SN-38-cyclodextrin complexation and its influence on the solubility, stability, and in vitro anticancer activity against ovarian cancer.

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether ß-cyclodextrin (SBEßCD), hydroxypropyl ß-cyclodextrin, randomly methylated ß-cyclodextrin, and methyl ß-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-ßCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEßCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an AP-type system. Aqueous solubility of SN-38 was enhanced by about 30-1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEßCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEßCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEßCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.

Hyaluronic acid-decorated PLGA-PEG nanoparticles for targeted delivery of SN-38 to ovarian cancer.

BACKGROUND: Extreme hydrophobicity and poor stability of SN-38, a highly potent topoisomerase I inhibitor, has prevented its clinical use. Its encapsulation into nanoparticles may be a way to overcome these problems. Here we report the use of SN-38-loaded hyaluronic acid (HA)-decorated poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) for targeted ovarian cancer therapy. MATERIALS AND METHODS: PLGA-PEG nanoparticles loaded with SN-38 were prepared by single- emulsion (O/W) solvent evaporation method. HA was decorated onto the nanoparticles by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling and the extent of HA conjugation was quantified by hexadecyltrimmethylammonium bromide (CTAB) assay. Cancer cell specificity of the NPs was determined by flow cytometry and cytotoxicity of the NPs was tested by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium (MTT) bromide assay. RESULTS: Mean size, zeta potential and encapsulation efficiency of PLGA-PEG-HA NPs were 265.6 ± 3.8 nm, -30.4 ± 0.1 mV and 75.8 ± 4.1%, respectively. Cellular uptake of PLGA-PEG-HA NPs was 8- and 16-fold higher in CD44-positive cell lines, SKOV-3 and OVCAR-8, as compared to CD44-negative cells (CHO). Cytotoxicity of the targeted NPs was significantly higher as compared to non-targeted NPs for the above cell lines. These results suggest that PLGA-PEG-HA NPs could be an efficient delivery system for SN-38 for targeted therapy of ovarian cancer.

Recent trends in cancer drug resistance reversal strategies using nanoparticles.

INTRODUCTION: Resistance to chemotherapy is a major obstacle in the successful amelioration of tumors in many cancer patients. Resistance is either intrinsic or acquired, involving mechanisms such as genetic aberrations, decreased influx and increased efflux of drugs. Strategies for the reversal of resistance involve the alteration of enzymes responsible for drug resistance, the modulation of proteins regulating apoptosis mechanisms and improving the uptake of drugs using nanotechnology. Novel strides in the reversal of drug resistance are emerging, involving the use of nanotechnology, targeting stem cells, etc. AREAS COVERED: This paper reviews the most recent cancer drug reversal strategies involving nanotechnology for targeting cancer cells and cancer stem cells (CSCs), for enhanced uptake of micro- and macromolecular inhibitors. EXPERT OPINION: Nanotechnology used in conjunction with existing therapies, such as gene therapy and P-glycoprotein inhibition, has been shown to improve the reversal of drug resistance; the mechanisms involved in this include specific targeting of drugs and nucleotide therapeutics, enhanced cellular uptake of drugs and improved bioavailability of drugs with poor physicochemical characteristics. Important strategies in the reversal of drug resistance include: a multifunctional nanoparticulate system housing a targeting moiety; therapeutics to kill resistant cancer cells and CSCs; cytotoxic drugs and a tumor microenvironment stimuli-responsive element, to release the encapsulated therapeutics.