This dissertation addresses the broad applicability of the nanomedicine platform core-cross-linked polymeric micelles (CCL-PMs) composed of thermosensitive mPEG-b-pHPMAmLacn block copolymers. In Chapter 1, a general introduction to nanomedicines is provided, with a particular focus on polymeric nanoparticles. In Chapter 2, the high tuneability of CCL-PMs with respect to particle size and carrier degradation characteristics is described, which can be achieved by modulating the molecular weight of the constituting block copolymer and the cross-linking, respectively. In addition, drug molecules can be covalently attached to the core of CCL-PMs via hydrolysable linkages, which allow the native drug to be released at a controllable rate under physiological conditions. By altering the hydrolytic sensitivity of these linkages, the release profile of drug from the CCL-PMs can be completely tuned (Chapter 2). In Chapter 3, the anticancer agent docetaxel was covalently entrapped in CCL-PMs and the therapeutic performance of the obtained nanomedicine was evaluated in vivo. Compared to the marketed formulation Taxotere®, docetaxel-entrapped CCL-PMs demonstrated superior antitumour efficacy and tolerability in rodents. In particular, a single intravenous dose of docetaxel-entrapped CCL-PMs resulted in complete regression of breast tumours in mice, leading to 100% survival of the animals. Besides small molecule drugs, a model therapeutic peptide, leuprolide, was covalently entrapped in CCL-PMs (Chapter 4). Compared to the soluble peptide, leuprolide entrapped in CCL-PMs showed a prolonged circulation profile in healthy rats and the leuprolide released from circulating CCL-PMs remained biologically active, as demonstrated by the change of plasma levels of testosterone in the animals. Further, in Chapter 5, the feasibility of subcutaneous administration of CCL-PMs is addressed, as the subcutaneous route is potentially more patient-friendly and cost-effective than the intravenous route. The model drugs either dexamethasone or paclitaxel was covalently entrapped in CCL-PMs, which were injected to healthy mice following intravenous and subcutaneous route of administration. Importantly, subcutaneous administration of drug-containing CCL-PMs resulted in high systemic availability, demonstrating subcutaneous delivery as a promising route to administer nanomedicines based on CCL-PMs. At the end, Chapter 6 summarises the results described in this dissertation and provides perspectives on the use of this nanomedicine platform based on CCL-PMs.
|Award date||29 Oct 2015|
|Place of Publication||Enschede|
|Publication status||Published - 29 Oct 2015|