Executive Summary : | An ideal intravenous drug delivery system (iDDS), should be able to overcome the challenges associated with each step of the delivery process i.e. circulation, accumulation, penetration, internalization and release. Regardless of a prolonged history of research in this field, iDDSs available in literature are not optimized for each stage of the cascade and are mainly focused on circulation and accumulation stages. Therefore, lower retention time and poor penetration in the tumor are still considered as the major obstacles of nanosystem-based cancer treatment. Size' of the nanostructures plays one of the most important role in defying the aforementioned obstacles. While EPR mediated nanosystem accumulation is generally favoured by a size ~ 100 nm but suffers in both tumor retention and penetration, nanoparticles having size ? 30 nm can effectively penetrate into deeper regions of tumors but suffer from rapid efflux and poor retention. Again, larger nanoparticles (~ 1 µm) can only accumulate at the superficial region of the tumor. Thus, it is highly necessary to prepare smart size-tunable nanosystems in order to breach the dimensional gaps. The subtle difference between normal and cancer cell environment such as pH, temperature, GSH concentration, ROS concentration etc. can be used as the tool for size tunability as well for necessary site specific changes. In spite of many attempts, there are quite a few existing gaps still need to be explored for better therapeutic efficacy such as, combination of size-tunability approach with other therapeutic techniques, consideration of multi drug resistance in tumor cells, incorporation of multimodal imaging guided synergistic therapy, and combination of aggregation strategy with shrinking strategy in order to facilitate longer retention and deeper penetration at the same time. In this project, our goal will be filling the aforementioned gaps by the following approaches (i) Combination of organic (polymeric nanoparticles) and inorganic (gold nanoparicles) iDDSs for designing size-tunable nanosystems to overcome the disadvantages associated with individual systems and to gain benefit from both kinds. (ii) Blending of size aggregation and shrinking approach by designing tumor extracellular environment responsive cross-linked nanogels with pH-responsive swelling-based retention property and incorporation of functionalized small sized gold nanoparticles for pH-responsive release from nanogels for promoting deeper penetration. (iii) Simultaneous incorporation of two different drugs in size-tunable nanosystems for synergism based therapeutic benefits in multi drug resistant tumor cells. (iv) Merging of size-tunable approach and multi-therapeutic approach by combining chemotherapy (CT) with photothermal therapy (PTT). (v) Incorporation of theranostic properties in the nanosystems for multi modal imaging guided diagnosis based on thermal, fluorescence and photoacoustic (PA) imaging. |