Research Projects

Drug delivery to brain tumors is driven by the ability of the nano-carriers’ transcytosis across the tightly regulated vasculature of the blood-brain barrier (BBB). The existing nanocarriers in therapeutics are typically made via multi-molecular self-assembly into large-sized aggregated micellar nanoparticles, and therefore, they predominantly lack the stealth character to breach BBB. Additionally, the multi-molecular nano-assemblies are known to disassemble under a dilution factor imposed on them while being administered intravenously under in vivo conditions. As a consequence, the injected nano-drug formulation inevitably experiences leaching in the bloodstream and reduces its chance to cross the BBB. The recent accounts pointed out that less than 1 % of the nanocarriers were found to exhibit promising output in brain tumor research. At this conjecture, one can foresee that the next generation nano-scaffolds for BBB drug administration are required to be designed to withstand against concentration gradient, and they should also carry substantial amounts of therapeutic drugs for brain tumor suppression. To accomplish this task, designing a single polymer chain or unimolecular micelle nanoparticle (UMNp) platform is an elegant strategy. The unimolecular micelles, in principle, would be devoid of the destabilization against concentration gradient under in vivo conditions. In this case, the increase (or decrease) in the polymer concentration would simply vary the number of carriers in solutions, as in the case of natural proteins in aqueous medium. Our research efforts in IISER Pune revealed that star-polymer architectures with appropriate geometry could readily self-assembled them into UMNp (Pranav et al ACS Biomater Sci Eng, 2023, 9, 743−759). These UMNp was found to be breaching the BBB (Mehak et al. Nanoscale (2024), 16(46), 21582-21593) and also to delivery payloads to pancreatic tumors in mice xenografts (Shahid et al. Small (2025), e2503155, DOI: 10.1002/smll.202503155). These preliminary results support our idea that by appropriate biomaterial engineering of UMNp, could overcome the existing limitation in BBB breaching to deliver the therapeutic drugs to brain tumors. The present research proposal aims to design and develop new classes of charge-tunable and target-specific unimolecular micelle nanoplatform based on polycaprolactone biodegradable and self-immolative polymer (Shahidkhan et al. Adv Healthcare Mater, 2024, 13, 2304599), and investigate the role of BBB breaching in vivo, and demonstrate its drug delivering in brain tumor-bearing mice xenograft. As part of the project UMNp having cationic, anionic, neutral and zwitterionic charges will be tailor-made while maintaining their size less than 25 nm so that the UMNp could cross the BBB via amino-acid transporters and adsorptive transcytosis mechanism to deliver the payloads. The designed UMNp would be tested for cellular internalization both in mammalian cell lines, brain cancer cell lines, and neuronal cell line to understand their uptake and cytotoxicity. FDA approved drugs for brain tumor treatment such as Carmustine, Lomustine, Tovorafenib, Temozolomide, and Trametinib will be encapsulated in the UMNp platform for initial screening and the best candidate will be taken further for in vivo studies. Developing brain tumour xenograft model is a challenging task and this has to be learned and optimized to test the UMNp-drug nanoformations. This proposal will provide a systematic study to explore the biodegradable unimolecular micelles as the next generation nano-delivery platform that promises to circumvent the shortcomings of conventional nanoparticle in BBB research. The newly developed star-PCL polymer UMNp and their nano-assemblies are expected to make a significant contribution for long-term impact in BBB research and the treatment of brain tumor.