Targetable biodegradable nanoparticles for delivery of chemotherapeutic and imaging agents to ovarian cancer

Abstract

Every year more than 10 million people develop cancers globally. Ovarian cancer, specifically, results in more than 22,000 new cases and 16,000 deaths from this disease yearly, more than any other cancer of the female reproductive system. In addition, because of non-specific symptoms and poor screening techniques, most ovarian cancer cases are discovered after the disease is in an advanced state. Consequently, aggressive and effective treatment options that incur minimal toxic effects to healthy tissue are in great need. In the present research, stealth biodegradable nanoparticles were developed as vehicles for the controlled and targeted delivery of chemotherapeutic agents for the treatment of ovarian cancer. The design of this delivery system consisted of nanoparticles of biodegradable polymers of the poly(lactic-co-glycolic acid) family loaded with the chemotherapeutic agent doxorubicin or the imaging agents rhodamine 6G, indocyanine green or gadopentetic acid. Nanoparticles were modified by incorporation of functional poly(ethylene glycol) on their surface to improve the stability of the colloidal suspension, increase their circulation lifetime in vivo, and provide a site for conjugation of targeting agents specific to ovarian tissue. Various methods were evaluated for this surface modification, including the use of polymer blends, the chemical conjugation of the polymers, and the polymerization of lactide and glycolide monomers initiated by heterofunctional poly(ethylene glycol). Nanoparticles incorporating poly(ethylene glycol) presented improved characteristics compared to unmodified particles including smaller size, higher stability and slower release of the chemotherapeutic agent doxorubicin The actual drug or agent content was decreased in the case of doxorubicin and rhodamine, but increased for indocyanine green as a result of improved agent-polymer interactions. Poly(ethylene glycol)-containing nanoparticles were conjugated to monoclonal antibody mAb106-105, which is specific to the extracellular domain of human folliclestimulating hormone (FSH) receptors. These receptors are only expressed in ovarian cells in women, thus providing a system that is highly specific to ovarian tissue. The interaction and therapeutic potential of nanoparticles with or without targeting antibodies were tested on OVCAR-3, Caov-3, and MDA-MB-231 cancer cells.