Mohammad Reza Vakili
University of Alberta
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Featured researches published by Mohammad Reza Vakili.
Molecular Pharmaceutics | 2014
Min Han; Mohammad Reza Vakili; Hoda Soleymani Abyaneh; Ommoleila Molavi; Raymond Lai; Afsaneh Lavasanifar
In this study, doxorubicin (DOX) was conjugated to a lipophilic triphenylphosphonium (TPP) that is selectively taken up by the mitochondrial membrane of cells. This new derivative of DOX, i.e., TPP-DOX, was characterized by infrared spectroscopy (IR), nuclear magnetic resonance ((1)H NMR, (13)C NMR), and mass spectrometry. The effect of TPP modification on DOX cell uptake, intracellular trafficking, eventual DOX induced cytotoxicity, and the level of cleaved caspase 3 and PARP in wild type MDA-MB-435/WT and DOX resistant MDA-MB-435/DOX cells was then evaluated and compared to that for free DOX. In general, free DOX cellular uptake appeared to be significantly higher in MDA-MB-435/WT than MDA-MB-435/DOX cells. Moreover, free DOX was able to enter the nucleus of MDA-MB-435/WT cells, but in MDA-MB-435/DOX cells, it was confined within the cytoplasm. The TPP-DOX, on the other hand, was localized in the cytoplasm of both cell phenotypes and showed preferential distribution to the mitochondria. Correspondingly, in MDA-MB-435/DOX cells, an enhanced cytotoxicity was observed for TPP-DOX (IC50 of 33.6 and 21.0 μM at 48 and 72 h incubation, respectively) in comparison to free DOX (IC50 of 126.7 and 77.96 μM at 48 and 72 h incubation, respectively). This observation was accompanied by the increased level of cleaved caspase 3 and PARP indicating enhanced apoptosis in both cell lines, particularly that of MDA-MB-435/DOX, for TPP-DOX compared to free DOX following 24 h treatment. The present study highlights promising application of TPP-DOX in reversing drug resistance in tumor cells.
Biomaterials | 2014
Qi Zhang; Mohammad Reza Vakili; Xing-Fang Li; Afsaneh Lavasanifar; X. Chris Le
Arsenic trioxide (ATO), dissolved in water as arsenous acid or inorganic arsenite (As(III)), is an effective chemotherapeutic agent against acute promyelocytic leukemia (APL). It has been under investigation as a potential treatment for a variety of solid tumors although with much poorer efficacy than for APL. The toxicity of As(III) and its derivatives is a common concern that has limited its use. The objective of the current study was to develop a polymeric micelle drug delivery system for efficient and controlled delivery of trivalent arsenicals to solid tumor cells. A polymeric micelle-based drug delivery system can potentially extend the duration of drug circulation in blood, restrict access of encapsulated drug to normal tissues, achieve tumor targeted drug delivery, enhance drug accumulation in the tumor area, and trigger drug release at tumor sites if designed properly. These, in turn, can lead to an improved therapeutic index for the polymeric micellar formulation of arsenic species compared to their free form. Towards this goal, a biodegradable block copolymer with pendent thiol groups on the hydrophobic block, i.e., methoxy poly(ethylene oxide)-block-poly[α-(6-mecaptohexyl amino)carboxylate-ε-caprolactone] [PEO-b-P(CCLC6-SH)], was synthesized and used for conjugation of a trivalent arsenical, phenylarsine oxide (PAO), to free thiol groups on the polymer backbone. PAO-loaded micelles had refined size distribution with an average diameter of 150 nm as evidenced by dynamic light scattering (DLS) in water. Prepared polymeric micelles were characterized for the level of PAO conjugation using inductively coupled plasma mass spectrometry (ICP-MS). The results showed 65% of total free thiols were conjugated to PAO providing an arsenic/polymer loading content of ~2.5 wt%. In vitro release study suggests prolonged release of PAO from its polymeric micellar carrier, which was accelerated in the presence of glutathione (GSH). Cytotoxicity studies against MDA-MB-435 cells show that the IC50 of PEO-b-P(CCLC6-S-PAO) is not significantly different from that of free PAO. The results indicate that PEO-b-P(CCLC6-SH) is a promising carrier for successful arsenic delivery for cancer therapy.
