Conjugation of cRGD Peptide to ChlorophyllaBased Photosensitizer (HPPH) Alters Its Pharmacokinetics with Enhanced Tumor-Imaging and Photosensitizing (PDT) Efficacy

Avinash Srivatsan, Manivannan Ethirajan, Suresh K. Pandey, Shipra Dubey, Xiang Zheng, Ting-Hsiu Liu, Masayuki Shibata, Joseph Missert, Janet Morgan, Ravindra K. Pandey
2011 Molecular Pharmaceutics  
The R v β 3 integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. Cyclic Arg-Gly-Asp (cRGD) peptide represents a selective R v β 3 integrin ligand that has been extensively used for research, therapy, and diagnosis of neoangiogenesis. For developing photosensitizers with enhanced PDT efficacy, we here report the synthesis of a series of bifunctional agents in which the 3-(1 0 -hexyloxyethyl)-3-devinylpyropheophorbide a (HPPH), a chlorophyll-based
more » ... itizer, was conjugated to cRGD and the related analogues. The cell uptake and in vitro PDT efficacy of the conjugates were studied in R v β 3 integrin overexpressing U87 and 4T1 cell lines whereas the in vivo PDT efficacy and fluorescence-imaging potential of the conjugates were compared with the corresponding nonconjugated photosensitizer HPPH in 4T1 tumors. Compared to HPPH, the HPPHÀcRGD conjugate in which the arginine and aspartic acid moieties were available for binding to two subunits of R v β 3 integrin showed faster clearance, enhanced tumor imaging and enhanced PDT efficacy at 2À4 h postinjection. Molecular modeling studies also confirmed that the presence of the HPPH moiety in HPPHÀcRGD conjugate does not interfere with specific recognition of cRGD by R v β 3 integrin. Compared to U87 and 4T1 cells the HPPHÀcRGD showed significantly low photosensitizing efficacy in A431 (R v β 3 negative) tumor cells, suggesting possible target specificity of the conjugate.
doi:10.1021/mp200018y pmid:21702452 pmcid:PMC3148296 fatcat:hadale77qbfkzluvda446j2t4y