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DTSTART;TZID="Pacific Time (US & Canada)":20261001T150000
DTEND;TZID="Pacific Time (US & Canada)":20261001T160000
SUMMARY:Chemistry Doctoral Final Exam – Vikrantvir Jain
LOCATION:Online
DESCRIPTION:Speaker: Vikrantvir Jain\n\nGroup: Dr. Anjali Sharma\n\nTitle: Rational Design and Engineering of Functional Dendrimers for Targeted Drug Delivery\n\nAbstract: Dendrimers are highly tunable nanomaterials whose well-defined architecture and multivalent surfaces enable precise control over drug conjugation, cellular targeting, subcellular localization, and surface chemistry. This dissertation explores the rational engineering of dendrimer platforms for targeted drug delivery, with a focus on hepatocellular carcinoma (HCC) and the influence of dendrimer structure on biological behavior.\n\nFirst, a galactose-functionalized dendrimer (Gal24) was developed as a hepatocyte-targeted carrier for silibinin, whose therapeutic application is limited by poor aqueous solubility and bioavailability. Conjugation of silibinin to Gal24 (Gal24-Sil) improved its solubility and enhanced anticancer activity in HepG2 and Hep3B cells. Gal24-Sil increased oxidative stress, disrupted mitochondrial membrane potential, promoted apoptosis and DNA damage, and reduced cellular proliferation, supporting the potential of Gal24 for targeted HCC therapy.\n\nBuilding on this strategy, a dual-targeted dendrimer incorporating triphenylphosphonium (TPP) and sorafenib (Gal24-TPP-Sora) was developed to combine hepatocyte targeting with mitochondrial-directed delivery. Sorafenib is a multikinase inhibitor used in the treatment of advanced HCC; however, its therapeutic efficacy can be limited by poor aqueous solubility, systemic exposure, and associated adverse effects. Because mitochondrial dysfunction and altered mitochondrial metabolism are important features of cancer cells, TPP was incorporated as a mitochondria-targeting moiety to promote subcellular localization of the dendrimer therapeutic within mitochondria. Gal24-TPP-Sora showed favorable stability and biocompatibility and enhanced mitochondrial localization compared with the non-TPP conjugate. Mitochondrial targeting increased oxidative stress, ATP depletion, membrane depolarization, apoptotic signaling, and DNA damage while reducing cell viability, proliferation, clonogenic growth, and migration.\n\nFinally, the influence of dendrimer surface chemistry on biological behavior was investigated using a surface-programmable PEG-functionalized dendrimer platform. Sequential click reactions generated a second-generation scaffold bearing 45 peripheral reactive groups. PEG-linked amine, carboxyl, and hydroxyl functionalities produced cationic D-NH₂, anionic D-COOH, and near-neutral D-OH dendrimers with distinct physicochemical properties. Cy5-labeled analogues were prepared for evaluation of cellular uptake and in vivo biodistribution.\n\nCollectively, this dissertation demonstrates the versatility of dendrimers for therapeutic conjugation, receptor-mediated targeting, subcellular targeting, and controlled surface modification. These studies provide a framework for rationally tuning dendrimer properties toward more selective and effective drug-delivery systems.
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