Nanomedicines and Translational Research Laboratory

We are working on the site-specific delivery of oligonucleotides and microRNA to hepatocytes or hepatic stellate cells for treatment of hepatitis and liver fibrosis. We have previously shown that the conjugation of siRNA to mannose-6-phosphate- PEG (M6P-PEG) can significantly enhance its delivery to hepatic stellate cells and this M6P-PEG-siRNA has the potential to treat liver fibrosis by inhibiting excess of collagen synthesis (Zhu et al, Bioconjug Chem, 2010, 21: 2119-2127).

We are developing several novel amphiphilic copolymers and lipopolymers for use as micellar delivery of small molecular weight hydrophobic anti-cancer drugs (Danquah et al, J. Polym. Sci.A Polym. Chem. 2013, 51: 347–362, Danquah et al, Biomaterials. 2010, 31:2358-70. and Li et al., Biomacromolecules. 2010, 11:2610-20).

Our research in pancreatic cancer is based upon the hypothesis that simultaneous delivery of anti-cancer molecule gemcitabine and a suitable miRNA could render a more effective treatment strategy for advanced pancreatic cancer. miRNAs are the key regulators of cancer stem cells (CSCs) which play a central role in inducing chemoresistance and implying metastatic potential to the pancreatic tumor cells (Singh S., et al., Cancer Lett. 2013, 334:211-20). To meet this objective, we have synthesized gemcitabine conjugated copolymer which undergoes self-assembly into micelles. These micelles provided high drug payload, sustained drug release, prevented its plasma degradation and significantly inhibited tumor growth compared to free drug when injected intravenously into pancreatic tumor bearing NSG mice (Chitkara D., et al., Bioconjug. Chem. 2013, DOI: 10.1021/bc400032x). To identify miRNAs involved in chemoresistance, a series of dysregulated miRNAs were identified from the CSCs isolated from gemcitabine resistant MIA PaCa-2R cells and human pancreatic cancer tissues. Then, gemcitabine conjugated copolymer and polymer for complex formation with miR-205 was used to establish the proof-of-concept. Indeed, we observed an increase in chemosensitivity of pancreatic cancer cells and a significant reduction in their invasive ability. Studies are in progress to further optimize the combination formulation, study their spatio-temporal kinetics and determine efficacy in orthotopic pancreatic tumor model.

We are developing targeted system for miRNA site-specific delivery for treating various liver diseases including cholestasis induced fibrosis, alcohol associated liver disease, and non-alcoholic fatty liver disease we are working on miRNA therapy for treating type I diabetes. We have shown that inhibition of Hh pathway and restoration of miR-29b1 using nanoparticles have the potential to act synergistically in treating cholestasis-induced liver fibrosis in mice. We are also working on the design/construction of plasmid and adenovirus-based shRNA for treating these diseases.

Hedgehog signaling is required for endodermal commitment and hepatogenesis after liver injury or ischemia reperfusion (I/R). We have determined the expression pattern of Hh signaling and its role in liver injury following I/R using Hh antagonists such as cyclopamine (CYA) and vismodegib (GDC 0449) (Pratap A., et al., Mol. Pharm. 8: 958–968, Pratap A., et al., J. Drug Target. 2012, 20:770-82). We plan to further study this approach by selectively targeting these drugs to the liver using mannose-6-phosphate ligand containing nanoparticles.

Medulloblastoma is an aggressive primary brain tumor in children and is classified into SHH, WNT, Group 3, and Group 4 by WHO where, each group shows different origins, pathogenesis, and therapeutic targets. Treatment of medulloblastoma is challenging due to diverse genetic make-up, chemoresistance and inefficient drug transport across the blood brain barrier (BBB). Repeated use of hedgehog inhibitors develops chemoresistance due to mutations in smoothened (SMO) (Kumar, V.,2017, Trends in pharmacological sciences, 38(12), 1061-1084). We aimed to overcome these problems by modulating GLI transcription using BRD4 inhibitor JQ1. We are also working on circumventing BBB for the treatment of medulloblastoma. Our ApoE conjugated JQ1 loaded NPs showed the potential to treat Group 3 and SHH driven MB in mice (Wang, Q., Journal of Controlled Release, 323, 463-474). Moreover, in continuation we studied that Hh inhibitor MDB5 and BRD4/PI3K dual inhibitor SF2523 synergistically inhibited the proliferation of DAOY and HD-MB03 cells when used in combination (Kumar, V., 2021. Biomaterials, 278, 121138). We are further in the progress to synthesize MDB5 and SF2523 analogs to improve their efficacy in therapy against medulloblastoma.

Our research on AML aims to develop nanoparticles that can simultaneously deliver an anti-cancer drug, venetoclax and a miRNA to overcome the chemoresistance and improve the therapeutic effect. AML is one of the most common and lethal hematologic malignancies in older adults. Venetoclax in combination with other agents was approved by FDA to treat older patients unfit for intensive chemotherapy, however, it will induce chemoresistance in patients. We identified miRNAs that are related to the MAPK or JAK/STAT3 signaling pathways, and showed that these miRNAs could overcome the chemoresistance and synergize with venetoclax in AML cells and animal model. To achieve the co-delivery of venetoclax and miRNA, a mixed micelle system designed by our lab was applied. We assumed that this delivery system would improve the stability of miRNA and enable a more efficient drug delivery into leukemic blasts.

Our research in inhalational drug delivery is based upon an industrial project from Genentech, Inc. Our main objective is to examine drug absorption, drug dissolution, drug permeability across bronchial respiratory epithelial cells as an in vitro model for aerosol deposition and transport across epithelia that uses particle deposition may be a good predictor of and help understand in vivo drug disposition. To achieve aerosol disposition directly on epithelial cells, we have modified the Next Generation Impactor on stages 3, 5 and 7 to allow particle deposition directly on cells and determined the in vitro deposition characteristics using modified NGI. (Kumar V., International Journal of Pharmaceutics Volume 583, 15 June 2020, 119404). Our next step is to use this approach and develop an in-vivo model for the treatment of COPD/asthma. We will use combination of bronchodilators or corticosteroids and formulate a dry powder inhalation. This will be examined for various in-vitro and in-vivo studies.