(4ap) Targeted Nanoparticles for Systemic Delivery of Therapeutic Agents to Solid Tumors in Animals and in Humans

Choi, C. H. J., California Institute of Technology
Davis, M. E., California Institute of Technology

Targeted, nanoparticle delivery of therapeutic molecules to solid tumors has the potential to provide safer and more effective therapies for cancer patients. Our research focuses on understanding how targeted nanoparticles can reach inside cancer cells of solid tumors from systemic administrations and how to optimize their ability to do so via their proper design.

PEGylated gold nanoparticles (PEG-AuNPs) are used as model nanoparticles to investigate the effects of physicochemical parameters (e.g., size, surface charge, and ligand density) on their pharmacokinetics and in vivo distribution, allowing for study at the whole body, tissue, and sub-cellular levels all from the same animal (1). When covalently attaching human transferrin (Tf), an endogenous protein commonly used as a ligand in active targeting therapies, on PEG-AuNPs with varying amounts spanning two orders of magnitude (while holding all other parameters constant), their intravenous injection into mice bearing Neuro2A tumors (mouse neuroblastoma cells over-expressing Tf receptors) reveals the key mechanism of active targeting in solid tumors. The pharmacokinetics and in vivo distribution (including particle content in the solid tumor) of the targeted nanoparticles are primarily a function of the colloidal properties of the nanoparticle and not the amount of Tf. However, the intracellular localization within cancer cells of the tumor is strongly a function of the Tf amount: It becomes more pronounced with increasing Tf amount only above the threshold Tf amount.

Results from mechanistic studies can provide insights for designing effective targeted nanoparticles for use in the clinic. In a recent Phase I clinical trial, melanoma patients received infusions of Tf-targeted, siRNA-containing nanoparticles. Using imaging techniques developed and verified in animal models, tumor biopsies obtained from several patients reveal intracellular accumulation of Tf-targeted nanoparticles within the melanoma cells (and not in adjacent tissues) in a dose dependent fashion. That is, more targeted nanoparticles reside inside the melanocytes within the tumor from patients who received higher doses of targeted nanoparticles (first reported for any targeted nanoparticles) (2). Thus, the patient data are largely consistent with the proposed mechanism of active targeting in solid tumors based on results from animal models.

References: (1) Choi, C.H.J., Alabi, C.A., Webster, P., Davis, M.E. Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles. Proc. Nat. Acad. Sci. USA, 107, 3, 1235-1240 (2010). (2) Davis, M.E., Zuckerman, J.E., Choi, C.H.J., Seligson, D., Tolcher, A., Alabi, C.A., Yen, Y., Heidel, J.D., Ribas, A. Evidence of RNAi in humans from systemically adminstered siRNA via targeted nanoparticles. Nature, 464, 7291, 1067-1070 (2010).