Image-guided therapeutic delivery to solid tumors with HPMA copolymers

Treatment of cancer is a significant challenge due to the heterogeneity of both tumors and patients. This realization has led to the field of personalized medicine in which patients can be selected for a therapy based on the specific needs. One potential area for personalized medicine is utilizing medical imaging to predict and monitor the therapeutic efficacy and safety of a particular targeted therapy. Development of image- guided therapeutics based on macromolecular carriers such as N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers is advantageous because they are water-soluble and can contain a wide range of comonomers to confer multifunctionality. HPMA copolymers are water-soluble nano-sized constructs which can improve the delivery of therapeutics to tumors by passive targeting via the enhanced permeability and retention effect. They can also increase tumor uptake using targeting ligands that are conjugated to the backbone of the copolymer. This dissertation focuses on the development of targeted HPMA copolymers for delivery of both therapeutics and imaging agents to solid tumors. Barriers to delivery of these constructs were addressed in various tumor models. In pancreatic tumors, the desmoplastic response, or dense extracellular matrix prevents delivery of drugs and macromolecules alike. Treating hyaluronic acid, a component of desmoplasia, with hyaluronidase allowed for increased delivery of HPMA copolymers based on HER2 and αvβ3 integrin targeting strategies for HPMA copolymers. Based on the selection of HER2 as a viable tumor targeting strategy, iv an image-guided drug delivery (IGDD) system was synthesized, characterized and evaluated in vitro in pancreatic tumor cell lines. In vitro results suggest that the designed construct was potentially capable of targeting, binding, treating and imaging pancreatic tumors for an IGDD approach. Lastly, a study was conducted in a prostate tumor model for localized tumor delivery of a 90Y radiolabeled HPMA copolymers for radiotherapy. Imaging tumor localization and biodistribution was accomplished using an equivalent 111In radiolabeled HPMA copolymer. Targeting and efficacy were accomplished via gold nanorod (GNR)-mediated hyperthermia and demonstrated antitumor efficacy in the prostate tumor mouse model. The combined studies demonstrate the current progress for development of an HPMA copolymer conjugate for image-guided therapy of solid tumors.