Tumor-pH-Sensitive PLLA-Based Microsphere with Acid Cleavable Acetal Bonds on the Backbone for Efficient Localized Chemotherapy.

Nanoparticle- and microsphere-based drug delivery systems (DDSs) have attracted wide attention in cancer therapy; those DDSs that are responsive to tumor environment can selectively identify tumor and normal tissues and therefore have shown enhanced anticancer efficacy and alleviated systemic toxicity. Here, tumor-pH-sensitive polymeric microspheres, which are prepared by multiblock poly(l-lactide) with pH-sensitive acetal bonds in the backbone, are employed to efficiently load water-soluble anticancer drug doxorubicin hydrochloride (DOX·HCl, drug loading content: ∼10%). The pH-sensitive DOX-loaded hollow microspheres were in the size range 2-10 µm and exhibited acid-accelerated degradation of polymer matrix and drug release, and thereby efficient in vitro cancer cell inhibition. The microspheres were further intratumorally injected into breast-tumor-bearing mice, and the in vivo anticancer experiment showed that pH-sensitive DOX-loaded microsphere showed better antitumor efficiency and prolonged life-span than its counterpart that does not have pH-responsive property. Moreover, negligible organ toxicity, especially cardiotoxicity that generally exists in DOX-involved chemotherapy where DOX is administrated by intravenous injection, was observed for DOX-loaded microspheres. Hence, tumor-pH-sensitive polymeric microspheres have appeared to be a simple and efficient platform for delivering hydrophilic anticancer drug with excellent anticancer efficacy and low systemic toxicity.

Cinnamaldehyde-Based Poly(ester-thioacetal) To Generate Reactive Oxygen Species for Fabricating Reactive Oxygen Species-Responsive Nanoparticles.

Due to the high oxidative stress of the tumor microenvironment, more and more researchers have been devoted to reactive oxygen species (ROS)-responsive nanodrug delivery systems for anticancer therapy. Herein, a ROS-responsive moiety, thioacetal, was synthesized, and cinnamaldehyde (CA) was introduced in the polymer chain to trigger the generation of ROS to expect the enhancement of the ROS-responsive effect. The poly(ester-thioacetal) mPEG2k - b-(NTA-HD)12 polymer, its self-assembled micelles, and the ROS-responsive behavior were characterized by 1H NMR and DLS. The anticancer drug doxorubicin (DOX) was adopted to prepare DOX-loaded poly(ester-thioacetal) micelles. The intracellular ROS detection indicated that the mPEG2k - b-(NTA-HD)12 polymer could degrade via the high concentration of ROS in cancer cells, and the released CA stimulated mitochondria to regenerate additional ROS. The flow cytometry results indicated that the ROS-responsive polymeric micelles showed faster cellular uptake compared to the control mPEG2k - b-PCL5k micelles. The ROS responsive DOX/mPEG2k - b-(NTA-HD)12 micelles exhibited much better anticancer efficiency on both 4T1 and HeLa cancer cells than DOX/mPEG2k - b-PCL5k micelles.

Leveraging a polycationic polymer to direct tunable loading of an anticancer agent and photosensitizer with opposite charges for chemo-photodynamic therapy.

Herein, we reported a primary amine containing polycationic polymer to load an oppositely charged anticancer drug (doxorubicin, DOX) and a photosensitizer (chlorin e6, Ce6) for combinational chemo-photodynamic therapy. The electrostatic interactions as well as other multiple interactions between the polymer and payloads endowed the drug-loaded nanoparticles with excellent stability. Moreover, the electrostatic attraction between the cationic polymer and anionic Ce6 dictated that Ce6 had higher loading efficiency than DOX. DOX showed pH-responsive drug release owing to the increased solubility of protonated DOX and reduced interaction with the partially protonated polymer under acidic conditions. In contrast, Ce6 showed pH-insensitive release because of the smaller change in solubility and the intense interactions between Ce6 and the polymer. Synergistic chemo/photodynamic therapy of 4T1 cancer cells was achieved by light-triggered reactive oxygen species (ROS)-mediated enhanced cellular uptake and effective endo/lysosomal escape of drug-loaded nanoparticles. Our study demonstrated that the polycationic polymer could act as a robust carrier for differential loading and release of oppositely charged cargos for combinational therapy.

Polymeric nanoparticles responsive to intracellular ROS for anticancer drug delivery.

Thioketal and thioether are moieties used to fabricate reactive oxygen species (ROS)-responsive polymers for drug delivery. In this paper, three amphiphilic copolymers of mPEG-poly(ester-thioether), mPEG-poly(thioketal-ester) and mPEG-poly(thioketal-ester-thioether) were synthesized. The ROS-responsive behaviors of the three copolymers nanoparticles as drug carriers were investigated. The ROS-sensitivity was demonstrated by NMR, DLS, and SEM. mPEG-poly(ester-thioether) nanoparticles exhibited the fastest drug release rate, which possessed the best ROS sensitivity. The in vitro anticancer activity of the DOX-loaded nanoparticles was studied, the results revealed that the mPEG-poly(ester-thioether) nanoparticles showed the most efficient anticancer activity. Notably, all the three ROS-responsive copolymers nanoparticles showed enhanced cellular uptake and anticancer efficacy comparing to the control mPEG-b-PCL nanoparticles.