Dr. Dhar’s team develop macromolecular technologies, which are engineered to nanoparticles and targeted to the mitochondria of cells and they have chemistry-based programs on combination therapy for various cancer. Some of these projects are discussed below.
1. Engineering of Biodegradable Nanoparticles for Mitochondrial Trafficking of Therapeutics and Targeted NPs for Brain Tumor: Mitochondria, the so-called "energy factory of cells” not only produce energy but also contribute immensely in cellular mortality management. Mitochondrial dysfunctions result in various diseases including but not limited to cancer, atherosclerosis, and neurodegenerative diseases. Directing therapeutics to the mitochondria is difficult due to the complex nature of mitochondria. Their lab recently optimized properties of a biodegradable tunable nano delivery vehicle for efficacious mitochondrial delivery of therapeutics. This work was applied to cancer, neurodegenerative diseases, and obesity. They also discovered that suitably optimized mitochondria targeted NPs could distribute in the white matter of the brain. Thus, they are utilizing this NP system to deliver therapeutics to the brain for common solid tumors which show central nervous system metastasis and for glioblastoma multiforme.
2. Nano Engineering of Immune Cells for Cancer Immunotherapy: Aggressive cancers represent the focus of increasing interest at the clinical, biological, and epidemiological level. One of the effective methods to tackle metastatic cancers will be to engage our immune system. Dendritic cells (DCs) are the most potent antigen-presenting cells, which can uniquely activate both the cognate and innate arms of the immune system. Our research involves ex vivo engineering of DCs using biodegradable NPs to produce interferon-gamma (IFN-), an important cytokine considered as a product of T and natural killer cells, for increased T-cell activity. We use a unique combination of mitochondrial stimulation of cancer cells using targeted NPs and light to produce TAAs.
3. Mitochondrial Genome as a Target for Chemo-resistant Cancers: Mitochondrial DNA (mtDNA) plays significant roles in cell death and progress of various cancers to the metastatic stage. Thus, targeting mtDNA could lead to novel and effective therapies for aggressive cancer. This can be particularly important for cisplatin-based chemotherapy. Cisplatin is a widely used and FDA approved chemotherapeutic agent which is highly effective against several cancers. Therapeutic action of cisplatin relies on its ability to form interstrand and intrastrand nuclear DNA (nDNA) cross-links. Resistance to cisplatin can result from several mechanisms, including accelerated DNA repair by nucleotide excision repair (NER) machinery. The lack of NER in the mitochondria and enhanced mtDNA mutation in aggressive cancers gives a strong rationale in directing cisplatin inside the mitochondrial matrix. They are developing such technologies for nanoparticle mediated cisplatin delivery in the form of activable prodrugs to the mitochondria of different cancer cells to attack mitochondrial genome, which lack such repair machinery for chemo-resistant cancers.
4. Overcoming Resistance by Attacking Different Pathways: Cancer-related mitochondrial alterations such as defective oxidative phosphorylation, mitochondrial biogenesis, down-regulation of ATP synthase, and mitochondrial reactive oxygen species provide unique targets for selective treatment modalities. Thus, engineering of small molecules known to work at different targets inside the mitochondria or developments of such molecule payload containing mitochondria-targeted NPs has the potential to provide tumor-specific anticancer agents. They are involved in the development of mitochondria-targeted prodrugs that can be locally activated at the target sites: some examples are dichloroacetic acid, 3-bromopyruvate, Bcl2 inhibitors. Dr. Dhar’s group is actively developing several prodrug approaches to target these pathways.