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Abstract
BackgroundSpecific properties of amphiphilic copolymeric micelles like small size, stability, biodegradability and prolonged biodistribution have projected them as promising vectors for drug delivery. To evaluate the potential of δ-valerolactone based micelles as carriers for drug delivery, a novel triblock amphiphilic copolymer poly(δ-valerolactone)/poly(ethylene glycol)/poly(δ-valerolactone) (VEV) was synthesized and characterized using IR, NMR, GPC, DTA and TGA. To evaluate VEV as a carrier for drug delivery, doxorubicin (DOX) entrapped VEV micelles (VEVDMs) were prepared and analyzed for in vitro antitumor activity.ResultsVEV copolymer was successfully synthesized by ring opening polymerization and the stable core shell structure of VEV micelles with a low critical micelle concentration was confirmed by proton NMR and fluorescence based method. Doxorubicin entrapped micelles (VEVDMs) prepared using a modified single emulsion method were obtained with a mean diameter of 90 nm and high encapsulation efficiency showing a pH dependent sustained doxorubicin release. Biological evaluation in breast adenocarcinoma (MCF7) and glioblastoma (U87MG) cells by flow cytometry showed 2-3 folds increase in cellular uptake of VEVDMs than free DOX. Block copolymer micelles without DOX were non cytotoxic in both the cell lines. As evaluated by the IC50 values VEVDMs induced 77.8, 71.2, 81.2% more cytotoxicity in MCF7 cells and 40.8, 72.6, 76% more cytotoxicity in U87MG cells than pristine DOX after 24, 48, 72 h treatment, respectively. Moreover, VEVDMs induced enhanced apoptosis than free DOX as indicated by higher shift in Annexin V-FITC fluorescence and better intensity of cleaved PARP. Even though, further studies are required to prove the efficacy of this formulation in vivo the comparable G2/M phase arrest induced by VEVDMs at half the concentration of free DOX confirmed the better antitumor efficacy of VEVDMs in vitro.ConclusionsOur studies clearly indicate that VEVDMs possess great therapeutic potential for long-term tumor suppression. Furthermore, our results launch VEV as a promising nanocarrier for an effective controlled drug delivery in cancer chemotherapy.
Highlights
Specific properties of amphiphilic copolymeric micelles like small size, stability, biodegradability and prolonged biodistribution have projected them as promising vectors for drug delivery
Another important characteristic of these micelles is the presence of water compatible polymers like polyethylene glycol (PEG) which improves the bioavailability of these drug delivery systems [14,15]
The 1H nuclear magnetic resonance 1H spectra (NMR) spectra acquired in deuterated chloroform, which is a good solvent for both blocks, contained signals from the protons of PEG as well as PVL
Summary
Specific properties of amphiphilic copolymeric micelles like small size, stability, biodegradability and prolonged biodistribution have projected them as promising vectors for drug delivery. The potential of polymeric micelles as drug carriers lie in their unique properties like small size, prolonged circulation, biodegradability and thermodynamic stability [10,11] These micelles have the ability to preferentially target tumor tissues by enhanced permeability and retention effect due to the small size of the carrier molecule which facilitates the entry within biological constraints proving their superiority over other particulate carriers [12,13]. PEG saturates these polymeric particles with water by making them soluble, and prevents opsonization of these nanocarriers by providing steric stabilization against undesirable aggregation and non-specific electrostatic interactions with the surroundings [16,17] This has resulted in an extensive study of drug formulations using copolymeric micelles with enhanced antitumor efficacy [18,19,20]. Its therapeutic potential is limited due to its short half life [27] and severe toxicity to healthy tissues resulting in myelosuppression and cardiac failure [28,29]
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