Radiotherapeutic synergism of thermogelling cisplatin-loaded polymers for cervical cancer treatment
Mentor: Robert A Cormack, Ph.D. (Dana Farber Cancer Institite)
Administering chemotherapy in conjunction with radiotherapy has become a cornerstone in the treatment of cancer. The application of some chemotherapy agents, such as the DNA-interfering drug Cisplatin, simultaneous with radiation therapy results in a greater effect than the sum of the individual monotherapies. Cisplatin is usually delivered intravenously and act as a potent radiosensitizer. However, the dose that can be given systemically is limited by several side effects including nausea, vomiting, weight loss, anemia, and neurotoxicity, among many more. Furthermore, the radiosensitizing effects of intravenous Cisplatin is not tumor specific and puts healthy tumor-surrounding tissue and organs at risk of becoming irradiated and damaged leading to infection and necrosis. Previous studies conducted in collaboration with Northeastern University, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute have engineered and characterized an injectable, thermogelling, cisplatin-loaded polymer formulation for sustained release at the tumor site in cervical cancer. This hydrogel is capable of being locally injected during standard of care radiation therapy procedures to form a biodegradable gel within the tumor to locally elute Cisplatin. Preliminary characterization and in-vitro studies indicate the hydrogel polymer is non-toxic, capable of gelling at body temperature, and has a drug release profile that can be optimized to provide a sustained release of the cytotoxic drug to have a synergistic effect with radiation to be used against cervical cancer cells. Our team will further investigate the efficacy of the hydrogel in destroying cervical cancer cells and minimizing the toxicities traditionally associated with therapeutic treatment through testing this targeted drug delivery system in-vivo studies in a mouse model. Subcutaneous, heterotopic injection of cervical cancer HeLa cells will induce tumor growth in immunocompromised mice. Cisplatin-loaded hydrogel will be injected locally at the tumor site where the supra-additive effects of applying radiation therapy can be further studied in the animal model.
Figure: Schematic of thermogelling polymers encapsulating cisplatin. For the purposes of our project, we characterized our hydrogel on the basis of its ability to gel before reaching body temperature and of its flow properties through differential scanning calorimetry and rheometry, respectively. Cisplatin loading parameters can be optimized to produce a hydrogel that releases a favorable drug concentration over a sustained period to best kill cervical cancer cells and radiosensitize the tumor to better respond to clinical radiation therapy. Moving forward from characterization studies and in-vitro experiments towards animal testing will determine the efficacy of the Cisplatin-loaded hydrogels in-vivo. Source: synthesis and characterization of thermally and chemically gelling injectable hydrogels for tissue engineering (Ekenseair et al. 2012) Source: