Photodynamic therapy (PDT) is an effective local therapy based on a tumor localizing photosensitizer (PS) activated by light directed at the treatment site. Current photosensitizers demonstrate some tumor selectivity, and light can be delivered almost anywhere in the body by thin, flexible optical fibers. However, for small, bulky, or buried lesions, it may be difficult to detect the malignancies and/or to properly place the optical fibers to illuminate the full extent of the tumor. We hypothesize development of a new approach to guided therapy utilizing highly selective optical and PET imaging, allowing tumor visualization, image-guided placement of the optical fibers, and subsequent photodynamic destruction of the lesions. Our project involves synthesis, characterization and pre-clinical validation of novel conjugates of tumor- avid PS carrying unique, near infrared (NIR) fluorescent dyes and the long half-life PET agent 124I. Preliminary work shows these conjugates provide very high in vivo tumor selectivity, while maintaining. We will determine if the conjugate selectivity can be further enhanced by linking tumor- or neovasculature-selective molecular targeting ligands such as an v3 integrin binding peptide. In addition, our approach can be extended to multi- modality interventions: The conjugate can deliver therapeutic radioisotopes, and PDT can super-additively potentiate radiotherapy.
The aims of this project are as follow:
Aim 1 : To prepare and characterize multi-functional conjugates containing a tumor-avidlong -wavelength photosensitizer linked to novel NIR cyanine dyes with the option of a 124I-label and a RGD peptide moiety that binds to tumor and neovasulature associated with integrin (v3).
Aim 2 : To characterize the different conjugates in vitro.
Aim 3 : To examine in animals the imaging and therapeutic potential of the conjugates and determine any added benefits of integrin targeted conjugates for imaging and therapy. This ?see and treat? approach targets cancers with an agent that can be detected by light and radioimaging, and then activated at a different wavelength to destroy the tumors. It is important to detect cancer at early stage as it plays critical role in cancer patient management since detection of stage 1 cancer is associated with a >90% 5 year survival rate. Our approach of designing ?Multimodality Agents? for the detection and treatment of cancer could play a major role in cancer therapy. The initial biological data obtained from the proposed compounds in mice model are quite promising in imaging tumors and tumor metastases without any significant toxicity. Therefore, this research warrants further investigation.
|James, Nadine S; Joshi, Penny; Ohulchanskyy, Tymish Y et al. (2016) Photosensitizer (PS)-cyanine dye (CD) conjugates: Impact of the linkers joining the PS and CD moieties and their orientation in tumor-uptake and photodynamic therapy (PDT). Eur J Med Chem 122:770-85|
|Patel, Nayan J; Manivannan, Ethirajan; Joshi, Penny et al. (2015) Impact of Substituents in Tumor Uptake and Fluorescence Imaging Ability of Near-Infrared Cyanine-like Dyes. Photochem Photobiol 91:1219-30|
|Gupta, Anurag; Wang, Shouyan; Marko, Aimee et al. (2014) Polyacrylamide-based biocompatible Nanoplatform enhances the tumor uptake, PET/fluorescence imaging and anticancer activity of a chlorophyll analog. Theranostics 4:614-28|
|James, Nadine S; Chen, Yihui; Joshi, Penny et al. (2013) Evaluation of polymethine dyes as potential probes for near infrared fluorescence imaging of tumors: part - 1. Theranostics 3:692-702|
|Ethirajan, Manivannan; Chen, Ping; Ohulchanskyy, Tymish Y et al. (2013) Regioselective synthesis and photophysical and electrochemical studies of 20-substituted cyanine dye-purpurinimide conjugates: incorporation of Ni(II) into the conjugate enhances its tumor-uptake and fluorescence-imaging ability. Chemistry 19:6670-84|
|Kozyrev, Andrei; Ethirajan, Manivannan; Chen, Ping et al. (2012) Synthesis, photophysical and electrochemistry of near-IR absorbing bacteriochlorins related to bacteriochlorophyll a. J Org Chem 77:10260-71|
|Wang, Shouyan; Kim, Gwangseong; Lee, Yong-Eun Koo et al. (2012) Multifunctional biodegradable polyacrylamide nanocarriers for cancer theranostics--a "see and treat" strategy. ACS Nano 6:6843-51|
|Ethirajan, Manivannan; Chen, Yihui; Joshi, Penny et al. (2011) The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem Soc Rev 40:340-62|
|Williams, Michael P A; Ethirajan, Manivannan; Ohkubo, Kei et al. (2011) Synthesis, photophysical, electrochemical, tumor-imaging, and phototherapeutic properties of purpurinimide-N-substituted cyanine dyes joined with variable lengths of linkers. Bioconjug Chem 22:2283-95|
|Srivatsan, Avinash; Ethirajan, Manivannan; Pandey, Suresh K et al. (2011) Conjugation of cRGD peptide to chlorophyll a based photosensitizer (HPPH) alters its pharmacokinetics with enhanced tumor-imaging and photosensitizing (PDT) efficacy. Mol Pharm 8:1186-97|
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