Multifunctional Drug Delivery System based on Poly-N-Vinylpyrrolydone Block Copolymer Micelles

Abstract

The traditional approach of systemically administering therapeutic agents to a patient suffers serious drawbacks, which became particularly apparent in cancer chemotherapy. Many of these issues, including dose-limiting toxicity, low bioavailability and short circulation time, can be successfully addressed by polymeric drug delivery systems based on amphiphilic block copolymers comprising hydrophobic and hydrophilic segments. Upon drug loading, the polymer forms micelles with a drug-loaded hydrophobic core (formed by the hydrophobic segments of the polymer) and a hydrophilic corona (formed by the hydrophilic segments). In this report we present a versatile system based on a biodegradable amphiphilic PVP-acrylic acid copolymer that could be applied for drug delivery and diagnostic purposes. Using curcumin from Curcuma longa as a model drug, we demonstrate that sub-100 nm micelles loaded with a hydrophobic drug can be produced and remain stable under physiological conditions. In vitro studies carried out on primary fibroblasts and a glioblastoma cell line (U87) show that cells readily uptake the obtained micelles via non-receptor mediated endocytosis. The observed micellar delivery is significantly more efficient compared to the cellular absorption of the free drug. We show that curcumin-loaded micelles exhibit cytotoxicity against the tested cell lines, while empty micelles do not. Due to the presence of free carboxylic acid groups we also show that a covalent attachment of cancer-cell targeting moieties to the polymer can be achieved in order to obtain selective drug delivery. Furthermore, we demonstrate that the PVP-acrylic acid copolymer is able to chelate Gd(III) ions within the micellar corona making the system suitable for MRI based imaging, and hence creating a theranostic platform comprising therapeutic and diagnostic capabilities.