Mani Prabaharan

Amphiphilic multi-arm-block copolymer conjugated with doxorubicin via pH-sensitive hydrazone bond for tumor-targeted drug delivery.

Folate-conjugated unimolecular micelles based on amphiphilic hyperbranched block copolymer, Boltorn H40-poly(l-aspartate-doxorubicin)-b-poly(ethylene glycol)/FA-conjugated poly(ethylene glycol) (H40-P(LA-DOX)-b-PEG-OH/FA), were synthesized as a carrier for tumor-targeted drug delivery. The anticancer drug DOX was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms by pH-sensitive hydrazone linkage. The size of the unimolecular micelles was determined as approximately 17-36 and 10-20 nm by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The release profiles of the DOX from the H40-P(LA-DOX)-b-PEG-OH/FA micelles showed a strong dependence on the environmental pH values. The DOX release rate increased in the acidic medium due to the acid-cleavable hydrazone linkage between the DOX and micelles. Cellular uptake of the H40-P(LA-DOX)-b-PEG-OH/FA micelles was found to be higher than that of the H40-P(LA-DOX)-b-PEG-OH micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. Degradation studies showed that the H40-P(LA-DOX)-b-PEG-OH/FA copolymer hydrolytically degraded into polymer fragments within six weeks. These results suggest that H40-P(LA-DOX)-b-PEG-OH/FA micelles could be a promising nanocarrier with excellent in vivo stability for targeting the drugs to cancer cells and releasing the drug molecules inside the cells by sensing the acidic environment of the endosomal compartments.

Folate-conjugated amphiphilic hyperbranched block copolymers based on Boltorn H40, poly(L-lactide) and poly(ethylene glycol) for tumor-targeted drug delivery.

Folate-conjugated amphiphilic hyperbranched block copolymer (H40-PLA-b-MPEG/PEG-FA) with a dendritic Boltorn H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell and a hydrophilic methoxy poly(ethylene glycol) (MPEG) and folate-conjugated poly(ethylene glycol) (PEG-FA) outer shell was synthesized as a carrier for tumor-targeted drug delivery. The block copolymer was characterized using (1)H NMR and gel permeation chromatography (GPC) analysis. Due to its core-shell structure, this block polymer forms unimolecular micelles in aqueous solutions. The micellar properties of H40-PLA-b-MPEG/PEG-FA block copolymer were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). An anticancer drug, doxorubicin in the free base form (DOX) was encapsulated into H40-PLA-b-MPEG/PEG-FA micelles. The DOX-loaded micelles provided an initial burst release (up to 4h) followed by a sustained release of the entrapped DOX over a period of about 40 h. Cellular uptake of the DOX-loaded H40-PLA-b-MPEG/PEG-FA micelles was found to be higher than that of the DOX-loaded H40-PLA-b-MPEG micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. In vitro degradation studies revealed that the H40-PLA-b-MPEG/PEG-FA block copolymer hydrolytically degraded into polymer fragments within six weeks. These results indicated that the micelles prepared from the H40-PLA-b-MPEG/PEG-FA block copolymer have great potential as tumor-targeted drug delivery nanocarriers.

Gold nanoparticles with a monolayer of doxorubicin-conjugated amphiphilic block copolymer for tumor-targeted drug delivery

