Research

Current Research Activity

Combinatorial-Designed Systemic Delivery Systems

Rationale designed drug delivery systems are necessary in order to address contemporary challenges, especially delivery of biological agents such as nucleic acid molecules. We are pursuing a combinatorial approach in designing novel nano-assemblies where each of the individual functional components are synthesized. Like Lego® pieces, these components come together to form nanoparticles in aqueous media. The formed particles are then evaluated in vitro and in vivo and specific structure-function relationship is obtained.

                        • Combinatorial approach in the design of multifunctional polymeric nano-delivery systems for cancer therapy. https://10.1039/c4tb01083c
                        • Redox-responsive targeted gelatin nanoparticles for delivery of combination wt-p53 expressing plasmid DNA and gemcitabine in the treatment of pancreatic cancer. https://10.1186/1471-2407-14-75
                        • Combinatorial-Designed Epidermal Growth Factor Receptor-Targeted Chitosan Nanoparticles for Encapsulation and Delivery of Lipid-Modified Platinum Derivatives in Wild-Type and Resistant Non-Small-Cell Lung Cancer Cells. https://10.1021/acs.molpharmaceut.5b00642
                        • Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer. https://10.1007/s11095-016-2016-z
                        • Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles. https://10.1038/mt.2015.225
                        • DHA-SBT-1214 taxoid nanoemulsion and anti-PD-L1 antibody combination therapy enhances antitumor efficacy in a syngeneic pancreatic adenocarcinoma model. https://10.1158/1535-7163.MCT-18-1046
                        • Improved anti-tumor efficacy of paclitaxel in combination with MicroRNA-125b-based tumor-associated macrophage repolarization in epithelial ovarian cancer. https://10.1016/j.canlet.2019.07.002

Trans-Nasal CNS Delivery

Delivery of disease modifying therapeutic to the brain for chronic diseases remains a critical challenge, especially with rising cases of age-related neurodegenerative diseases. In collaboration with Dr. Benjamin Bleier at Mass Eye and Ear, we have pioneered to use of Minimally Invasive Nasal Depot (MIND) approach for trans-nasal delivery. In combination with MIND, we have also investigated various implantable delivery modalities, including osmotic implants for sustained drug release over a longer period of time.

Oral Delivery Systems

The oral route of administration remains an important method of drug delivery for both local and systemic therapies. In addition to small molecule oral delivery to improve systemic bioavailability, we are focused on oral delivery of nucleic acid molecules for therapeutic (e.g., inflammatory bowel disease, celiac disease, etc) and vaccination purposes. Using multicompartmental formulations, we have engineered oral nucleic acid formulations for regiospecific delivery in different parts of the gastro-intestinal tract as well as targeting specific cell populations.

 

 

 

 

 

 

 

 

Reprogramming Immune Cells

Genetic reprogramming of myeloid cells using siRNA and microRNA can afford specific phenotypes that have therapeutic applications in cancer, inflammatory diseases, and fibrotic diseases. We have utilized the inherent tropism of peritoneal macrophages to various disease sites in the body by reprogramming these cells into a “healing” phenotype.

                        • Macrophage-targeted delivery systems for nucleic acid therapy of inflammatory diseases.  https://10.1016/j.jconrel.2014.04.021
                        • Modulation of Macrophage Functional Polarity towards Anti-Inflammatory Phenotype with Plasmid DNA Delivery in CD44 Targeting Hyaluronic Acid Nanoparticles. https://10.1038/srep16632
                        • Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis. https://10.1016/j.biomaterials.2015.05.028
                        • MicroRNA-223 Induced Repolarization of Peritoneal Macrophages Using CD44 Targeting Hyaluronic Acid Nanoparticles for Anti-Inflammatory Effects. https://10.1371/journal.pone.0152024
                        • Modification of tumor cell exosome content by transfection with wt-p53 and microRNA-125b expressing plasmid DNA and its effect on macrophage polarization. https://10.1038/oncsis.2016.52
                        • Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems. https://10.1038/srep30110 

Mitochondrial Nanomedicines

More than the powerhouse of the cells, mitochondria function and dysfunction is critical to cellular survival in cancer and neurodegenerative disease/aging. We are investigating nano-therapeutic approaches to modulate mitochondrial networks and other dynamic intracellular events in the context of these diseases using nanotechnology based delivery systems.

Nanomedicine Affecting Intercellular Communications

Intercellular communication through extracellular vesicles (EVs) and tunneling nanotubes (TNTs) is a critical cellular requirement in both healthy and diseased tissues. In the context of diseases, such as cancer, communication between the tumor cells and other cells in the tumor microenvironment is critical to development of metastasis, immunosuppression, and therapeutic resistance. We are investigating different methods to affect intercellular communications using nanoparticle-encapsulated therapeutics.

 

Vaccine Adjuvants and Delivery Systems

In collaboration with Dr. Kenneth Anderson at Dana Farber, we are investigating multiple myeloma peptide (e.g., BCMA) and mRNA vaccination strategies developed using biodegradable polymeric and lipid formulations. Additionally, we are collaborating with pharmaceutical companies to develop novel adjuvants and immune potentiators for subunit and mRNA vaccines.

                        • A Self-Emulsified Adjuvant System Containing the Immune Potentiator Alpha Tocopherol Induces Higher Neutralizing Antibody Responses than a Squalene-Only Emulsion When Evaluated with a Recombinant Cytomegalovirus (CMV) Pentamer Antigen in Mice. https://doi.org/10.3390/pharmaceutics15010238
                        • Formulation design, optimization and in vivo evaluations of an alpha-tocopherol-containing self-emulsified adjuvant system using inactivated influenza vaccine. Journal of Controlled Release, 316, 12-21. https://10.1016/j.jconrel.2019.10.042
                        • Formulation design, optimization and in vivo evaluations of an alpha-tocopherol-containing self-emulsified adjuvant system using inactivated influenza vaccine. https://10.1016/j.jconrel.2019.10.042
                        • The droplet size of emulsion adjuvants has significant impact on their potency, due to differences in immune cell-recruitment and activation. https://10.1038/s41598-019-47885-z