ROS-Responsive Mitochondria-Targeting Blended Nanoparticles: Chemo- and Photodynamic Synergistic Therapy for Lung Cancer with On-Demand Drug Release upon Irradiation with a Single Light Source

Abstract

Mitochondria in cancer cells maintain a more negative membrane potential than normal cells. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Thus, the strategy of targeting mitochondria can maximize the photodynamic therapeutic efficiency for cancer. Here we report, for the first time, synthesis of a new mitochondria-targeting drug delivery system, ZnPc/CPT-TPPNPs. To synthesize this novel compound, polyethylene glycol was functionalized with thioketal linker-modified camptothecin (TL-CPT) and triphenylphosphonium to form the block copolymer, TL-CPT-PEG1K-TPP. The ZnPc/CPT-TPPNPs was constructed for delivery of the photosensitizer Zinc phthalocyanine (ZnPc) by blending the block copolymer TL-CPT-PEG1K-TPP with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)] (DSPE-PEG).Triphenylphosphine can accumulate selectively several hundred-fold within mitochondria. The thioketal linker is ROS-responsive and CPT can be released upon ROS cleavage. We also show that the ZnPc loaded in ZnPc/CPT-TPPNPs absorbed the 633 nm laser to produce ROS, which could be utilized both in photodynamic therapy and to cleave the thioketal linker thereby releasing camptothecin for chemotherapy. Thus, the mitochondria-targeting nanoparticles could elevate photodynamic therapeutic efficacy. Our results showed that surface modification of the nanoparticles with triphenylphosphine cations facilitated efficient subcellular delivery of the photosensitizer to mitochondria. The nanoparticles had a good ROS-responsive effect to release CPT, which could transfer to the nucleus and interfere with DNA replication as a topoisomeraseⅠinhibitor. Thus, the blended nanoparticles provide a new promising approach as a mitochondria-targeting ROS-activated chemo- and photodynamic therapy with a single light source for lung cancer.

ROS‐Responsive Blended Nanoparticles: Cascade‐Amplifying Synergistic Effects of Sonochemotherapy with On‐demand Boosted Drug Release During SDT Process

“…Briefly, the paclitaxel pro‐drug PTX‐TL was synthesized by combining the ROS‐sensitive thioketal linker (TL) and paclitaxel (PTX), and conjugated to NH 2 ‐PEG 1K ‐NH 2 . The chemical formula of PTX‐TL‐PEG 1K ‐NH 2 was validated by 1 H NMR spectra ( Figure A), with the methyl protons of TL showing peaks at 1.51 and 1.57 ppm, and those from PEG 1K between 3.40 and 3.57 ppm, the proton peak of NH 2 in PEG 1K ‐NH 2 showing at 7.73–7.74 ppm, which was consistent with previous report . In addition, the characteristic peak of PTX could be found all in PTX‐TL‐PEG1 K ‐NH 2 and the “2‐H” proton of PTX‐TL‐PEG 1K ‐NH 2 at 5.64 ppm .…”

Oxidation‐Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues

“…This strategy can work for most classes of oxidation‐sensitive polymers, for example, polyoxalates, or selenides (even a single selenium atom activated through indocyanine green (ICG) upon NIR irradiation), but its most interesting application is probably in de‐PEGylation reactions based on cleavage of thioketals. For example, a mitochondria‐targeted PEG connected to camptothecin through a thioketal linkage and co‐formulated with a porphyrin was used for a light‐triggered release of the chemotherapeutic agent . A similar approach was used to destabilize PEG‐PLA micelles encapsulating both a ROS photogenerator (chlorin e6) and a drug (paclitaxel), which was released upon thioketal cleavage …”

Sensors, Imaging Agents, and Theranostics to Help Understand and Treat Reactive Oxygen Species Related Diseases

“…Cui and co‐workers have developed a mitochondria‐targeting nanoparticle using two polymers based on thioketal, 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE) and PEG. This enabled the ability to deliver and release the anticancer drug camptothecin and photosensitizer zinc phthalocyanine (ZnPc) for dual therapy (PDT and chemotherapy) of lung cancer, triggered by ROS generated upon light irradiation.…”