Tumor-targeted cholesteryl-hyaluronic acid-drug conjugates as nano therapeutics against drug-resistant tumors

Cancer drug resistance has become one of the most challenging burdens in the treatment of cancer patients. The cancer cells surviving from chemotherapy or molecularly targeted therapy develop resistance through multiple intrinsic or acquired mechanisms, and give rise to relapsed tumors or metastases that are even more difficult to eliminate. Nanomedicine which has a potential of overcoming known shortcomings of many anticancer drugs, has stimulated the development of many novel drug delivery strategies. Rational design of such DDS for the specific targeting of cancer cells could significantly benefit the cancer treatment. We developed cholesteryl-hyaluronic acid (CHA) nanogel-drug conjugates for efficient treatment of cancer cells and, especially, drug-resistant and CD44-expressing cancer cells. In the design of CHA nanogel-drug conjugates, we focused on the enhancing of various aspects of drug delivery, including drug solubility, loading capacity, nanogel size, drug release from nanogel in cytoplasm and active tumor targeting. The stronger cytotoxicity of CHA-drug nanogels in cancer cells and spheroids compared to simple HA-drug conjugates was due to better cellular uptake determined by the higher affinity of CHA nanogels to the cellular membrane and only partly by the binding with CD44 receptors overexpressed in drug-resistant cancer cells. We also demonstrated fast penetration and high therapeutic activity of CHA nanogel-drug conjugates in 3D-cultures of multicellular cancer spheroids. The nanogel showed prolonged circulation in blood and improved PK parameters compared to free drug, which leads to increased bioavailability of drug against tumors. This novel conjugate efficiently accumulated in tumors in vivo via EPR effect and was effectively inhibiting tumor growth in xenograft tumor animal models. Curcumin is a potential anticancer drug; however, its direct use in patients has failed due to poor stability and bioavailability. Instead, CHA-CUR showed strong stability in GI conditions, good bioavailability through oral administration and efficient tumor growth inhibition in orthotropic tumor model. It was also active against the same cellular targets as curcumin and demonstrated increased apoptosis and cytotoxicity compared to curcumin against different cancer cells. Therefore, this simple nanodrug exhibits high potential as novel anticancer drug type with therapeutic and preventive applications.