56P - cRGDfK (cRGD) conjugated pyropheophorbide-a (Pyro), a new tumour photodynamic agent, is highly accumulated and specific in tumour cell killing

Abstract

BackgroundPyropheophorbide-a (Pyro) is a highly promising photosensitizer for tumor photodynamic therapy (PDT), while its very limited tumor-accumulation ability seriously restricts its clinically applications. Higher accumulation of photosensitizers are very important for the treatment of deeply seated and larger tumors. 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, with the aim to development a highly tumor specific photosensitizers for PDT application. MethodsIn order to further reduce the non-specific uptake and thus reduce the background distribution of the conjugates in the 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 strong hydrophobic Pyro macrocycle and cRGD ligand. While hydrophilic modification may affect the PDT activity of photosensitizers via reduction of the membrane attachment. We reported here the synthesis and characterization of these conjugates. Their tumor accumulation ability and photodynamic induced cell killing ability were evaluated through both in vitro cell-base experiment and in vivo distribution and tumor therapy experiments with tumor-bearing mice. ResultsAs a result, the synthesized conjugate significantly improved the tumor enrichment and tumor selectivity of Pyro, and abolished the xenograft tumors in the murine model through one time of PDT treatment. ConclusionsIn view of the simple synthesis process and excellent tumor treatment ability, this compound has good clinical application potential. Legal entity responsible for the studyTianjin Union Medical Center. FundingNankai University. DisclosureAll authors have declared no conflicts of interest.