1. Academic Validation
  2. cRGD Peptide-Conjugated Pyropheophorbide-a Photosensitizers for Tumor Targeting in Photodynamic Therapy

cRGD Peptide-Conjugated Pyropheophorbide-a Photosensitizers for Tumor Targeting in Photodynamic Therapy

  • Mol Pharm. 2018 Apr 2;15(4):1505-1514. doi: 10.1021/acs.molpharmaceut.7b01064.
Wenjing Li 1 Sihai Tan 2 Yutong Xing 1 Qian Liu 1 Shuang Li 1 Qingle Chen 1 Min Yu 3 Fengwei Wang 4 Zhangyong Hong 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences , Nankai University , Tianjin 300071 , P. R. China.
  • 2 Tianjin University of Traditional Chinese Medicine , Tianjin 300193 , P. R. China.
  • 3 Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital , National Clinical Research Center for Cancer , Tianjin 300060 , P. R. China.
  • 4 People's Hospital of Tianjin , Tianjin 300180 , P. R. China.
Abstract

Pyropheophorbide-a (Pyro) is a highly promising photosensitizer for tumor photodynamic therapy (PDT), although its very limited tumor-accumulation ability seriously restricts its clinical applications. A higher accumulation of photosensitizers is very important for the treatment of deeply seated and larger tumors. The conjugation of Pyro with tumor-homing peptide ligands could be a very useful strategy to optimize the physical properties of Pyro. Herein, we reported our studies on the conjugation of Pyro with a cyclic cRGDfK (cRGD) peptide, an Integrin binding sequence, to develop highly tumor-specific photosensitizers for PDT application. To further reduce the nonspecific uptake and, thus, reduce the background distribution of the conjugates in normal tissues, we opted to add a highly hydrophilic polyethylene glycol (PEG) chain and an extra strongly hydrophilic carboxylic acid group as the linker to avoid the direct connection of the strongly hydrophobic Pyro macrocycle and cRGD ligand. We reported here the synthesis and characterization of these conjugates, and the influence of the hydrophilic modification on the biological function of the conjugates was carefully studied. The tumor-accumulation ability and photodynamic-induced cell-killing ability of these conjugates were evaluated through both in vitro cell-based experiment and in vivo distribution and tumor therapy experiments with tumor-bearing mice. Thus, the synthesized conjugate significantly improved the tumor enrichment and tumor selectivity of Pyro, as well as abolished the xenograft tumors in the murine model through a one-time PDT treatment.

Keywords

integrin; peptide conjugate; photodynamic therapy; photosensitizer; pyropheophorbide-a.

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