Development of lymphatic drug delivery platforms for the treatment of carcinomas

Abstract

Many cancers, such as breast cancer, lung cancer, and head and neck cancer, preferentially metastasize via the lymphatic system prior to their systemic invasion. Conventional chemotherapy has limited penetration into the lymphatics due to its anatomy, because drug molecules have to diffuse from the blood capillaries into the surrounding tissues and further enter the lymph vessels to reach the diseased lymph nodes. Therefore, chemotherapy can be of limited benefit in treating lymph node disease. In addition, due to the systemic administration and wide distribution, conventional intravenous chemotherapy causes a variety of organ toxicities, including but not limited to: renal toxicity, cardiotoxicity, and hepatic toxicity. This limits its use in the clinic, expecially for the elderly or late-stage patients who cannot tolerate systemic toxicities. Therefore, there is a critical need to develop of a localized drug delivery platform that confines the anti-cancer drugs to the site of the disease. This dissertation focuses on the development of subcutaneously delivered drug platforms for the treatment of cancers that are known to be lymphatically metastatic. The goal is to improve the anti-cancer efficacy and reduce the non-specific organ toxicities of small molecule chemotherapeutic agents. To achieve this goal, three polymer-based anti-cancer conjugates: hyaluronan-cisplatin (HA-Pt), hyaluronan-doxorubicin (HA-DOX), and sugar star polymer-nitric oxide prodrug 1 (sugar-NO1), were synthesized, characterized, and evaluated in preclinical rodent models. The route of drug administration along with the controlled release of the drug from the platforms, both play an important role in improving the biopharmaceutical properties of these conjugates. This is demonstrated by the extended systemic rentention, as well as the elevated local accumulation of the drug in the draining lymph nodes of the tumor, when compared to standard intravenous chemotherapy. The HA-Pt and HA-DOX conjugates exhibited reduced renal toxicity and cardiotoxicity, respectively, relative to the conventional intravenous chemotherapy in rats. Because of the improved pharmarcokinetic and toxicological profiles of the polymer-drug conjugates, animals that were treated with the subcutaneous conjugates demonstrated enhanced inhibition of the tumor progression and increased survival rates. To understand the increased anti-cancer activity of the conjugates on a cellular level, the interaction and internalization of the nanocarriers into tumor cells was also investigated using a gold nanoparticle tagged HA-Pt conjugate and a fluorescently labeled HA-DOX conjugate. In the clinic, cisplatin and doxorubicin are often administered in combination with other anti-tumor agents as a "chemo cocktail" to prevent chemoresistance. Additionally, nitric oxide has been shown to improve the cytotoxicity of cisplatin therapy via a synergistic effect. Therefore, the development of a nitric oxide prodrug cisplatin combinational therapy, with increased anti-proliferative activity against cancer cells, was investigated; and it is also presented in this disssertation and compared to cisplatin treatment alone. In conclusion, this thesis work has led to the successful preclinical development of two localized drug delivery platforms and one promising candidate for the treatment of metastatic carcinomas. The motivation for drug delivery scientists to develop more efficacious and less toxic chemotherapies will be presented.