Abstract
ABSTRACT
The oral route is the preferred mode of drug administration due to its non-invasive nature, economical benefits, and the potential to improve patients’ quality of life. Oral administration of anticancer agents can be tailored to maintain plasma concentrations above therapeutic level and ensure prolonged and effective exposure of cancer cells to the chemotherapeutic agent. However in cancer therapy, most drugs are administered intravenously due to their low oral bioavailability and gastrointestinal (GI) toxicity. The use of a nanocarrier system for oral delivery of anticancer drugs can eliminate the toxicity to the GI tract, improve the bioavailability and take advantage of the wide fenestrations of tumour vasculature to accumulate in the tumour tissue. Despite a plethora of research being dedicated to the development of nanosized formulations, there is still no oral anticancer nanomedicine in clinical use. This thesis evaluates the potential of styrene maleic acid (SMA) micelles as a nanocarrier system for oral anticancer drug delivery.
SMA micelles encapsulating epirubicin (as a fluorescent model of anticancer drug) or a fluorescent dye, DiI (1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate) or paclitaxel (PTX) were synthesised and characterised. All the SMA micelles had a good recovery (80 – 97%). Their sizes were > 7 nm enabling them to escape renal clearance and prolong their circulatory half-lives. The SMA micelles had a neutral charge which would aid in reducing opsonisation in the circulation. The SMA micelles were more stable at physiological pH and intestinal pH as compared to gastric pH. Nevertheless, all the SMA micelles showed less than 15% release in gastric environment in the initial 2 h, which is the gastric transit time. Furthermore, on comparing the release rate of 7.5 and 18% loaded SMA-Epi micelles, it was observed that lower loaded micelles showed faster release of the drug. However, both the micelles showed less than 15% release in the initial 8 h.
The SMA-Epi micelles were efficiently transported across the intestinal epithelium using in vitro and ex vivo model, while maintaining the tissue integrity. SMA micelles showed uptake by clathrin-dependent endocytosis and micropinocytosis through the cells of the intestinal epithelium. The in vivo biodistribution of SMA micelles was evaluated using DiI. Oral administration of SMA-DiI resulted in 2-fold higher accumulation in liver and spleen, and 15-fold higher accumulation in the tumour as compared to the free DiI. Furthermore, it was observed that the SMA micelles show dual uptake through enterocytes and M cells in an in vivo tumour model, which was confirmed by visualising the accumulation of SMA micelles in the Peyer`s patches.
Furthermore, the antitumour efficacy of the orally administered SMA micelles encapsulating PTX was evaluated in the last section. The maximum tolerated dose (MTD) of SMA-PTX through oral administration was higher than the commercially available PTX formulation (PTX, Ebewe), for both single (120 vs 60 mg/kg) and repeated doses (60 vs 30 mg/kg). Thus the SMA-PTX could be administered at higher doses to achieve better therapeutic efficacy. In a CT-26 (Balb/c colon cancer cells) orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 and 60 mg/kg reduced tumour weight by 54 and 69% respectively, as compared to the control group, while no significant reduction in tumour weight was observed with 30 mg/kg of PTX (Ebewe). This therapeutic effect is attributed to the enhanced tumour accumulation of the SMA micellar system, through the systemic circulation as well as paracellular transport through the epithelium lining the colon tumours. However, oral administration of SMA-PTX did not show significant reduction in tumour size in a MDA-MB-231 breast cancer xenograft model, as compared to the control, at a dose of 30 mg/kg. In both the tumour models, oral administration of SMA-PTX micelles did not show any liver or kidney toxicity. In conclusion, SMA micelles could provide an effective strategy for safe oral administration of PTX in cancer therapy for GI tumours. Nevertheless, further optimisation of dose and dosing schedule would be needed to ascertain the efficacy of oral administration of SMA-PTX in breast cancer xenograft model.