Designing nanocarriers to penetrate cartilage and improve delivery of biologic drugs for osteoarthritis;

摘要

Osteoarthritis is a debilitating joint disease that affects over 30 million people and has no disease-modifying therapies. The current standard of care for the disease is merely palliative until joint replacement is necessary. Disease-modifying osteoarthritis drugs have been tested in the clinic, but all have been unsuccessful in clinical trials. A key point of failure for several of these drugs has been inefficient and inadequate delivery to target cartilage cells. Cartilage is avascular and thus cannot be targeted efficiently through the systemic circulation. Due to the localized nature of osteoarthritis, direct injection of therapeutics into affected joints is an attractive solution to this problem. However, delivery via this approach remains impeded by rapid turnover of the synovial fluid within joints and the dense, highly charged nature of cartilage tissue.;To overcome this biological barrier, we took advantage of a recently demonstrated phenomenon in which positively charged nanomaterials electrostatically interact with anionic cartilage, both avoiding joint clearance and facilitating diffusion through the tissue in the process. This work describes two strategies using such polycationic materials to deliver insulin-like growth factor 1 (IGF-1), a promising anabolic growth factor for osteoarthritis that has known delivery challenges. The first approach used an electrostatic assembly of IGF-1, poly(L-glutamic acid), and poly(L-arginine) into a nanoscale complex coacervate, or nanoplex, for delivery of unmodified, bioactive IGF-1. The second approach involved a densely charged polyamidoamine (PAMAM) dendrimer, end-grafted with poly(ethylene glycol) (PEG) of various molecular weights at various % end group functionalization.;From this panel of nearly 50 PEGylated dendrimers, an optimally charged dendrimer was selected based on criteria of cartilage uptake and nontoxicity. The selected dendrimer was covalently modified with IGF-1. Both systems were tested to ensure that they could deliver bioactive IGF-1, penetrate human thickness cartilage tissue, extend joint residence time in vivo, and mitigate the progression of early traumatic osteoarthritis in rats. Both the nanoplex and optimally PEGylated dendrimer-IGF-1 achieved these goals, suggesting that polycationic nanocarriers could potentially improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.;