Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (TTCI) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (TTCI NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC₅₀ values of TTCI NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM TTCI NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.

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.

Mitochondrial dysfunction is a feature of cancer cells and targeting cancer mitochondria has emerged as a promising anticancer therapy. In this study, a novel mitochondria-targeted and ROS-responsive drug delivery nanoplatform was developed from the TPP-TK-Chlorambucil (TTCb) prodrug for effective pancreatic cancer therapy. Mitochondria targeting ligand TPP and DNA alkylating drug chlorambucil were connected by a linker containing ROS-cleave thioketal. DSPE-PEG2000 was utilized as the assisting component to increase the accumulation of nanoparticles in the tumor by the EPR effect. This smart nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability and remarkable therapeutic performance in cells. The formulated nanoparticles (TTCb-NPs) rapidly revealed high cellular uptake, which demonstrated that higher accumulation in mitochondria facilitated chlorambucil targeted delivery to mitochondria where it acts on mtDNA and induces cell death. The results of in vitro antitumor activity demonstrated that the IC₅₀ values of TTCb-NPs in three pancreatic cancer cells were around 20–30 μM, which was lower than that of chlorambucil. 50 μM TTCb-NPs could significantly inhibit the growth of BxPC3 cells. Therefore, TTCb-NPs are promising as drug delivery systems with organelle targeting and ROS-stimulated control release. These results demonstrated that the synthesized TTCb-NPs exhibited therapeutic potential for the treatment of refractory pancreatic tumors.

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.

Multidrug resistance, in particular the challenge of drug efflux transporter-mediated chemoresistance, remains the major obstacle for effective chemotherapy. Therefore, manipulating energy metabolism in cancer cells to reduce the expression of P-glycoprotein (P-gp) and disrupt redox homeostasis may be a potential strategy to surmount cancer therapeutic resistance. Herein, a PEGylated co-delivery nanoplatform (LND-DOX NPs) that is capable of decreasing chemotherapeutic drug efflux and increasing the sensitivity of tumor cells to DOX by manipulating energy metabolism and disrupting redox homeostasis is rationally designed. As a result, the LND-DOX NPs increased DOX retention in MCF-7/Adr cells and displayed remarkable antitumor capabilities. The IC₅₀ value of LND-DOX NPs in MCF-7/Adr cells was about 5 μM. Therefore, this study provides a potentially effective strategy against cancer therapeutic resistance.