Immunotherapy has a great potential in advancing cancer treatment, especially in light of recent ... more Immunotherapy has a great potential in advancing cancer treatment, especially in light of recent discoveries and therapeutic interventions that lead to complete response in specific subgroups of melanoma patients. By using the body's own immune system, it is possible not only to specifically target and eliminate cancer cells while leaving healthy cells unharmed but also to elicit long-term protective response. Despite the promise, current immunotherapy is limited and fails in addressing all tumor types. This is probably due to the fact that a single treatment strategy is not sufficient in overcoming the complex antitumor immunity. The use of nanoparticle-based system for immunotherapy is a promising strategy that can simultaneously target multiple pathways with the same kinetics to enhance antitumor response. Here, we will highlight the recent advances in the field of cancer immunotherapy that utilize lipid-based nanoparticles as delivery vehicles and address the ongoing challenges and potential opportunities.
Inflammation plays an important role in the microenvironment of lung cancer. The present study ai... more Inflammation plays an important role in the microenvironment of lung cancer. The present study aimed to evaluate the association of inflammatory biomarker networks with chemotherapies for patients with non-small cell lung cancer (NSCLC). The sera of healthy non-smokers (n = 14) and patients with NSCLC (n = 50), 36 with adenocarcinoma and 14 with squamous cell carcinoma, were collected. Healthy patients were untreated, while those with NSCLC were either chemotherapy-naïve or had received one and two courses of chemotherapy. The cytokine concentrations were measured using multiplexed cytokine immunoassays. The clinical informatics was scored with a Digital Evaluation Score System (DESS) to assess the severity of the patients. All patients completed follow-up for up to 2 years. Among the 40 mediators measured, 13 significantly differed between patients with lung cancer and healthy controls, while 18 differed between untreated patients and those with stage IV adenocarcinoma who had unde...
ABSTRACT The rapid clearance of drugs from human cells is carried out by MRP1 and other proteins ... more ABSTRACT The rapid clearance of drugs from human cells is carried out by MRP1 and other proteins of the ABC transporter superfamily. Selective mutations carried out by DeGorter indicated that replacement of Y324 by phenylalanine (but not by tryptophan or alanine) enhances the capacity of the protein to extrude various drugs. In this study we investigate the effect of mutation on the structure of the isolated transmembrane domain of MRP1 through molecular dynamics simulations of the protein embedded in a POPC membrane. The simulations reveal a persistent tendency of the translocation path to experience a partial constriction, losing ∼50 % of the water inside the conducting path. While the Wt, Y324W and Y324A transporters all experienced the same constriction, the Y324F transporter, the one having a higher clearance rate than the Wt, retains a fully open configuration. The structure of the Y324F mutant reveals an alternate set of stabilizing interactions that force a kink in transmembrane helix 6, which keeps the protein in a fully open outward-facing configuration thus providing a molecular-level account for the higher activity of the mutant. The ability of the simulations to corroborate the experimental observations implies that the homology model of MRP1 is a proper representation of the internal interactions between the residues in the protein, and can be used as a reliable model for studying the human multidrug resistance function of the MRP1 protein.
Gene therapy is suggested to be one of the most specific and efficient modulations for gene defic... more Gene therapy is suggested to be one of the most specific and efficient modulations for gene deficient diseases and extended to other diseases like cancer and inflammation, even though there are still challenges to be faced, such as specific and selective delivery, minimal to no toxicity, efficient metabolism, simplicity, and measurable efficiency. It is important to identify and validate drug-able disease-specific targets for molecular and cellular therapies, while it is equally important to have disease biomarkers to trace and define the biological effects of molecular and cellular therapies. The importance and significance of allostery in molecular and cellular therapies and "allosteric disease", "allosteric effect", and "allosteric drug" should be more carefully examined and validated. Cell therapy has been attracting an increasing amount of consideration in the development of new treatments for diseases. Molecular and Cellular Therapies (MCT) is a new, open-access journal, devoted to molecular mechanisms, preclinical and clinical research and development of gene-, peptide-, protein-, and cell-based therapies.
Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic ... more Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they play additional functions in diverse physiological processes not related to drug efflux. Here we show that the human multidrug transporter P-glycoprotein, P-gp (also named MDR1, ABCB1), is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that P-gp is important for full activation of the Type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of P-gp function by verapamil or inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the Type I response in infected cells. This function of P-gp was specific to Type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to c-di-AMP, a molecule that was shown ...
The metastable-to-stable phase-transition is commonly observed in many fields of science, as an u... more The metastable-to-stable phase-transition is commonly observed in many fields of science, as an uncontrolled independent process, highly sensitive to microscopic fluctuations. In particular, self-assembled lipid suspensions exhibit phase-transitions, where the underlying driving mechanisms and dynamics are not well understood. Here we describe a study of the phase-transition dynamics of lipid-based particles, consisting of mixtures of dilauroylphosphatidylethanolamine (DLPE) and dilauroylphosphatidylglycerol (DLPG), exhibiting a metastable liquid crystalline-to-stable crystalline phase transition upon cooling from 60°C to 37°C. Surprisingly, unlike classically described metastable-to-stable phase transitions, the manner in which recrystallization is delayed by tens of hours is robust, predetermined and controllable. Our results show that the delay time can be manipulated by changing lipid stoichiometry, changing solvent salinity, adding an ionophore, or performing consecutive phase-...
RNAi-based nanomedicine platforms (RNPs) have progressed from tools to study gene expression in v... more RNAi-based nanomedicine platforms (RNPs) have progressed from tools to study gene expression in vitro into clinical trials. Numerous RNPs strategies have been documented with an efficient ability to condense RNAi payloads and induce potent gene silencing. Moreover, some of these RNPs have been explored in various animal models, and some have even made it to the clinic. Still, there is lack of a clinically approved RNAi-based delivery strategy most probably due to unpredicted clinical toxicity. In this study, we prepared common RNPs such as cationic liposomes, polyamines, and hyaluronan-coated lipid-based nanoparticles and tested these strategies for global toxicity parameters such as changes in bodyweight, liver enzyme release, and hematological profiling. We found that polyamines such as polyethyleneimine and Poly-L-lysine released high levels of liver enzymes into the serum and reduced C57BL/6 mice bodyweight upon three intravenous injections. In addition, these polyamines dramati...
Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacl... more Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacle in cancer treatment. The ATP Binding Cassettes (ABC) transporter super family that act as extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins have prominent roles in cancer MDR. One of the most efficient strategies to modulate this active drug efflux from the cells is to physically block the pump proteins and thus change the balance between drug influx and efflux toward an accumulation of drug inside the cell, which eventually cumulates into cell death. MDR modulators (also known as chemosensitizers) were found among drugs approved for non-cancer indications. Yet, toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Previous reports have shown that drugs belonging to the selective serotonin reuptake inhibitors (SSRI) family, which are clinically used as antidepressants, can act as effective...
RNAi-based approaches have contributed significantly to the improved understanding of gene expres... more RNAi-based approaches have contributed significantly to the improved understanding of gene expression and function in vitro. The ability to apply these strategies in vivo to validate the role of specific genes in normal or pathological conditions, and to induce gene silencing, has led to new possibilities for using RNAi as a novel therapeutic modality. However, the translation of RNAi from an effective genomic tool into clinical applications has been hindered by the challenge of delivering RNAi molecules to their target tissues by systemic administration, particularly to hematopoietic cells. This feature review describes the current systemic RNAi delivery platforms targeted to leukocytes, with a focus on the integrin-targeted stabilized nanoparticles strategy, which uses leukocyte integrins for the delivery of siRNAs exclusively to cells of the immune system.
This review centers on recent findings with respect to modulating cancer multidrug resistance (MD... more This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known antidepressant fluoxetine (prozac). The MDR phenomena and mechanisms are discussed, including the roles of ABC transporters as MDR-pumps and the potential involvement of cancer stem cells. The three generations of MDR reversal agents (chemosensitizers) are reviewed, introducing the concept of single-pump and multi-pump agents. The current status of chemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testing novel candidates. Major in vitro and in vivo findings are summarized showing that fluoxetine is a chemosensitizer of the multi-pump type, and proposing it be considered a fourth-generation chemosensitizer. In concluding, we contemplate future prospects of modulating MDR in the clinic.
Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resis... more Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cell...
Naturally occurring high-Mr hyaluronan, bound to the surface of nanoliposomes (denoted targeted h... more Naturally occurring high-Mr hyaluronan, bound to the surface of nanoliposomes (denoted targeted hyaluronan liposomes, or tHA-LIP), is a candidate for active targeting to tumors, many of which overexpress the hyaluronan receptors CD44 and RHAMM. The surface-bound hyaluronan also provides a hydrophilic coat that, similar to polyethylene glycol, may promote long-term circulation. We recently reported the successful targeting of mitomycin C, mediated by tHA-LIP, in tumor-bearing syngeneic mice. Hypothesizing that this targeting is carrier-specific, rather than drug-specific, we report here studies with doxorubicin (DXR)-loaded tHA-LIP, in syngeneic and human xenograft models. Saline, free DXR, DXR-loaded nontargeted liposomes (nt-LIP), and Doxil served as controls. The tHA-LIP were long-circulating, more than all controls, in healthy and tumor-bearing (C57BL/6/B16F10.9; BALB/c/C-26) mice. Mediated by tHA-LIP, DXR accumulation in tumor-bearing lungs was 30-, 6.7-, and 3.5-fold higher tha...
International journal of cancer. Journal international du cancer, Jan 20, 2004
The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the ... more The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the door for targeting by the naturally-occurring high-M(r) hyaluronan. This is the first time effective in vivo tumor targeting is reported for mitomycin C (MMC) loaded inside nano-sized hyaluronan-liposomes (denoted tHA-LIP). The severe adverse effects of free MMC made it a rational candidate for an effective targeted carrier. In vitro, loading MMC inside tHA-LIP increased drug potency 100-fold, in cells overexpressing, but not in cells underexpressing, hyaluronan receptors. Both types of liposomes were non-toxic and reduced MMC-related toxicity in healthy C57BL/6 mice. In 3 tumor models, BALB/c bearing C-26 solid tumors; C57BL/6 bearing B16F10.9 or (separately) D122 lung metastasis, tHA-LIP were long-circulating, 7-fold and 70-fold longer than nt-LIP and free MMC, respectively. tHA-LIP-mediated MMC accumulation in tumor-bearing lungs was 20% of injected dose, compared to 0.6% and 4% with ...
Lyophilized unilamellar liposomes (ULV), the dosage form of choice for shelf-life, revert upon re... more Lyophilized unilamellar liposomes (ULV), the dosage form of choice for shelf-life, revert upon reconstitution to the larger multilamellar liposomes (MLV), which is detrimental to the many carrier-mediated therapies that require small particles. High doses of sugars such as trehalose, sucrose and others, included in the original formulations for cryoprotection, were shown to prevent the conversion to MLV. In this study we set out to test whether hyaluronan (HA), the surface-bound ligand in our previously developed targeted bioadhesive liposomes (BAL), can also act as a cryoprotectant. The studies included structural and physicochemical characterization of original and reconstituted hyaluronan-ULV (HA-ULV). For each HA-ULV, similar regular ULV (RL-ULV) served as controls. Four properties were tested: particle size, zeta potential, encapsulation efficiency and half-life of drug release (tau(1/2)), for three drugs-chloramphenicol (CAM), vinblastine (VIN) and mitomycin C (MMC). Encapsula...
Omentum-based matrices fabricated by decellularization have the potential to serve as autologous ... more Omentum-based matrices fabricated by decellularization have the potential to serve as autologous scaffolds for tissue engineering. Transplantation of such scaffolds prepared from the patient's own biomaterial may reduce the immunogenic response after transplantation. Recently we reported on the potential of the decellularized omentum to support the assembly of functional vascularized cardiac patches. Here we compared five distinct protocols for omentum decellularization, utilizing chemical, physical and biological processes. We analyzed the efficiency of cell removal, scaffold macro and micro structure, biochemical composition and the ability of seeded cells to attach and proliferate in the matrix. Moreover, we assessed the ability of the distinct scaffolds to promote the organization of cardiac tissue.
