Developing Clinically Applicable, Cancer-Targeting Polymeric Nanoconjugates

点击翻译按钮获取中文摘要

DESCRIPTION (Provided by the applicant) Abstract: Metal catalysts mediate well-controlled, living polymerizations with quantitative initiation and monomer conversion, which facilitates the preparation of polymeric materials with narrow polydispersities and well-defined molecular weights. These well-controlled chemistries, however, show little impact on the formulation of polymeric nanomedicine. Current polymeric nanomedicine still relies on conventional conjugation or encapsulation for drug incorporation, which results in inevitable heterogeneity during nanomedicine formulation. These formulation heterogeneity in particle size, size distribution, drug distribution and variation between batch-to- batch for the drug loading and incorporation efficiency creates tremendous problems for the clinical translations of these nanomedicine delivery vehicles. We propose to study an unprecedented approach to bridge the gap between the control offered by modern polymerization chemistry and the lack of control of current nanomedicine formulation. More specifically, we aim to develop polymer-drug nanoconjugate, a new paradigm of drug delivery nanomedicine with characteristics distinctly different from the current polymeric nanoparticles (nanoencapsulates). In the preparation of polymer-drug nanoconjugates, we use hydroxyl- containing drug molecules as the initiators to mediate a ring-opening polymerization of lactide in the presence of a Mg(II) catalyst. The resulting polylactide-drug conjugate is subsequently nanoprecipitated to form sub-100 nm nanoparticles in uniform size. Compared to current nanoencapsulates, our preliminary study demonstrated that polymeric nanoconjugates show 100% drug incorporation efficiency with pre-definable drug loading by LA/drug ratio. Moreover, nanoconjugates do not show burst drug release, a drawback commonly associated with polymeric nanoencapsulates. Using pyrenemethanol as the model drug, we demonstrated that gram- or larger-scale, highly loaded nanoconjugates can be formulated with several hours. The simplicity for the preparation of large-scale nanoconjugates with controlled loading and release characteristics suggests its great potential for clinical translation. To study the in vivo applicability of nanoconjugates, we propose to develop polylactide-docetaxel nanoconjugates with integrated aptamer ligand for the targeted treatment of the advanced prostate cancer. Public Health Relevance: Polymeric nanoencapsulate as drug delivery vehicles have been investigated for more than 30 years, but only a few of them have been tested clinically and even less been approved by the Food and Drug Administration for clinical applications. We propose to develop nanoconjugates via metal-catalysts mediated, drug-initiated ring-opening polymerization strategy followed by nanoprecipitation.