This work reports a dimeric BODIPY (BDP)-loaded liposome with conjugation of anti-HIF antibodies for dual hypoxia marker imaging and nitroreductase (NTR)-activatable photodynamic therapy (PDT) against hypoxic tumors.

Background: Natural cyclopeptide RA-XII, isolated from Rubia yunnanensis, is a promising chemotherapeutic agent for colon cancer. The photosensitizer protoporphyrin-IX attached with triphenylphosphonium (TPP) could possess mitochondria targeting capacity and exert photodynamic therapy (PDT) by inducing oxidizing damage to the mitochondria and cell apoptosis eventually. In this work, pH-sensitive liposomes were constructed to simultaneously deliver RA-XII as a chemotherapeutic drug and modified porphyrin as a mitochondria-targeting photosensitizer to treat colon cancer, and verified its mechanism of action and antitumor therapeutic efficacy. Methods: The colon cancer targeting liposome nanoparticle RA/TPPP-Lip was synthesized using thin film hydration. The therapeutic effect and targeting ability of RA/TPPP-Lip was investigated in vitro. And use HCT116 cell allogeneic subcutaneous transplantation tumor model to investigate the anti-tumor and targeting effects of RA/TPPP-Lip in vivo. Results: RA/TPPP-Lip gained the targeting ability through surface-modified HA to increase the accumulation of RA-XII and TPPP in colon cancer cells. A series of in vitro experimental results showed that TPPP produced cytotoxic ROS under laser irradiation to directly damage cell mitochondria and played a combined role with RA-XII, making RA/TPPP-Lip the best colon cancer cell growth inhibitory effect. Furthermore, in vivo antitumor experiments showed that the RA/TPPP-Lip substantially accumulated at the tumor site and efficiently repressed tumor growth in nude mice. Conclusion:We have successfully designed a new cancer-targeted nanomedicine platform (RA/TPPP-Lip) for the collaborative treatment of colon cancer, which can achieve the targeted continuous release of multiple therapeutic drugs. This work provides a new strategy for precise combination therapy, which may promote the further development of collaborative cancer treatment platforms.

A programmed drug delivery system that can achieve sequential release of multiple therapeutics under different stimulus holds great promise to enhance the treatment efficacy and overcome multi-drug resistance (MDR) in tumor. Herein, multi-organelle-targeted and pH/ cytochrome c (Cyt c) dual-responsive nanoparticles were designed for combination therapy on resistant tumor. In this system (designated DGLipo NPs), doxorubicin (Dox) was intercalated into the DNA duplex containing a Cyt c aptamer, which subsequently loaded in the dendrigraftpoly-L-lysines (DGL) cores of DGLipo NPs, while cyclopeptide RA-V was doped into the pH-sensitive liposomal shells. After dual modification with c(RGDfK) and mitochondria-penetrating peptide (MPP), DGLipo NPs could successively deliver the two drugs into lysosome and mitochondria of cancer cells, and achieve sequential drug release in virtue of the unique characteristic of these two organelles. The organelle-specific and spatiotemporally controlled release of Dox and RA-V led to enhanced therapeutic outcomes in MDR tumor. More significantly, the DGLipo NPs were successfully applied to monitor Cyt c release during mitochondria-mediated apoptotic process. This work represents a versatile strategy for precise combination therapy against resistant tumor with spatiotemporal control, and provides a potential tool for Cyt c-related apoptotic studies.

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Activatable theranostic agents, which combine fluorescent reporters with masked chemotherapeutic agents that are activated by tumor-associated stimuli, would be attractive candidates to improve the tumor selectivity of chemotherapy. This work reports a ROS/GSH dual-activatable and O2‑evolving theranostic nanosystem (RA-S-S-Cy@PLGA NPs) for highly selective therapy against hypoxic tumors and in situ fluorescence-tracking of cancer chemotherapy.Methods: In this system, the newly designed theranostic agent (RA-S-S-Cy) is composed of a disulfide bond as a cleavable linker, a near infrared (NIR) active fluorophore as a fluorescent tracker, and a natural cyclopeptide RA-V as the active anti-cancer agent. Upon reaction with the high level of intracellular glutathione (GSH), disulfide cleavage occurs, resulting in concomitant active drug RA-V release and significant NIR fluorescence increase. To further improve the tumor targeting of RA-S-S-Cy and achieve redox dual-responsiveness, RA-S-S-Cy was incorporated into the c(RGDfK)-targeted PLGA nanoparticles together with an O2-generating agent (catalase) to produce RA-S-S-Cy@PLGA NPs.Results: The cell-specific and redox dual-activatable release of RA-V lead to enhanced therapeutic outcomes in vivo and in vitro. More significantly, the RA-S-S-Cy@PLGA NPs were successfully applied for monitoring of drug release and chemotherapeutic efficacy in situ by “turn-on” NIR fluorescence.Conclusions: RA-S-S-Cy@PLGA NPs would be efficient theranostic nanosystems for more precise therapy against hypoxic tumors and provides a potential tool for deeper understanding of drug release mechanisms.