Photodestruction of Ovarian Cancer: ErbB3 Targeted Apta*

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DESCRIPTION (provided by applicant): PhotoSensitizer Nanoparticle Aptamer Conjugate Therapy (SNACT) is an application of targeted photodynamic therapy (PDT) involving the administration of a photosensitizer (PS) encapsulated in aptamer-bound nanoparticles (NP), followed by light activation of the PhotoSensitizer Nanoparticle Aptamer Conjugate (SNAC). The systemic toxicity associated with radio- and chemo-conjugates may thus be significantly reduced in SNACT due to the dual selectivity provided by the target localizing ability of the aptamer and the spatial control of illumination. The goal of this research is to develop SNACT targeted to ErbB3 for the destruction of minimal residual ovarian cancer (OVCA). The choice of ErbB3 as the molecular target is based on: (I) ErbB3 is overexpressed in many cancers, including OVCA, (ii) ErbB3 works in concert with ErbB1 and ErbB2; inactivation of ErbB3 could, in principle, inhibit the ErbB1 and ErbB2 pathways that are stimulated by heterodimerization with ErbB1, and (iii) the sequence for aptamer A30 targeted to ErbB3 is published, thus making the synthesis possible. Aptamers have advantages over targeting agents such as monoclonal antibodies; these include higher specificity, relatively small size, ease of synthesis, and absence of immunogenicity. The essential components of the projects are: (i) synthesis and stabilization of SNACs, (ii) demonstration of the selective phototoxicity of SNACs in vitro and in vivo, and (iii) development of optical imaging techniques with quantum dots to serve as reporters of therapeutic efficacy and of dosimetry parameters. The study is a collaboration of three investigators, each with expertise in one of the three components, and will be, to our knowledge, the first using aptamer-based targeted PDT; this will provide a model for a highly selective, externally activated therapy, an approach that can be adapted for other targets as reagents become available. The proposed aptamer A30 recognizes ErbB3, and the PS is benzoporphyrin derivative monoacid (BPD) encapsulated in PLGA. BPD is approved as the first-line therapy for age-related macular degeneration and PLGA is FDA-approved for a few clinical trials. The SNACs will be characterized for photochemical and biochemical properties and interactions with target and non-target cells. In vivo, SNACT will be investigated in xenograft models of human OVCA with different levels of ErbB3 expression in short-term tumor reduction and long-term survival studies. The envisioned studies provide nanovector-based, highly selective, externally activated multifunctional therapeutics with optical reporters of efficacy. These studies will provide a new approach for the treatment of a disease with dismal survival statistics and will address a serious public health concern for women; the proposed in vivo optical imaging studies, if successful, would provide patient-customized therapy.