(184b) Alternating Copolymer Structures For Targeted In Vivo Imaging And Therapy In Cancer | AIChE

(184b) Alternating Copolymer Structures For Targeted In Vivo Imaging And Therapy In Cancer

Authors 

Miller, M. T. - Presenter, Massachusetts Institute of Technology
Brower, K. P. - Presenter, Massachusetts Institute of Technology
Zhou, J. - Presenter, Massachusetts Institute of Technology
Colton, C. K. - Presenter, Massachusetts Institute of Technology
Pandey, M. K. - Presenter, University of Massachusetts
Tyagi, R. - Presenter, University of Massachusetts
Watterson, A. C. - Presenter, University of Massachusetts


The biggest single problem that prevents a dramatic reduction in the mortality due to cancer is the limitation on current medical imaging techniques, computed tomography (CT) and magnetic resonance imaging (MRI), that provide detailed anatomical snapshots of the body but fail to provide accurate, basic information necessary to manage the patient's disease optimally. The limitations are manifested in several ways: (1) Small primary tumors go undetected. (2) Metastatic disease is grossly underdiagnosed. (3) Treatment response to therapy is poorly measured. A related problem in cancer therapy is the lack of selectivity of chemotherapeutic agents that are toxic to proliferating cells. The resulting side effects limit dosing and prevent use altogether.

A solution to this problem is to selectively carry contrast agents and drugs into cancer cells so as to enhance uptake and selectivity. We have developed a highly adaptable amphiphilic alternating copolymer system that self-assembles into micelles for in vivo imaging agent and therapeutic delivery applications in cancer. These unique alternating copolymer micelle nanoparticles were designed as delivery vehicles targeted to human cancer cells expressing the underglycosylated mucin-1 antigen, which is found on almost all epithelial cell adenocarcinomas, by use of the peptide EPPT. The synthetic scheme includes the enzymatic polymerization of multifunctional linker molecules (dimethyl 5-hydroxyisopthalate) with poly(ethylene glycol). This chemo-enzymatic synthesis is much faster and more convenient than an entirely chemical synthesis. Polymerization studies are underway to control molecular weight and scale up the enzymatic reaction while trying to better understand the importance of mass transfer limitations during this reaction. Subsequent synthetic steps have been developed to attach peptides (for targeting), perfluorocarbons (19F MR imaging), fluorescent dyes (NIRF imaging), and radioiodine (nuclear imaging and radioimmunotherapy) to the backbone. Attachment of hydrocarbon or perfluorocarbon sidechains provides amphiphilicity to produce the multimodal self-assembling micelles. Additionally, an encapsulation procedure for the chemotherapeutic agent, doxorubicin, has been established. Development of the synthetic schemes has been coupled with in vitro toxicity experiments using various cell viability assays to minimize the toxic effect of these copolymer structures. Other in vitro studies are underway that include the investigation of cellular uptake by I125 radioactive analysis and fluorescence confocal microscopy and the exploration of the treatment of cancer cells by delivery of encapsulated doxorubicin. Theoretical models of polyvalent binding are employed to predict the results of the in vitro uptake experiments.