The overall purpose of this study is the development of multifunctional core-shell Layered Double Hydroxide Nanoparticle (LDHN)-based nanovectors for the targeted ablation and imaging of advanced cancer disease. This novel, non-polymeric platform will be designed to possess the following features: 1) metallic or quantum dot core/LDH ceramic shell for imaging the delivered nanovector and for ablation of cancer cells, 2) intercalated apoptosis-inducing chemotherapeutic drugs (genotoxins) or siRNA within the ceramic LDH shell, and 3) functionalized outermost surfaces for targeting cancer cells. It is hypothesized that the incorporation of targeting, imaging, and ablation/chemotherapeutic capabilities on a single biocompatible nanoscale delivery platform is a powerful approach for prostate cancer therapy, with direct application in the treatment of residual and metastatic disease. Inorganic ceramics are attractive materials for biological applications due to their inherent biocompatibility and stability in physiological environments. LDH nanoparticles are a class of inorganic ceramics that have a general formula of M2+1-xM3+x(OH)2.(An-)x/n.mH2O, where M2+ is a divalent cation, M3+ is a trivalent cation, and An- is the interlayer anion of valence n. Their unique structure readily allows the intercalation of a variety of anionic apoptosis-inducing therapeutics via ion exchange. In the present application, we will employ core-shell LDH-based nanovectors for the targeted delivery of anionic therapeutics (conjugated adriamycin and anti-bcl-2 siRNA) to prostate cancer cells. The core will consist of fluorescent semiconductor quantum dots and silver nanorods for fluorescent and near-infra red (NIR) imaging, respectively. The Ag core-LDH shell structure will have an additional attribute of hyperthermic ablation of cancer cells through the use of the longitudinal plasmon resonance mode. The Prostate-Specific Membrane Antigen (PSMA) is a cell-surface receptor over-expressed in all stages of prostate cancer disease and is therefore appropriate for targeting malignant prostate cancer cells. Bimolecular (peptides and antibodies) targeting the PSMA will be conjugated to surface-activated LDHNs in order to specifically target malignant prostate cells. The platform will be evaluated in vitro for the targeted delivery of the intercalated drugs in LDHN to prostate cancer cell lines and non-malignant cells.
Our specific aims for this endeavor are: 1: Synthesis and characterization of core-shell layered double hydroxide nanoparticles (LDHN) with controlled size and narrow size distribution; with cores of semiconductor quantum dots and silver nanorods for simultaneous imaging and therapy, 2. Surface-activation of LDHN, and conjugation of poly(ethylene glycol) (PEG) and Prostate-Targeting Biomolecules (PTBs) on LDHNs, 3) Intercalation of chemotherapeutic molecules within the LDHN structure, and 3. In vitro evaluation to determine the uptake, intracellular localization, efficacy, selectivity, mechanisms of ablation, and biocompatibility of PTB- LDHN nanovectors. The team of investigators brings together complementary experience in ceramic materials engineering, polymer and surface chemistry, molecular and cellular biology, and molecular therapeutics and engineering, for the design, generation, characterization and in vitro evaluation of multifunctional core-shell LDHN nanovectors as prostate cancer therapeutics. Successful completion of the proposed research will result in novel targeted therapeutics with built-in redundancy and imaging for advanced prostate cancer disease, and can serve as a general platform for therapeutic delivery and imaging of other metastatic carcinomas. ? ? Project Narrative: The goal of our collaborative research is to develop targeted multifunctional core-shell Layered Double Hydroxide (LDH) nanovectors for the targeted destruction and optical imaging of advanced cancer disease. Towards that end, we carry out the design, synthesis, and characterization of core-shell LDH nanoparticles. While the core will consist of fluorescent quantum dots or near infra red (NIR) active silver (Ag) nanorods, the shell of layered double metal hydroxides will have apoptosis-inducing genotoxins and siRNA that are intercalated within its structure. In addition to apoptosis-inducing molecules, cancer cell destruction will also be facilitated by hyperthermic ablation in the case of Ag-nanorod based core-shell nanoparticles, resulting in dual therapy. Cancer cell targeting biomolecules (peptides and antibodies) will be conjugated to the outermost layer of the LDH shell leading to multifunctional nanovectors that possess targeting, imaging, and dual therapeutic capabilities (ablation and chemotherapy) on a single delivery platform. Extensive in vitro evaluation of cytotoxicity, mechanisms of cell death, and selectivity of the core-shell LDH nanovectors will be carried out using human prostate cancer cell lines and untransformed prostate epithelial cells in order to evaluate the efficacy of these novel nanovectors. ? ? ?
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