Multifunctional Nanoparticles for Cancer Therapy

One of the major challenges of today’s medicine in cancer therapy is to deliver drugs specifically to defected cells/tissues. Drugs encapsulated in nanoparticles have the potential to achieve this goal since nanoparticles can across physiological barriers and tissues, passively deliver reagents to tumor sites by EPR effect, and also be served as a targetable form to enhance cell specificity. Recent discoveries based on inorganic nanoparticles have opened up exciting and new possibilities in this field. The objective of this study will include: (1) to develop one as simple as possible preparation procedure for the introduction of multi-functional groups onto nanoparticle surface, (2) to minimize nanoparticles aggregation and nonspecific binding by introducing adequate functional groups, and (3) to have high drug loading efficiency in the formulation as well as great drug efficacy in vivo. We will develop a multifunctionalized nanoparticle formulation, which contains 4 parts – (1) the stable nanoparticles; (2) a drug to be delivered; (3) a PEG moiety to modulate the PK properties; and (4) a fluorescence marker that can help localizing the particles, both in cellular and animal studies. The completion of this project may potentially lead us to the development of a new ODN-loaded delivery system with widespread clinical applications in the treatment of cancers. This is a 3 year project and the Specific Aims are: Year 1 (Aim1) Aim 1.1 To prepare and characterize tri-functionalized silica-based nanoparticles Aim 1.2 To design and evaluate strategies for optimizing incorporation of antisense/chemotherapeutic agent, PEG, and a fluorescence marker into tri-functionalized nanoparticles Year 2 (Aim2) Aim 2 To evaluate in vitro properties of AsODN/drug -loaded nanoparticles in tumor cells (cellular uptake, intracellular trafficking and localization, cytotoxicity, protein down-regulation, and apoptosis) Year 3 (Aim3) Aim 3 To evaluate the in vivo properties of these PEGylated drug-loaded nanoparticles, including the pharmacokinetic parameters, biocompatibility, in vivo biodistribution and tumor localization, and antitumor efficacy in murine xenograft models