Nanomicelle Based Peroral Delivery System for Enhanced Absorption and Sustained Release of 10-Hydrocamptothecin

An effective sustained-release peroral drug delivery system is needed for chemotherapy. Here, we show that such a system can be achieved by designing polymeric nanomicelles combining mucoadhesion, enhanced absorption and controlled release. Chitosan and glyceryl-monooleate have many desirable properties, so we synthesized a novel chitosan derivative, chitosan-conjugated glyceryl monooleate. We loaded 10-hydroxycamptothecin (HCPT) into the cores of nanomicelles by pH-coacervation, which significantly improved drug loading and stability. We studied the pharmacokinetics of these drug-loaded nanomicelles, and they demonstrated remarkably prolonged circulation time in vivo up to 72 h. Orally administered HCPT-loaded nanomicelles also showed comparable antitumor effects and smaller changes in body weight compared to HCPT administered by injection. Most importantly, by using in vivo pharmacokinetic and pharmacodynamic studies, we showed that comparable antitumor effects can be achieved by peroral administration of HCPT-loaded nanomicelles every three days, and that the nanomicelles had less severe side effects. In vivo imaging provided direct evidence that the micelles were absorbed and exhibited sustained release after oral administration. These results indicate a promising future for nanomicelle-based peroral drug delivery as a superior alternative to injection, and they also provide guiding principles for designing amphiphilic copolymers.