Executive Summary : | Cancer is one of the major reasons for high mortality rate, worldwide. There are about 9.9 million new cases reported annually, out of which 4.4 million end up in death. It is also reported that 15-16% of the reported breast cancer cases end up being fatal. This could be attributed to the malignant nature of breast cancer cells leading to formation of secondary tumors in distal organs through metastasis. Among the treatment options available, surgical resection, radiation, and chemotherapy remain the golden standard. However, they are limited in their clinical outcomes owing to the adverse side effects and non-affordability.In the recent years, Cancer immunotherapy has emerged as a potential alternative to the conventional treatment modalities.The developed immune response not only enhances the anti-tumor effects but also creates a memory that could thereby prevent metastasis and recurrence of cancer.Given the advantages and the limitation of majority of cancer treatments available today, a better approach combing the conventional modalities with immunotherapy would pave the way for more reliable and efficient treatment.However, systemic delivery of these inhibitors suffers from poor pharmacokinetic profile, circulation time and subsequently adverse side effects. Nanotechnology has emerged as an affordable alternative in this perspective, owing to their unique physico-chemical properties compared to their bulk counterpart. Several nanomaterials have been developed for targeted and sustained drug delivery, combining multiple treatment modalities in a single platform for synergistic effect etc.Despite the technical advancements in these fields of research, they still face several critical challenges to be tackled and the most important ones include the increasing resistance of cancer cells to their treatments, requirement of multiple and frequent dosing and associated side effects and the ability to target deep seated or unknown metastatic tumors at distal sites. To overcome these challenges, in this proposal, we intend to develop a nano transformable thermosensitive hydrogel for targeted chemo-immunotherapy of advanced metastatic tumors.The thermosensitive hydrogel upon cross-linking, degrades into self-stabilized polymeric nanoparticles at physiological conditions.These polymeric nanoparticles can target deep seated metastatic secondary tumors by virtue of enhanced permeation and retention (EPR) effect. The hydrogel can also home within its matrix, several therapeutic moieties for a synergistic effect.In this study, we intend to incorporate within the hydrogel, a combination of chemotherapeutic drugs (Eg: Doxorubicin, Paclitaxel) and immune-adjuvants (Anti PDL-1/Anti-CTLA-4) for breast cancer.Overall, the proposed formulation can help target the metastatic deep seated/unknown tumors, which is otherwise not easy to detect or removable using surgery and can generate an anti-tumor immune response to stop further regrowth and spread of tumor cells. |