in pancreatic
Ibrahim 2002 NA Linear tumors used a different experimental paradigm than the aforemen-
Nyman 2005 NA Linear
tioned Von Hoff et al. study [62]. This study used a genetically
368 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372

samples are being collected, which will allow an assessment of

nab-paclitaxel-induced effects on tumor stroma. Preliminary results
(n = 10 evaluable pancreatic adenocarcinoma samples) have sug-
gested that treatment with 2 cycles of nab-paclitaxel 125 mg/m2
plus gemcitabine 1000 mg/m2 qw 3/4 led to disruption of the tumor
stroma as revealed by less abundant collagen fibers around tumors.
Final results of this trial may help to answer whether the nab-
paclitaxel-induced stromal depletion seen in xenograft mouse models
also occurs in humans with pancreatic cancer [57,63].
Similar to the synergistic effect postulated above for nab-paclitaxel
and gemcitabine in pancreatic cancer, accumulating evidence suggests
that taxanes may also alter tumor physiology in a way that enhances
the activity of capecitabine treatment. To achieve antitumor activity,
capecitabine must be converted to the active fluoropyrimidine
5-fluorouracil by three enzymes located in the liver and directly in
the tumors [65,66]. The last enzyme to act in this process, known
as thymidine phosphorylase, has been shown to be preferentially
expressed at higher levels in some tumors than in the surrounding
normal tissues [67]. Furthermore, preclinical and clinical studies
have shown that taxane treatment may increase levels of this en-
zyme, suggesting a biological rationale for combining taxanes with
capecitabine [68–70]. This mechanistic synergy together with
nab-paclitaxel clinical data suggesting efficacy and tolerability ad-
vantages over sb-paclitaxel, led Schwartzberg et al. to examine the
combination therapy of nab-paclitaxel with capecitabine in a phase
II MBC study [66]. The trial reported encouraging efficacy findings,
Fig. 1. Two routes of albumin to reach tumors. The left half of the figure shows albumin
metabolism of a growing tumor, whereas the right half reflects the cytotoxic effect on
including a response rate of 61%; however, data on nab-paclitaxel's
tumor cells from the uptake of albumin-bound paclitaxel. Albumin and albumin-bound effect on levels of thymidine phosphorylase were not reported.
paclitaxel are hypothesized to reach the tumor interstitium by both transcytosis and
the EPR effect. 5. Clinical experience with nab-paclitaxel

engineered mouse model of pancreatic cancer that replicates the The unique properties of nab-paclitaxel described in this review may
molecular and clinical features of the disease, including resistance to account for the differences seen in the efficacy and safety profiles vs. the
gemcitabine. The study demonstrated that combination treatment solvent-based taxanes sb-paclitaxel and docetaxel [19,71]. For example,
with nab-paclitaxel and gemcitabine resulted in significantly smaller in a phase III MBC trial, patients receiving nab-paclitaxel exhibited
tumors compared with gemcitabine alone. Additionally, the study a higher ORR (33% vs. 19%, p = 0.001) and a longer time to tumor
showed an enhancement of gemcitabine levels in tumors conferred progression (23.0 vs. 16.9 weeks, hazard ratio = 0.75, p = 0.006)
by the addition of nab-paclitaxel to gemcitabine similar to the effect compared with those receiving sb-paclitaxel (Table 4) [19]. As for toler-
seen in the Von Hoff et al. study described above [57]. However, a ability (Table 5) in this trial, patients receiving nab-paclitaxel had a
different mechanism was ascribed to account for the higher tumor lower rate of grade 4 neutropenia (9% vs. 22%, p b 0.001) and a higher
levels of gemcitabine: a downregulation by nab-paclitaxel of the rate of grade 3 sensory neuropathy (10% vs. 2%, p b 0.001). The median
gemcitabine-metabolizing enzyme cytidine deaminase (CDA) rather time to improvement of grade 3 sensory neuropathy to grade ≤ 2 was
than a nab-paclitaxel-specific effect on tumor stroma. The authors numerically shorter for nab-paclitaxel (22 vs. 79 days) [72].
found that exposure to paclitaxel leads to the production of reactive The results of a phase III trial comparing nab-paclitaxel plus
oxygen species (ROS), which in turn destabilize CDA, thus preventing carboplatin vs. sb-paclitaxel plus carboplatin for the first-line treat-
the breakdown of gemcitabine in cancer cells (Fig. 3). The key role of ment of advanced non-small cell lung cancer (NSCLC) have recently
ROS in this process was demonstrated by an experiment in which an been published (Tables 4 and 5) [73]. The positive findings for nab-
ROS scavenger, N-acetylcysteine (NAC), negated the ability of paclitaxel plus carboplatin led to FDA approval of the combination
paclitaxel to stabilize gemcitabine. The authors also noted that the as first-line treatment for patients with locally advanced or meta-
tolerability of nab-paclitaxel allows a dose sufficient to induce static NSCLC who are not candidates for curative surgery or radiation
synergistic activity with gemcitabine. Because mice cannot tolerate therapy [21]. The nab-paclitaxel plus carboplatin group demonstrat-
doses of sb-paclitaxel as high as those of nab-paclitaxel [37], it is ed a significantly higher ORR in the intent-to-treat population (33%
unclear whether sb-paclitaxel could achieve the same degree of vs. 25%, p = 0.005) and trends toward both a longer progression-
combinatorial activity with gemcitabine in this experimental para- free survival (PFS; 6.3 vs. 5.8 months, p = 0.214) and OS (12.1 vs.
digm as nab-paclitaxel. 11.2 months, p = 0.271). Patients in the nab-paclitaxel arm
A recently completed phase III study in the metastatic setting experienced less grade ≥ 3 neuropathy, neutropenia, arthralgia,
(ClinicalTrials.gov trial number NCT00844649) [57] and an ongoing and myalgia but higher rates of thrombocytopenia and anemia. In-
pilot study in the neoadjuvant setting [63], both evaluating the terestingly, the difference in ORR in patients with squamous histol-
combination of nab-paclitaxel plus gemcitabine, may provide further ogy (41% vs. 24%, p b 0.001) was higher than in the intent-to-treat
insight into these hypotheses. A press release on the results of the population, suggesting that squamous cell non-small cell lung cancer
phase III metastatic pancreatic cancer trial announced that the study may be more responsive to treatment with a nab-paclitaxel-based
met its primary endpoint by demonstrating a significantly longer median regimen. This intriguing finding warrants further examination in
overall survival for nab-paclitaxel plus gemcitabine vs gemcitabine alone mechanistic studies and clinical trials.
[64]. Detailed analyses from that trial may shed light toward the mecha- Phase III trials on nab-paclitaxel were recently completed in pancre-
nism(s) by which nab-paclitaxel leads to higher tumor levels of atic cancer and melanoma, disease states in which taxane-based treat-
gemcitabine. In the neoadjuvant trial alluded to above [63], tumor ments have not traditionally demonstrated sufficient activity for label
 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372 369