Acta Biomaterialia | 2015
Nazila Safaei Nikouei; Mohammad Reza Vakili; Markian S. Bahniuk; Larry D. Unsworth; Ali Akbari; Jianping Wu; Afsaneh Lavasanifar
In this study we report on the development, characterization and plasma protein interaction of novel thermoresponsive in situ hydrogels based on triblock copolymers of poly(ethylene glycol) (PEG) and poly(α-carboxyl-co-benzyl carboxylate)-ε-caprolactone (PCBCL) having two different degrees of carboxyl group substitution on the PCBCL block. Block copolymers were synthesized through ring-opening polymerization of α-benzyl carboxylate-ε-caprolactone by dihydroxy PEG, leading to the production of poly(α-benzyl carboxylate-ε-caprolactone)-PEG-poly(α-benzyl carboxylate-ε-caprolactone) (PBCL-PEG-PBCL). This was followed by partial debenzylation of PBCL blocks under controlled conditions, leading to the preparation of PCBCL-PEG-PCBCL triblock copolymers with 30 and 54mol.% carboxyl group substitution. Prepared PCBCL-PEG-PCBCL block copolymers have been shown to have a concentration-dependent sol to gel transition as a result of an increase in temperature above ∼29°C, as evidenced by the inverse flow method, differential scanning calorimetry and dynamic mechanical analysis. The sol-gel transition temperature/concentration and dynamic mechanical properties of the gel were found to be dependent on the level of carboxyl group substitution. Both hydrogels (30 and 54mol.% carboxyl group substitution) showed similar amounts of protein adsorption but striking differences in the profiles of the adsorbed proteome. Additionally, the two systems showed similarities in their clot formation kinetics but substantial differences in clot endpoints. The results show great promise for the above-mentioned thermoreversible in situ hydrogels as biocompatible materials for biomedical applications.
Nanomedicine: Nanotechnology, Biology and Medicine | 2016
Shyam M. Garg; Arash Falamarzian; Mohammad Reza Vakili; Hamidreza Montazeri Aliabadi; Hasan Uludağ; Afsaneh Lavasanifar
AIM To develop delivery systems for efficient siRNA delivery to breast cancer. METHODS Poly(ethylene oxide)-block-poly(ϵ-caprolactone-grafted-spermine) (PEO-b-P(CL-g-SP)) micelles were modified with cholesterol group in their core and with RGD4C peptide on their shell. Transfection efficiency of complexed MCL-1 siRNA in MDA-MB-435 was investigated, in vitro and in vivo following intratumoral and intravenous injection. RESULTS Cholesteryl modification of the core significantly increased the transfection efficiency of PEO-b-P(CL-g-SP)-complexed siRNA, in vitro, but not following intratumoral or intravenous administration, in vivo. Instead, RGD4C modification of the micellar shell enhanced transfection efficiency of complexed MCL-1 siRNA in tumor upon intravenous administration. CONCLUSION RGD4C-PEO-b-P(CL-g-SP) micelles, without or with cholesterol modification, can provide efficient delivery of siRNA to breast tumors following systemic administration.
Colloids and Surfaces B: Biointerfaces | 2015
Shyam M. Garg; Mohammad Reza Vakili; Afsaneh Lavasanifar
A series of block copolymers based on methoxy poly(ethylene oxide)-block-poly(ɛ-caprolactone) (PEO-b-PCL), PEO-b-PCL bearing side groups of benzyl carboxylate (PEO-b-PBCL), or free carboxyl (PEO-b-PCCL) on the PCL backbone with increasing degrees of polymerization of the PCL backbone were synthesized. Prepared block copolymers assembled to polymeric micelles by co-solvent evaporation. The physical stability of prepared micelles was assessed by measuring their tendency toward aggregation over time using dynamic light scattering (DLS). The resistance of micelles against dissociation in the presence of a micelle destabilizing agent, i.e., sodium dodecyl sulfate (SDS), was also investigated using DLS. The rate of micellar core degradation was determined using (1)H NMR for polymer molecular weight measurement upon incubation of micelles in PBS (pH=7.4) at 37°C followed by dialysis of the remaining polymer at different time intervals. The effect of pendent group chemistry in the micellar core on the adsorption of serum proteins to micellar structure was then evaluated using Bradford Protein assay kit. Finally, the effect of micellar core structure on the induction of bone marrow derived dendritic cell (BMDC) maturation and secretion of IL-12 was studied as a measure of micellar immunogenicity. The results showed micelle structures from polymers with higher degree of polymerization in the hydrophobic block and/or those with more hydrophobic substituents on the core-forming block, to be more stable. This was reflected by a decreased tendency for micellar aggregation, reduced dissociation of micelles in the presence of SDS, and diminished core degradation. All micelles were shown to have insignificant adsorption of serum protein suggesting that the hydrophilic PEO shell provided sufficient protection of the core. However, the protein adsorption increased with increase in the hydrophobicity and molecular weight of the core-forming block. Irrespective of the micellar core structure, all tested micelles were found to be non-immunogenic in BMDCs.