Gold (Au) nanoparticles (NPs) stabilized with a monolayer of folate-conjugated poly(L-aspartate-doxorubicin)-b-poly(ethylene glycol) copolymer (Au-P(LA-DOX)-b-PEG-OH/FA) was synthesized as a tumor-targeted drug delivery carrier. The Au-P(LA-DOX)-b-PEG-OH/FA NPs consist of an Au core, a hydrophobic poly(l-aspartate-doxorubicin) (P(LA-DOX)) inner shell, and a hydrophilic poly(ethylene glycol) and folate-conjugated poly(ethylene glycol) outer shell (PEG-OH/FA). The anticancer drug, doxorubicin (DOX), was covalently conjugated onto the hydrophobic inner shell by acid-cleavable hydrazone linkage. The DOX loading level was determined to be 17 wt%. The Au-P(LA-DOX)-b-PEG-OH/FA NPs formed stable unimolecular micelles in aqueous solution. The size of the Au-P(LA-DOX)-b-PEG-OH/FA micelles were determined as 24-52 and 10-25 nm by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The conjugated DOX was released from the Au-P(LA-DOX)-b-PEG-OH/FA micelles much more rapidly at pH 5.3 and 6.6 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. Cellular uptake of the Au-P(LA-DOX)-b-PEG-OH/FA micelles facilitated by the folate-receptor-mediated endocytosis process was higher than that of the micelles without folate. This was consistent with the higher cytotoxicity observed with the Au-P(LA-DOX)-b-PEG-OH/FA micelles against the 4T1 mouse mammary carcinoma cell line. These results suggest that Au-P(LA-DOX)-b-PEG-OH/FA NPs could be used as a carrier with pH-triggered drug releasing properties for tumor-targeted drug delivery.

Review Paper: Chitosan Derivatives as Promising Materials for Controlled Drug Delivery

Chitosan, a natural based-polymer obtained by alkaline deacetylation of chitin, is nontoxic, biocompatible, and biodegradable. These properties make chitosan a good candidate for the development of conventional and novel drug delivery systems. Chitosan has been found to be used as a support material for gene delivery, cell culture, and tissue engineering. However, practical use of chitosan has been mainly confined to the unmodified forms. For a breakthrough in utilization, especially in the field of controlled drug delivery, graft copolymerization onto chitosan will be a key point, which will introduce desired properties and enlarge the field of the potential applications of chitosan by choosing various types of side chains. Chemical modification of chitosan is useful for the association of bioactive molecules to polymer and controlling the drug release profile. This paper reviews the various methods of preparation of chitosan derivatives intended for controlled drug delivery. From the studies reviewed it is concluded that chitosan derivatives are promising materials for controlled drug and nonviral gene delivery.

Stimuli-responsive chitosan-graft-poly(N-vinylcaprolactam) as a promising material for controlled hydrophobic drug delivery.

A novel type of pH- and thermo-responsive copolymer, chitosan-graft-poly(N-vinylcaprolactam) (chitosan-g-PNVCL), was prepared by grafting carboxyl-terminated poly(N-vinylcaprolactam) (PNVCL-COOH) chains onto a chitosan backbone as a drug-delivery carrier. The formation of chitosan-g-PNVCL was confirmed by FT-IR and 1H NMR techniques. Chitosan-g-PNVCL showed a definite phase transition at 32 degrees C as occurs in pure PNVCL. The swelling degree of the chitosan-g-PNVCL beads was found to be higher at pH 2.2 than at pH 7.4. Moreover, the swelling degree of the beads decreased with increased environmental temperature. Compared to the chitosan beads, the release profile of chitosan-g-PNVCL beads showed a slower and more controlled release of the entrapped ketoprofen. The release behavior of the chitosan-g-PNVCL beads was influenced by both the pH and temperature of the medium. The MTT assay showed no obvious cytotoxicity of chitosan-g-PNVCL against a human endothelial cell line over a concentration range of 0-400 microg x mL(-1). These results suggest that chitosan-g-PNVCL could be a potential stimuli-responsive material for controlled drug delivery, and it may improve the bioavailability, efficacy, and compliance of the encapsulated drugs. [Reaction: see text].

Amphiphilic multi-arm block copolymer based on hyperbranched polyester, poly(L-lactide) and poly(ethylene glycol) as a drug delivery carrier.

A novel type of biodegradable/biocompatible amphiphilic hyperbranched copolymer (H40-PLA-b-MPEG) was synthesized. Its micellar properties were studied by DLS, fluorescence spectroscopy and TEM. The drug release profile showed that the H40-PLA-b-MPEG micelles provide an initial burst release, followed by a sustained release of the entrapped hydrophobic model drug over a period of 4 to 58 h. The copolymer degraded hydrolytically within 6 weeks under physiological conditions. The MTT assay showed no obvious cytotoxicity against a human endothelial cell line at a concentration range of 0-400 microg x mL(-1). These results indicate that the H40-PLA-b-MPEG micelles have great potential as hydrophobic drug delivery carriers.

