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RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

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† Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States
‡ School of Pharmacy, Jiangsu Vocational College of Medicine, Yancheng 224005, China
§ School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
*E-mail: [email protected]; Phone: 1-336-716-8440.
Cite this: Mol. Pharmaceutics 2017, 14, 8, 2793–2804
Publication Date (Web):July 12, 2017
https://doi.org/10.1021/acs.molpharmaceut.7b00321
Copyright © 2017 American Chemical Society
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Abstract

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Advances in photodynamic therapy of cancer have been restrained by lack of cancer specificity and side effects to normal tissues. Molecularly targeted photodynamic therapy can achieve higher cancer specificity by combination of active cancer targeting and localized laser activation. We aimed to use albumin as a carrier to prepare targeted nanoconjugates that are selective to cancer cells and smaller than conventional nanoparticles for superior tumor penetration. IRDye 700DX (IR700), a porphyrin photosensitizer, was covalently conjugated to human serum albumin that was also linked with tumor-targeting RGD peptides. With multiple IR700 and RGD molecules in a single albumin molecule, the resultant nanoconjugates demonstrated monodispersed and uniform size distribution with a diameter of 10.9 nm. These targeted nanoconjugates showed 121-fold increase in cellular delivery of IR700 into TOV21G ovarian cancer cells compared to control nanoconjugates. Mechanistic studies revealed that the integrin specific cellular delivery was achieved through dynamin-mediated caveolae-dependent endocytosis pathways. They produced massive cell killing in TOV21G cells at low nanomolar concentrations upon light irradiation, while NIH/3T3 cells that do not express integrin αvβ3 were not affected. Because of their small size, targeted albumin nanoconjugates could penetrate tumor spheroids of SKOV-3 ovarian cancer cells and produced strong phototoxicity in this 3-D model. Owing to their cancer-specific delivery and small size, these targeted nanoconjugates may become an effective drug delivery system for enabling molecularly targeted photodynamic therapy of cancer.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.7b00321.

  • Penetration of Doxil in tumor spheroids of SKOV-3 cells (PDF)

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  15. Yue Sun, Haiping Wang, Pan Wang, Kun Zhang, Xiaorui Geng, Quanhong Liu, Xiaobing Wang. Tumor targeting DVDMS-nanoliposomes for an enhanced sonodynamic therapy of gliomas. Biomaterials Science 2019, 7 (3) , 985-994. https://doi.org/10.1039/C8BM01187G
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  23. Hermas R. Jiménez, María Arbona. Spectroscopic studies of water-soluble superstructured iron(III) porphyrin. Interaction with the bovine serum albumin protein. Journal of Coordination Chemistry 2018, 71 (6) , 890-905. https://doi.org/10.1080/00958972.2018.1434624
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