Pharmaceutical Research | 2014
Hoda Soleymani Abyaneh; Mohammad Reza Vakili; Afsaneh Lavasanifar
PurposeTo investigate the effect of polymerization method on the stability and drug release properties of polymeric micelles formed using stereo-active block copolymers.MethodsDiblock copolymers consisting of methoxy poly ethylene oxide (MePEO) and poly(lactide)s (PLA)s of different stereochemistry were synthesized by bulk or solution polymerization. Polymers and micelles were characterized for their chemical structure by 1H NMR, optical rotation by polarimetry, critical micellar concentration by fluorescence spectroscopy, thermal properties by differential scanning calorimetry, morphology by transmission electron microscopy and size as well as kinetic stability by dynamic light scattering. Release of encapsulated nimodipine from polymeric micelles at different levels of loading was also investigated.ResultsSolution polymerization yielded a higher degree of crystallinity for stereo-regular PLA blocks. Consequently, the related polymeric micelles were kinetically more stable than those prepared by bulk polymerization. At high drug loading levels, the release of nimodipine was more rapid from polymeric micelles with crystalline cores. At lower levels of drug loading, drug release was slower and independent of the stereochemistry of the core.ConclusionsThe results underline the effect of polymerization method in defining core crystallinity in stereoregular block copolymer micelles. It also shows the impact of core crystallinity on enhancing micellar stability and drug release.
Acta Biomaterialia | 2015
Hoda Soleymani Abyaneh; Mohammad Reza Vakili; Fanglin Zhang; Phillip Choi; Afsaneh Lavasanifar
UNLABELLED To circumvent the problem of burst drug release from polymeric micelles, we designed three layered ABC micelles consisting of methoxy poly(ethylene oxide) (PEO) as the shell layer (A block); poly(lactic acid) (PLA) of different stereo-chemistries as the outer core (B block) and poly(α-benzylcarboxylate-ε-caprolactone) (PBCL) or poly(ε-caprolactone) (PCL) as the inner core (C block). The micelles were used to encapsulate a model hydrophobic drug, nimodipine. The effect of PLA (B block) incorporation and stereochemistry on the formation of semi crystalline outer cores in ABC triblock copolymer micelles, micelle stability, drug loading and release was then assessed in comparison to diblock copolymer micelles. The PLA outer core was expected to act as a barrier lowering the rate of drug diffusion out of the micellar carrier owing to a high Flory Huggins interaction parameter between nimodipine and PLA (χ=1.35). Introduction of PLA outer cores in ABC block copolymer micelles reduced the burst release of nimodipine from polymeric micelles without jeopardizing its high encapsulation efficiency. In ABC polymeric micelles with stereo-regular PLA blocks; semi-crystalline outer PLA cores were not formed, which was in contrast to PEO-PLA diblock copolymer micelles. Accordingly, PLA stereo-chemistry had no significant effect on drug release in ABC polymeric micelles. In contrast to diblock copolymers, no sign of stereo-complexation in mixed micelles composed of a 50:50 mixture of PdLA and PlLA containing ABC triblock copolymers was observed. The results showed the capability of properly designed ABC triblock copolymer micelles as reservoirs for drug solubilization and depot release at nanoscale dimensions. STATEMENT OF SIGNIFICANCE Polymeric micelles are core-shell nanostructures that are widely used for drug delivery. Their hydrophobic core accommodates poor water soluble drugs and their hydrophilic shell allows the whole structure to be water soluble. A common problem with the use of polymeric micelles is leakage of the incorporated drug from these carriers. Here we have shown that a properly designed three layered (ABC) block copolymer micelle with drug compatible blocks at the inner core and drug incompatible blocks at the outer core can be used to reduce the initial fast rate of drug release while providing high amount of drug encapsulated in the core. Moreover, changes in the chemical structure of the inner core may be used to modify the stability of these systems.
