Russell Mumper, Ph.D.
Nanomedicine research in Mumper Lab includes: (1) lipid-based nanoparticles to address multi-drug resistance; (2) lipid-based nanoparticles as vaccine delivery systems; (3) cell-targeted drug-polymer conjugates.
LIPID-BASED NANOPARTICLES TO ADDRESS MULTI-DRUG RESISTANCE
The Mumper lab has been engineering solid-lipid nanoparticles and oil-filled (“BTM”) nanocapsules to deliver chemotherapeutics to overcome at least two ATP-dependent ABC- transport systems common in many human cancers. The nanoparticles/nanocapsules are developed and optimized by experimental design, combining Taguchi array and sequential simplex optimization (Figure 1). Both solid lipid NPs and BTM NPs overcome at least two ATP-dependent ABC-transport systems (MDR and MRP-associated) resulting in up to a 200- fold reduction in IC50 values in human lung, colon, ovarian, leukemia, breast, melanoma, and prostate cells. In-vivo evidence supporting that lipid-based NPs address MDR in human colon, leukemia, and ovarian xenograft models has been published. BTM NPs containing paclitaxel could completely inhibit the growth of multi-drug resistant NCI/ADR-RES ovarian tumors in athymic nude mice after intravenious injection. Ideally, the BTM NPs offer hope to cancer patients that have failed taxane or anthracycline-regimens due to ABC-transport- mediated resistance. Moreover, the inclusion of cell-specific targeting ligands on the nanocapsules may afford the targeting of metastatic resistant cancer cells.
LIPID-BASED NANOPARTICLES AS VACCINE DELIVERY SYSTEMS
The overall goal of this research project is to engineer a safe and effective nanoparticle-based vaccine delivery system to co-deliver multiple HIV proteins and adjuvant(s) as a prophylactic or therapeutic HIV vaccine. The Mumper lab has developed solid lipid nanoparticles and oil- filled nanocapsules and have demonstrated enhanced humoral and cellular immune responses to a number of different HIV antigens (Tat, Nef, Env, Gag p24, Gag p41) and model antigens, with co-delivery of selected adjuvants (i.e., CpG) that activate specific innate response pathways. Among other attributes, the NPs are antigen dose sparing, enhance MHC I presentation, and enhance the production of neutralizing antibodies. An optimized system has shown no toxicity in DCs with no induction of the inflammasome pathway or production of systemic cytokines after subcutaneous injection while still eliciting strong antigen-specific humoral and cellular immune responses. Current approaches are focused on engineering of lipid-based NPs for high affinity binding to multiple his-tagged HIV proteins. Figure 2 shows the uptake of protein-labeled BTM NPs in mouse dendritic cells.
CELL-TARGETED DRUG-POLYMER CONJUGATES
The Mumper lab is developing polymer conjugates of drugs and/or imaging agents to be utilized as improved cancer therapeutics or diagnostics. Project 1 (led by Saurabh Wadhwa) pertains to tumor-targeted anti-cancer conjugates of poly-l-glutamic acid (PGA) with D- penicillamine alone or in combination with Idarubicin for the intracellular elevation of reactive oxygen species and induction of apoptosis. D-penicillamine is an aminothiol that is cytotoxic to cancer cells via dose dependent generation of reactive oxygen species (ROS) by copper catalyzed oxidation. Fig. 3 shows the time-dependent uptake of PGA-D-pen conjugate in human leukemia cells. Current approaches are targeting dual-drug PGA conjugates to specific tumor cells. Project 2 (led by Dr. Anuraag Sarangi) pertains to targeted in-vivo imaging of cancer stem cells using a PGA- conjugate of a near- infrared (NIR) imaging agent. An antibody specific for cancer stem cells has been conjugated to PGA- NIR fluorescent dye.
Figure 4 shows uptake of the stem cell-targeted PGA conjugate in two cancer cell lines (HepG2 and HuH7) that express the stem cell marker in 65% and 80% of cells, respectively. Studies are planned to assess the ability of the targeted PGA-conjugate to image cancer stem cells in various mouse cancer models.