Multifunctional Novel Nanoplatform for Effective Synergistic Chemo-Photodynamic Therapy of Breast Cancer by Enhancing DNA Damage and Disruptions of Its Reparation.

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that has been widely used for anti-tumor therapy by the generation of excessive highly cytotoxic ROS. However, the poor water solubility of the photosensitizer, reactive oxygen species (ROS) depleting by high concentrations of glutathione (GSH) in the tumor microenvironment and the activation of DNA repair pathways to combat the oxidative damage, will significantly limit the therapeutic effect of PDT. Herein, we developed a photosensitizer prodrug (CSP) by conjugating the photosensitizer pyropheophorbide a (PPa) and the DNA-damaging agent Chlorambucil (Cb) with a GSH-responsive disulfide linkage and demonstrated a multifunctional co-delivery nanoplatform (CSP/Ola nanoparticles (NPs)) together with DSPE-PEG2000 and PARP inhibitor Olaparib (Ola). The CSP/Ola NPs features excellent physiological stability, efficient loading capacity, much better cellular uptake behavior and photodynamic performance. Specifically, the nanoplatform could induce elevated intracellular ROS levels upon the in situ generation of ROS during PDT, and decrease ROS consumption by reducing intracellular GSH level. Moreover, the CSP/Ola NPs could amplify DNA damage by released Cb and inhibit the activation of Poly(ADP-ribose) polymerase (PARP), promote the upregulation of γ-H2AX, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. In vitro investigations revealed that CSP/Ola NPs showed excellent phototoxicity and the IC50 values of CSP/Ola NPs against MDA-MB-231 breast cancer cells were as low as 0.05-01 µM after PDT. As a consequence, the co-delivery nanoplatform greatly promotes the tumor cell apoptosis and shows a high antitumor performance with combinational chemotherapy and PDT. Overall, this work provides a potential alternative to improve the therapeutic efficiency of triple negative breast cancer cell (TNBC) treatment by synergistically enhancing DNA damage and disrupting DNA damage repair.

Carrier-free nanomedicines self-assembled from palbociclib dimers and Ce6 for enhanced combined chemo-photodynamic therapy of breast cancer.

Palbociclib is the world's first CDK4/6 kinase inhibitor to be marketed. However, it is not effective in the treatment of triple negative breast cancer (TNBC) due to the loss of retinoblastoma protein expression. Thus, combinatorial chemotherapy is indispensable for TNBC treatment. Herein, a carrier-free nanomedicine self-assembled from palbociclib dimers and Ce6 for enhanced combined chemo-photodynamic therapy of breast cancer is reported. The dimeric prodrug (Palb-TK-Palb) was synthesized by conjugating two palbociclib molecules to the connecting skeleton containing a ROS-responsive cleavable thioketal bond. The Palb-TK-Palb/Ce6 NP co-delivery nanoplatform was prepared through the self-assembly of Palb-TK-Palb, Ce6 and DSPE-PEG2000. This novel carrier-free formulation as an efficient therapeutic agent showed efficient therapeutic agent loading capacity, high cellular uptake and huge therapeutic performance against breast cancer cells. The results of in vitro antitumor activity and cell apoptosis demonstrated that Palb-TK-Palb/Ce6 NPs presented a better inhibitory effect on the growth of cancer cells due to the palbociclib and Ce6 co-delivery nanomedicine-mediated synergistic chemo-photodynamic therapy. The IC50 values of Palb-TK-Palb/Ce6 NPs in MDA-MB-231 cells were around 1-2 µM and 2 µM and the Palb-TK-Palb/Ce6 NPs showed an increase in apoptosis up to 91.9%. In general, the carrier-free nanomedicine self-assembled from palbociclib dimers and Ce6 provides options for combinatorial chemo-photodynamic therapy.