Fig. 2. nab-Paclitaxel and albumin-mediated transport (adapted from Desai et al. 2006
[37]). A, Increasing concentrations of Cremophor EL/ethanol inhibit the ability of paclitaxel
to bind to albumin. B, nab-Paclitaxel achieves a 4-fold higher degree of transcytosis across
endothelial cells compared with sb-paclitaxel.
Reprinted from Clinical Cancer Research, 2006, 12/4, 1317–1324, Desai, N, et al., Increased
antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of
cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based
paclitaxel, with permission from AACR.

indications. These studies were predicated on nab-paclitaxel-based

phase II studies that showed promising results in both of these cancer Fig. 3. Paclitaxel destabilizes CDA via ROS in cultured pancreatic cancer cells (adapted
types [57,74], suggesting again something unique about how nab- from Frese et al. [62]). KPC cells were pretreated with paclitaxel (P) and/or NAC and
(A) incubated with CM-H2DCFDA to assess intracellular ROS via flow cytometry
paclitaxel vs. the other taxanes may be interacting with these tumors.
(n = 3). B, protein lysates were generated from KPC cells treated for 36 h with
In addition, growing evidence support not only the activity but also 10 μmol/L P and/or 5 mmol/L NAC and immunoblotted for indicated proteins. C, KPC
the feasibility of nab-paclitaxel in the neoadjuvant as well as adjuvant cells were pretreated with 10 μmol/L P and/or 5 mmol/L NAC for 36 h and incubated
treatment of breast cancer [60,75–77]. with 1 μmol/L gemcitabine for 1 h. Intracellular dFdCTP was measured (n = 3).
Reprinted from Cancer Discovery, 2012, 2/3, Frese KK, et al., nab-Paclitaxel Potentiates
Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of
Pancreatic Cancer, with permission from AACR.
6. Conclusions

nab-Paclitaxel was developed in the wake of clinical data showing

promising efficacy but less than ideal safety profiles for the taxanes that nab-paclitaxel is more able to take advantage of the normal trans-
sb-paclitaxel and docetaxel. Its formulation without solvents allows port properties of albumin than the other taxanes. Specifically, albumin
nab-paclitaxel to avoid the toxicities associated with the excipients has been shown to accumulate in tumors by means of the EPR effect
in the current commercial formulations of sb-paclitaxel and docetaxel [35,36], and albumin is also thought to cross endothelial cells by
that may limit the ability to deliver these agents [5]. Thus, nab- receptor-mediated transcytosis [33,34]. Supporting the idea that
paclitaxel represents a taxane option that may provide clinical benefit nab-paclitaxel may leverage endothelial cell transcytosis to reach
combined with a reasonable toxicity profile. the tumor interstitium, in vitro experiments have shown that nab-
In addition to facilitating an advantageous therapeutic index, nab- paclitaxel is 4-fold more efficient than sb-paclitaxel at crossing layers
paclitaxel may also afford a benefit in terms of pharmacokinetic of endothelial cells [37]. It is thought that tumors may take in albumin
profile. Specifically, nab-paclitaxel has demonstrated a larger volume as a source of nutrients [22,40,41], possibly explaining how albumin-
of distribution, more rapid clearance, a higher fraction of unbound drug, bound drugs appear to be optimized to reach tumors (Fig. 1).
and higher systemic exposures and maximal concentrations of unbound Much research remains to be done to fully understand how
drug relative to sb-paclitaxel [23,28]. Because its drug delivery is not com- the unique formulation of nab-paclitaxel may allow it to interact
plicated by drug entrapment in solvent micelles, nab-paclitaxel continues differently with tumors. For example, although some correlative
to demonstrate pharmacokinetic advantages relative to sb-paclitaxel clinical data suggest that SPARC may play a role in the function of
[23,28]. nab-paclitaxel [38,57,59], further research will be required to shed
While preclinical experiments suggest that nab-paclitaxel achieves a light as to how this occurs. Another example that emphasizes this
higher uptake by tumors vs. sb-paclitaxel [37], which may be explained need for more mechanistic research is the differing proposals from
by the pharmacokinetic advantages described above, it is also possible two separate research groups to explain the shared finding that
370 D.A. Yardley / Journal of Controlled Release 170 (2013) 365–372

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