cRGD Peptide-Conjugated Pyropheophorbide-a Photosensitizers for Tumor Targeting in Photodynamic Therapy
| Autor: | Zhangyong Hong, Fengwei Wang, Wenjing Li, Qingle Chen, Min Yu, Sihai Tan, Yutong Xing, Shuang Li, Qian Liu |
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| Rok vydání: | 2018 |
| Předmět: |
Chlorophyll
Male medicine.medical_treatment Mice Nude Pharmaceutical Science Peptide Photodynamic therapy 010402 general chemistry Peptides Cyclic 01 natural sciences Polyethylene Glycols Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Drug Discovery medicine Animals Humans Tissue Distribution Photosensitizer Integrin binding chemistry.chemical_classification Mice Inbred BALB C Photosensitizing Agents Ligand (biochemistry) 0104 chemical sciences Photochemotherapy chemistry 030220 oncology & carcinogenesis Biophysics Molecular Medicine Female Hydrophobic and Hydrophilic Interactions Linker Conjugate |
| Zdroj: | Molecular Pharmaceutics. 15:1505-1514 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.7b01064 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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