Immunotherapy has a great potential in advancing cancer treatment, especially in light of recent ... more Immunotherapy has a great potential in advancing cancer treatment, especially in light of recent discoveries and therapeutic interventions that lead to complete response in specific subgroups of melanoma patients. By using the body's own immune system, it is possible not only to specifically target and eliminate cancer cells while leaving healthy cells unharmed but also to elicit long-term protective response. Despite the promise, current immunotherapy is limited and fails in addressing all tumor types. This is probably due to the fact that a single treatment strategy is not sufficient in overcoming the complex antitumor immunity. The use of nanoparticle-based system for immunotherapy is a promising strategy that can simultaneously target multiple pathways with the same kinetics to enhance antitumor response. Here, we will highlight the recent advances in the field of cancer immunotherapy that utilize lipid-based nanoparticles as delivery vehicles and address the ongoing challenges and potential opportunities.
Inflammation plays an important role in the microenvironment of lung cancer. The present study ai... more Inflammation plays an important role in the microenvironment of lung cancer. The present study aimed to evaluate the association of inflammatory biomarker networks with chemotherapies for patients with non-small cell lung cancer (NSCLC). The sera of healthy non-smokers (n = 14) and patients with NSCLC (n = 50), 36 with adenocarcinoma and 14 with squamous cell carcinoma, were collected. Healthy patients were untreated, while those with NSCLC were either chemotherapy-naïve or had received one and two courses of chemotherapy. The cytokine concentrations were measured using multiplexed cytokine immunoassays. The clinical informatics was scored with a Digital Evaluation Score System (DESS) to assess the severity of the patients. All patients completed follow-up for up to 2 years. Among the 40 mediators measured, 13 significantly differed between patients with lung cancer and healthy controls, while 18 differed between untreated patients and those with stage IV adenocarcinoma who had unde...
ABSTRACT The rapid clearance of drugs from human cells is carried out by MRP1 and other proteins ... more ABSTRACT The rapid clearance of drugs from human cells is carried out by MRP1 and other proteins of the ABC transporter superfamily. Selective mutations carried out by DeGorter indicated that replacement of Y324 by phenylalanine (but not by tryptophan or alanine) enhances the capacity of the protein to extrude various drugs. In this study we investigate the effect of mutation on the structure of the isolated transmembrane domain of MRP1 through molecular dynamics simulations of the protein embedded in a POPC membrane. The simulations reveal a persistent tendency of the translocation path to experience a partial constriction, losing ∼50 % of the water inside the conducting path. While the Wt, Y324W and Y324A transporters all experienced the same constriction, the Y324F transporter, the one having a higher clearance rate than the Wt, retains a fully open configuration. The structure of the Y324F mutant reveals an alternate set of stabilizing interactions that force a kink in transmembrane helix 6, which keeps the protein in a fully open outward-facing configuration thus providing a molecular-level account for the higher activity of the mutant. The ability of the simulations to corroborate the experimental observations implies that the homology model of MRP1 is a proper representation of the internal interactions between the residues in the protein, and can be used as a reliable model for studying the human multidrug resistance function of the MRP1 protein.
Gene therapy is suggested to be one of the most specific and efficient modulations for gene defic... more Gene therapy is suggested to be one of the most specific and efficient modulations for gene deficient diseases and extended to other diseases like cancer and inflammation, even though there are still challenges to be faced, such as specific and selective delivery, minimal to no toxicity, efficient metabolism, simplicity, and measurable efficiency. It is important to identify and validate drug-able disease-specific targets for molecular and cellular therapies, while it is equally important to have disease biomarkers to trace and define the biological effects of molecular and cellular therapies. The importance and significance of allostery in molecular and cellular therapies and "allosteric disease", "allosteric effect", and "allosteric drug" should be more carefully examined and validated. Cell therapy has been attracting an increasing amount of consideration in the development of new treatments for diseases. Molecular and Cellular Therapies (MCT) is a new, open-access journal, devoted to molecular mechanisms, preclinical and clinical research and development of gene-, peptide-, protein-, and cell-based therapies.
Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic ... more Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they play additional functions in diverse physiological processes not related to drug efflux. Here we show that the human multidrug transporter P-glycoprotein, P-gp (also named MDR1, ABCB1), is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that P-gp is important for full activation of the Type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of P-gp function by verapamil or inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the Type I response in infected cells. This function of P-gp was specific to Type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to c-di-AMP, a molecule that was shown ...
The metastable-to-stable phase-transition is commonly observed in many fields of science, as an u... more The metastable-to-stable phase-transition is commonly observed in many fields of science, as an uncontrolled independent process, highly sensitive to microscopic fluctuations. In particular, self-assembled lipid suspensions exhibit phase-transitions, where the underlying driving mechanisms and dynamics are not well understood. Here we describe a study of the phase-transition dynamics of lipid-based particles, consisting of mixtures of dilauroylphosphatidylethanolamine (DLPE) and dilauroylphosphatidylglycerol (DLPG), exhibiting a metastable liquid crystalline-to-stable crystalline phase transition upon cooling from 60°C to 37°C. Surprisingly, unlike classically described metastable-to-stable phase transitions, the manner in which recrystallization is delayed by tens of hours is robust, predetermined and controllable. Our results show that the delay time can be manipulated by changing lipid stoichiometry, changing solvent salinity, adding an ionophore, or performing consecutive phase-...
RNAi-based nanomedicine platforms (RNPs) have progressed from tools to study gene expression in v... more RNAi-based nanomedicine platforms (RNPs) have progressed from tools to study gene expression in vitro into clinical trials. Numerous RNPs strategies have been documented with an efficient ability to condense RNAi payloads and induce potent gene silencing. Moreover, some of these RNPs have been explored in various animal models, and some have even made it to the clinic. Still, there is lack of a clinically approved RNAi-based delivery strategy most probably due to unpredicted clinical toxicity. In this study, we prepared common RNPs such as cationic liposomes, polyamines, and hyaluronan-coated lipid-based nanoparticles and tested these strategies for global toxicity parameters such as changes in bodyweight, liver enzyme release, and hematological profiling. We found that polyamines such as polyethyleneimine and Poly-L-lysine released high levels of liver enzymes into the serum and reduced C57BL/6 mice bodyweight upon three intravenous injections. In addition, these polyamines dramati...
Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacl... more Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacle in cancer treatment. The ATP Binding Cassettes (ABC) transporter super family that act as extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins have prominent roles in cancer MDR. One of the most efficient strategies to modulate this active drug efflux from the cells is to physically block the pump proteins and thus change the balance between drug influx and efflux toward an accumulation of drug inside the cell, which eventually cumulates into cell death. MDR modulators (also known as chemosensitizers) were found among drugs approved for non-cancer indications. Yet, toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Previous reports have shown that drugs belonging to the selective serotonin reuptake inhibitors (SSRI) family, which are clinically used as antidepressants, can act as effective...
RNAi-based approaches have contributed significantly to the improved understanding of gene expres... more RNAi-based approaches have contributed significantly to the improved understanding of gene expression and function in vitro. The ability to apply these strategies in vivo to validate the role of specific genes in normal or pathological conditions, and to induce gene silencing, has led to new possibilities for using RNAi as a novel therapeutic modality. However, the translation of RNAi from an effective genomic tool into clinical applications has been hindered by the challenge of delivering RNAi molecules to their target tissues by systemic administration, particularly to hematopoietic cells. This feature review describes the current systemic RNAi delivery platforms targeted to leukocytes, with a focus on the integrin-targeted stabilized nanoparticles strategy, which uses leukocyte integrins for the delivery of siRNAs exclusively to cells of the immune system.
This review centers on recent findings with respect to modulating cancer multidrug resistance (MD... more This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known antidepressant fluoxetine (prozac). The MDR phenomena and mechanisms are discussed, including the roles of ABC transporters as MDR-pumps and the potential involvement of cancer stem cells. The three generations of MDR reversal agents (chemosensitizers) are reviewed, introducing the concept of single-pump and multi-pump agents. The current status of chemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testing novel candidates. Major in vitro and in vivo findings are summarized showing that fluoxetine is a chemosensitizer of the multi-pump type, and proposing it be considered a fourth-generation chemosensitizer. In concluding, we contemplate future prospects of modulating MDR in the clinic.
Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resis... more Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cell...
Naturally occurring high-Mr hyaluronan, bound to the surface of nanoliposomes (denoted targeted h... more Naturally occurring high-Mr hyaluronan, bound to the surface of nanoliposomes (denoted targeted hyaluronan liposomes, or tHA-LIP), is a candidate for active targeting to tumors, many of which overexpress the hyaluronan receptors CD44 and RHAMM. The surface-bound hyaluronan also provides a hydrophilic coat that, similar to polyethylene glycol, may promote long-term circulation. We recently reported the successful targeting of mitomycin C, mediated by tHA-LIP, in tumor-bearing syngeneic mice. Hypothesizing that this targeting is carrier-specific, rather than drug-specific, we report here studies with doxorubicin (DXR)-loaded tHA-LIP, in syngeneic and human xenograft models. Saline, free DXR, DXR-loaded nontargeted liposomes (nt-LIP), and Doxil served as controls. The tHA-LIP were long-circulating, more than all controls, in healthy and tumor-bearing (C57BL/6/B16F10.9; BALB/c/C-26) mice. Mediated by tHA-LIP, DXR accumulation in tumor-bearing lungs was 30-, 6.7-, and 3.5-fold higher tha...
International journal of cancer. Journal international du cancer, Jan 20, 2004
The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the ... more The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the door for targeting by the naturally-occurring high-M(r) hyaluronan. This is the first time effective in vivo tumor targeting is reported for mitomycin C (MMC) loaded inside nano-sized hyaluronan-liposomes (denoted tHA-LIP). The severe adverse effects of free MMC made it a rational candidate for an effective targeted carrier. In vitro, loading MMC inside tHA-LIP increased drug potency 100-fold, in cells overexpressing, but not in cells underexpressing, hyaluronan receptors. Both types of liposomes were non-toxic and reduced MMC-related toxicity in healthy C57BL/6 mice. In 3 tumor models, BALB/c bearing C-26 solid tumors; C57BL/6 bearing B16F10.9 or (separately) D122 lung metastasis, tHA-LIP were long-circulating, 7-fold and 70-fold longer than nt-LIP and free MMC, respectively. tHA-LIP-mediated MMC accumulation in tumor-bearing lungs was 20% of injected dose, compared to 0.6% and 4% with ...
Lyophilized unilamellar liposomes (ULV), the dosage form of choice for shelf-life, revert upon re... more Lyophilized unilamellar liposomes (ULV), the dosage form of choice for shelf-life, revert upon reconstitution to the larger multilamellar liposomes (MLV), which is detrimental to the many carrier-mediated therapies that require small particles. High doses of sugars such as trehalose, sucrose and others, included in the original formulations for cryoprotection, were shown to prevent the conversion to MLV. In this study we set out to test whether hyaluronan (HA), the surface-bound ligand in our previously developed targeted bioadhesive liposomes (BAL), can also act as a cryoprotectant. The studies included structural and physicochemical characterization of original and reconstituted hyaluronan-ULV (HA-ULV). For each HA-ULV, similar regular ULV (RL-ULV) served as controls. Four properties were tested: particle size, zeta potential, encapsulation efficiency and half-life of drug release (tau(1/2)), for three drugs-chloramphenicol (CAM), vinblastine (VIN) and mitomycin C (MMC). Encapsula...
Omentum-based matrices fabricated by decellularization have the potential to serve as autologous ... more Omentum-based matrices fabricated by decellularization have the potential to serve as autologous scaffolds for tissue engineering. Transplantation of such scaffolds prepared from the patient's own biomaterial may reduce the immunogenic response after transplantation. Recently we reported on the potential of the decellularized omentum to support the assembly of functional vascularized cardiac patches. Here we compared five distinct protocols for omentum decellularization, utilizing chemical, physical and biological processes. We analyzed the efficiency of cell removal, scaffold macro and micro structure, biochemical composition and the ability of seeded cells to attach and proliferate in the matrix. Moreover, we assessed the ability of the distinct scaffolds to promote the organization of cardiac tissue.
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