Molecularly-Targeted Gold-Based Nanoparticles forCancer Imaging and Near-Infrared Photothermal Therapy

[摘要] This thesis advances the use of nanopartic1es as multifunctional agents formolecularly-targeted cancer imaging and photothermal therapy. Cancer mortality hasremained relatively unchanged for several decades, indicating a significant need forimprovements in care. Researchers are evaluating strategies incorporating nanopartic1esas exogenous energy absorbers to deliver heat capable of inducing cell death selectivelyto tumors, sparing normal tissue. Molecular targeting of nanopartic1es is predicted toimprove photothermal therapy by enhancing tumor retention. This hypothesis isevaluated with two types of nanopartic1es.The nanopartic1es utilized, silica-gold nanoshells and gold-gold sulfidenanopartic1es, can convert light energy into heat to damage cancerous cells. For in vivoapplications nanopartic1es are usually coated with poly(ethylene glycol) (PEG) toincrease blood circulation time. Here, heterobifunctional PEG links nanopartic1es totargeting agents (antibodies and growth factors) to provide cell-specific binding. Thisapproach is evaluated through a series of experiments.In vitro, antibody-coated nanopartic1es can bind breast carcinoma cells expressingthe targeted receptor and act as contrast agents for multiphoton microscopy prior toinducing cell death via photoablation. Furthermore, antibody-coated nanopartic1es canbind tissue ex vivo at levels corresponding to receptor expression, suggesting they shouldbind their target even in the complex biological milieu. This is evaluated by comparingthe accumulation of antibody-coated and PEG-coated nanoparticles in subcutaneousglioma tumors in mice. Contrary to expectations, antibody targeting did not yield morenanoparticles within tumors. Nevertheless, these studies established the sensitivity ofglioma to photothermal therapy; mice treated with PEG-coated nanoshells experienced57% complete tumor regression versus no regression in control mice. Subsequentexperiments employed intracranial tumors to better mimic the clinical setting. Thesetumors are highly vascularized, so nanoparticles were addressed toward receptorsabundantly expressed on tumor vessels using growth factors as a novel targeting strategy.Photothermal therapy with these vascular-targeted nanoparticles disrupted tumor vessels,leading to a 2.2-fold prolongation of median survival versus control mice.This work confirms that nanoparticle surface coating can affect biodistributionand therapeutic efficacy. With continued optimization of molecular targeting strategies,imaging and photothermal therapy mediated by nanoshells and gold-gold sulfidenanoparticles may offer an effective alternative to conventional cancer management.

[发布机构] Rice University

[效力级别] Biomedical