Biodegradable and biocompatible multi-arm star amphiphilic block copolymer as a carrier for hydrophobic drug delivery

Multi-arm star amphiphilic block copolymers (SABCs) with approximately 32 arms were synthesized and characterized for drug delivery applications. A hyperbranched polyester, boltorn H40 (H40), was used as the macroinitiator for the ring-opening polymerization of epsilon-caprolactone (epsilon-CL). The resulting multi-arm H40-poly(epsilon-caprolactone) (H40-PCL-OH) was further reacted with carboxyl terminated methoxy poly(ethylene glycol) (MPEG-COOH) to form H40-PCL-b-MPEG copolymers. The resulting SABCs were characterized by (1)H NMR spectroscopy and gel permeation chromatography (GPC). The critical aggregation concentration (CAC) of H40-PCL-b-MPEG was 3.8 mg/L as determined by fluorescence spectrophotometry. Below the CAC, stable unimolecular micelles were formed with an average diameter of 18 nm as measured by TEM. Above the CAC, unimolecular micelles exhibited agglomeration with an average diameter of 98 nm. The hydrodynamic diameter of these agglomerates was found to be 122 nm, as measured by dynamic light scattering (DLS). The drug loading efficacy of the H40-PCL-b-MPEG micelles was 26 wt%. Drug release study showed an initial burst followed by a sustained release of the entrapped hydrophobic model drug, 5-fluorouracil, over a period of 9-140 h. These results indicate that the H40-PCL-b-MPEG micelles have great potential as hydrophobic drug delivery carriers.

Thermosensitive Micelles Based on Folate-Conjugated Poly(N-vinylcaprolactam)-block-Poly(ethylene glycol) for Tumor-Targeted Drug Delivery

Thermosensitive PNVCL-b-PEG block copolymer coupled with folic acid was prepared as an anti-cancer drug carrier. This polymer self-assembled into stable micelles in aqueous solutions at above 33 degrees C. At 37 degrees C, the release profile of PNVCL-b-PEG-FA micelles showed a slower and more controlled release of the entrapped 5-FU than that at 25 degrees C. The blank and 5-FU-loaded PNVCL-b-PEG-FA micelles did not induce remarkable cytotoxicity against the EA.hy 926 human endothelial cell line; however, 5-FU-loaded PNVCL-b-PEG-FA micelles showed a cytotoxicity effect against 4T1 mouse mammary carcinoma cells due to the availability of loaded anti-cancer drugs delivered to the inside of the cancer cells by the folate-receptor-mediated endocytosis process.

An Amphiphilic Nanocarrier Based on Guar Gum-graft-Poly(ε-caprolactone) for Potential Drug-Delivery Applications

Amphiphilic guar gum grafted with poly(ε-caprolactone) (GG-g-PCL) was fabricated as a drug-delivery carrier using microwave irradiation. The structure of the GG-g-PCL co-polymer was characterized by 1H-NMR spectroscopy. By microwave irradiation, GG-g-PCL with high grafting percentage (>200%) was obtained in a short reaction time. The GG-g-PCL co-polymer is capable of self-assembling into nanosized spherical micelles in aqueous solution with the diameter of around 75–135 nm and 60–100 nm, as determined by DLS and TEM, respectively. The critical micelle concentration (CMC) of GG-g-PCL was found to be approx. 0.56 mg/l in a phosphate buffer solution. The drug-release profile showed that the GG-g-PCL micelles provided an initial burst release followed by a sustained release of the entrapped hydrophobic model drug, ketoprofen, over a period of 10–68 h. Under physiological conditions, the GG-g-PCL co-polymer hydrolytically degraded into lower-molecular-weight fragments within a 7-week period. These results suggest that the GG-g-PCL micelles could be used as a nanocarrier for in vitro controlled drug delivery.