Nanoparticles for the Delivery of Diagnostic and Therapeutic Agents

Dr. Xiuling Lu is leading the research effort in these areas.  This includes:

1. Dual Therapeutic/Imaging Nanovectors for Assessing Enhanced Anti‐Tumor Activity of Chemotherapeutic Agents: Many studies now suggest that physiologic barriers to drug delivery to tumors represent a major mechanism of drug resistance to anti‐tumor agents. Physiologic abnormalities in tumors include increased interstitial fluid volume and pressure, decreased oncotic gradients and increased interstitial deposition of high molecular weight proteins such collagen. All of these factors decreased convectional delivery of molecules and nano-particles into tumor inter-stitial space and to tumor cells therein. Previous pre-clinical studies and clinical trials by our collaborator, Dr. John Rinehart, demonstrated that dexamethasone (DEX) administered prior to chemo‐therapy increases the effectiveness of chemotherapy and decreases toxicity. The molecular mechanisms mediating these observations may involve DEX downregulation of NF-κB induced pro-oncogenic signals and pro-inflammatory cytokines. However, systemic DEX administration induces clinical toxicities, most notably immunosuppression by T-cell depletion and inhibition.

Our goal is to enhance DEX delivery into tumors and systemic regions harboring macrophage populations while minimizing T-cell toxicity and enhancing chemotherapy uptake into tumors. This can be achieved with nanoparticle-DEX palmitate formulations that exploit passive accumulation in tumors and the reticuloendothelial system (RES) via the enhanced vascular permeability and retention (EPR) effect and the natural clearance mechanisms for pegylated nanoparticles. Studies in animal models that suggest that failure of drug delivery to the tumor interstitial space is a major mechanism of drug resistance have not been confirmed in patients with cancer. Tissue pharmacokinetics in patients is not yet practical in either the setting of clinical research or clinical practice. To overcome this limitation, we are preparing dual therapeutic/imaging nanovectors by entrapping Dex palmitate in nanoparticles that also have Gd or 64Cu bound to their surfaces. These nanoparticles will allow for the examination of this important hypothesis in clinical medicine by Magnetic Resonance Imaging or Positron Emission Tomography.

2. Neutron-Activatable Nanoparticles for Tarqeted Radionuclide Therapy of Tumors: The goal of this project is to develop a neutron-activatable biologically targeted radiotherapeutic nanoparticle (NP) for the treatment of peritoneal metastases in ovarian cancer, the main cause for morbidity and mortality of this disease. We hypothesize that administering these NPs intraperitoneally can deliver efficacious radiation doses specifically to ovarian tumors. The novelty of this agent is that it is produced by the neutron activation of stable Holmium atoms (165Ho) in the NP matrix. The radionuclide produced by neutron irradiation of these NPs, 166Ho, decays by the emission of beta particles capable of delivering sufficient absorbed radiation doses to targeted cells. The surface of these NPs can be functionalized targeting ligand directed against ovarian tumors. Retention of the NPs in the peritoneal cavity can be determined using SPECT/CT imaging as 166Ho also emits 81 keV photons. The process of rendering the NPs radioactive after they have been prepared allows their preparation in compliance with FDA current Good Manufacturing Practices without having to handle hazardous quantities of radioactivity, and permits flexibility in terms of adding different targeting ligands.