Nanomedicine: Nanotechnology, Biology and Medicine | 2016
Praful R. Nair; Sa Karthick; Kyle R. Spinler; Mohammad Reza Vakili; Afsaneh Lavasanifar; Dennis E. Discher
AIM In order to improve the delivery of aromatic drugs by micellar assemblies, and particularly by long and flexible filomicelles, aromatic groups were integrated into the hydrophobic block of a degradable diblock copolymer. MATERIALS & METHODS Aromatic filomicelles were formed by self-directed assembly of amphiphilic diblock copolymer PEG-PBCL with suitable block ratios. Worm-like filomicelles with an aromatic core were loaded with a common chemotherapeutic, Paclitaxel, for tests of release as well as effects on cancer cell lines in vitro and in vivo. RESULTS Aromatic filomicelles loaded more Paclitaxel than analogous aliphatic systems. Cell death and aneuploidy of surviving cells (which indicates toxicity) were highest for carcinoma lines treated in vitro with the new filomicelles. Initial tests in vivo also suggest more potent tumor shrinkage. CONCLUSION Flexible filomicelles with an aromatic core form an efficient drug delivery system that leads to higher cell death than previously reported systems, while inducing aneuploidy in surviving cells.
Molecular Pharmaceutics | 2017
Hoda Soleymani Abyaneh; Mohammad Reza Vakili; Alireza Shafaati; Afsaneh Lavasanifar
Stereoregularity of polymers is known to influence their physicochemical and functional properties in the bulk form. Recent studies have also provided evidence for the effect of polymer stereoregularity on the physicochemical and functional properties of their self-assembled nanostructures. Research in this area has witnessed a relatively rapid pace in the past few years; however, to the best of our knowledge, a proper review of the literature has not been made to date. The goal of this review article was to fill this gap and provide a detailed overview on the current knowledge and understanding on the effect of block copolymer stereoregularity on the properties of their self-assembled nanocarriers such as size, morphology, thermodynamic and kinetic stability, and drug loading and release. Emphasis is placed on poly(ester) containing block copolymers because of their safe history of human use and extensive application in drug delivery research.
Molecular Pharmaceutics | 2017
Shyam M. Garg; Mohammad Reza Vakili; Ommoleila Molavi; Afsaneh Lavasanifar
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) in tumor cells and tumor associated dendritic cells (DCs) plays a major role in the progression of cancer. JSI-124 (cucurbitacin I) is a potent inhibitor of STAT3; however, its poor solubility and nonspecificity limit its effectiveness in cancer immunotherapy. In order to achieve a nanocarrier for solubilization and passive targeting of JSI-124 to tumor cells and tumor associated DCs, the drug was chemically conjugated to pendent COOH groups of self-associating poly(ethylene oxide)-block-poly(α-carboxylate-ε-caprolactone) (PEO-b-PCCL). Developed PEO-b-P(CL-JSI-124) conjugates self-assembled to polymeric micelles of 40 nm size range with negligible drug release under physiological mimicking conditions. The conjugation of JSI-124 to PEO-b-PCCL was confirmed by 1H NMR, thin layer chromatography (TLC), and HPLC with a conjugation of 8.9% w/w of the polymer. As expected, JSI-124 nanoconjugates showed lower potency in p-STAT3 inhibition and direct anticancer activity in B16-F10 melanoma cells. Interestingly, JSI-124 nanoconjugates were more powerful than free drug in reducing the level of p-STAT3 in tumor exposed bone marrow derived dendritic cells (BMDCs). The JSI-124 nanoconjugates were also significantly more active than free drug in reversing the immunosuppressive effect of B16-F10 tumor and led to significantly better phenotypical and functional stimulation of tumor exposed immature BMDCs in the presence of immune adjuvants like LPS and CpG. Our findings points to great promise for PEO-b-P(CL-JSI-124) micelles for modulation of immunosuppressive microenvironment in melanoma tumors, implicating application of this strategy in cancer immunotherapy.