Design of Smart Polymeric Nanomedicines

J. Kopeček, J. Yang
University of Utah,
United States

Keywords: biomaterials, nanomedicine

Summary:

The science of polymeric biomedical materials has moved from copying/mimicking Nature’s design to modifying it and designing bioactive materials. The level of our understanding of the relationship between structure and properties has reached levels needed for the design of new materials different from those in Nature. The latter approach has the highest potential for scientific and application breakthroughs in the near future. Based on this outline, the evolution of biomedical materials will be discussed, including the following three topics: a) Long-circulating macromolecular therapeutics based on backbone degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers. We have recently designed multiblock HPMA copolymers that contain enzymatically degradable oligopeptide sequences in the main chain. These HPMA copolymer-drug (epirubicin, gemcitabine, paclitaxel) conjugates have demonstrated enhanced efficacy in the treatment of animal tumor models when compared to non-degradable HPMA copolymer conjugates or free drugs. b) Antibody-drug conjugates (ADCs). A new design of ADCs that consists of rituximab (RTX) and semitelechelic HPMA copolymer–epirubicin conjugates. The latter were selectively attached to RTX via reduced disulfide bonds. Such design allows the introduction of a large payload of drug on the antibody without adding attachment sites and without compromising the antigen-targeting ability. c) Drug-free macromolecular therapeutics. Inspired by the self-assembly of hybrid HPMA copolymers grafted with complementary coiled-coil forming oligopeptides we designed a new therapeutic platform for the treatment of CD20 positive B-cell lymphomas. Biorecognition of peptide or oligonucleotide motifs at the B-cell surface triggers apoptosis. This is a new concept, where the biological activity is based on the biorecognition of complementary motifs at cell surface. This results in CD20 crosslinking, significantly increased calcium influx, decrease of mitochondrial potential, Bcl-2 downregualtion, activation of caspase signaling pathways, and apoptosis initiation.