NIR and Reduction Dual-Sensitive Polymeric Prodrug Nanoparticles for Bioimaging and Combined Chemo-Phototherapy

The combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) based on a single nanosystem is highly desirable for cancer treatment. In this study, we developed a versatile Pt(IV) prodrug-based nanodrug, PVPt@Cy NPs, to realize synchronous chemotherapy, PDT and PTT and integrate cancer treatment with bioimaging. To construct PVPt@Cy NPs, the amphiphilic Pt(IV)-based polymeric prodrug PVPt was synthesized by a facile one-pot coupling reaction, and then it was used to encapsulate an optotheranostic agent (HOCyOH, Cy) via hydrophobic interaction-induced self-assembly. These NPs would disaggregate under acidic, reductive conditions and NIR irradiation, which are accompanied by photothermal conversion and reactive oxygen species (ROS) generation. Moreover, the PVPt@Cy NPs exhibited an enhanced in vitro anticancer efficiency with 808-nm light irradiation. Furthermore, the PVPt@Cy NPs showed strong NIR fluorescence and photothermal imaging in H22 tumor-bearing mice, allowing the detection of the tumor site and monitoring of the drug biodistribution. Therefore, PVPt@Cy NPs displayed an enormous potential in combined chemo-phototherapy.

A Co-delivery System Based on a Dimeric Prodrug and Star-Shaped Polymeric Prodrug Micelles for Drug Delivery

Chemotherapy is one of the commonly used therapies for the treatment of malignant tumors. Insufficient drug-loading capacity is the major challenge for polymeric micelle–based drug delivery systems of chemotherapy. Here, the redox-responsive star-shaped polymeric prodrug (PSSP) and the dimeric prodrug of paclitaxel (PTX) were prepared. Then the dimeric prodrug of PTX (diPTX, diP) was loaded into the core of the star-shaped polymeric prodrug micelles of PSSP by hydrophobic interaction forming the redox-responsive prodrug micelles of diPTX@PSSP for intracellular drug release in tumor cells. The hydrodynamic diameter of diPTX@PSSP nanoparticles was 114.3 nm ± 2.1 (PDI = 0.219 ± 0.016), and the micelles had long-term colloidal stability and the drug-loading content (DLC) of diPTX and PTX is 16.7 and 46.9%, respectively. The prepared micelles could broke under the reductive microenvironment within tumor cells, as a result, the dimeric prodrug of diP and polymeric prodrug micelles of PSSP were rapidly disassembled, leading to the rapid release of intracellular drugs. In vitro release studies showed that under the condition of reduced glutathione (GSH) (10 mM), the release of PTX was significantly accelerated with approximately 86.6% released within 21 h, and the released PTX in cytoplasm could promote the disintegration of microtubules and induce cell apoptosis. These results indicated that the new type of this reduction-sensitive nanodrug delivery system based on dimeric prodrug@polymeric prodrug micelles would be a promising technology in chemotherapy.

Diagnosis and Simultaneous Treatment of Musculoskeletal Injury Using H2O2-Triggered Echogenic Antioxidant Polymer Nanoparticles in a Rat Model of Contusion Injury

Ultrasound is clinically used for diagnosis and interventions for musculoskeletal injuries like muscle contusion, but contrast of ultrasonography still remains a challenge in the field of the musculoskeletal system. A level of hydrogen peroxide (H2O2) is known to be elevated during mechanical tissue damage and therefore H2O2 can be exploited as a diagnostic and therapeutic marker for mechanical injuries in the musculoskeletal system. We previously developed poly(vanillin-oxalate) (PVO) as an inflammation-responsive polymeric prodrug of vanillin, which is designed to rapidly respond to H2O2 and exert antioxidant and anti-inflammatory activities. The primary aim of this study is to verify whether PVO nanoparticles could serve as contrast agents as well as therapeutic agents for musculoskeletal injuries simultaneously. In a rat model of contusion-induced muscle injury, PVO nanoparticles generated CO2 bubbles to enhance the ultrasound contrast in the injury site. A single intramuscular injection of PVO nanoparticles also suppressed contusion-induced muscle damages by inhibiting the expression of pro-inflammatory cytokines and inflammatory cell infiltration. We, therefore, anticipate that PVO nanoparticles have great translational potential as not only ultrasound imaging agents but also therapeutic agents for the musculoskeletal disorders such as contusion.

Polymeric Nanovectors Incorporated with Ganciclovir and HSV-tk Encoding Plasmid for Gene-Directed Enzyme Prodrug Therapy

In the area of gene-directed enzyme prodrug therapy (GDEPT), using herpes simplex virus thymidine kinase (HSV-tk) paired with prodrug ganciclovir (GCV) for cancer treatment has been extensively studied. It is a process involved with two steps whereby the gene (HSV-tk) is first delivered to malignant cells. Afterward, non-toxic GCV is administered to that site and activated to cytotoxic ganciclovir triphosphate by HSV-tk enzyme expressed exogenously. In this study, we presented a one-step approach that both gene and prodrug were delivered at the same time by incorporating them with polymeric micellar nanovectors. GCV was employed as an initiator in the ring-opening polymerization of ε-caprolactone (ε-CL) to synthesize hydrophobic GCV-poly(caprolactone) (GCV–PCL), which was furthered grafted with hydrophilic chitosan to obtain amphiphilic polymer (GCV–PCL–chitosan) for the fabrication of self-assembled micellar nanoparticles. The synthesized amphiphilic polymer was characterized using Fourier transform infrared spectroscopy and proton nuclear magnetic resonance. Micellar prodrug nanoparticles were analyzed by dynamic light scattering, zeta potential, critical micelle concentration, and transmission electron microscopy. Polymeric prodrug micelles with optimal features incorporated with HSV-tk encoding plasmids were cultivated with HT29 colorectal cancer cells and anticancer effectiveness was determined. Our results showed that prodrug GCV and HSV-tk cDNA encoded plasmid incorporated in GCV–PCL–chitosan polymeric nanocarriers could be delivered in a one-step manner to HT-29 cells and triggered high cytotoxicity.

Poly(N-vinylcaprolactam) and Salicylic Acid Polymeric Prodrug Grafted onto Medical Silicone to Obtain a Novel Thermo- and pH-Responsive Drug Delivery System for Potential Medical Devices

New medical devices with anti-inflammatory properties are critical to prevent inflammatory processes and infections in medical/surgical procedures. In this work, we present a novel functionalization of silicone for medical use with a polymeric prodrug and a thermosensitive polymer, by graft polymerization (gamma rays), for the localized release of salicylic acid, an analgesic, and anti-inflammatory drug. Silicone rubber (SR) films were functionalized in two stages using graft polymerization from ionizing radiation (60Co). The first stage was grafting poly(N-vinylcaprolactam) (PNVCL), a thermo-sensitive polymer, onto SR to obtain SR-g-PNVCL. In the second stage, poly(2-methacryloyloxy-benzoic acid) (P2MBA), a polymeric prodrug, was grafted to obtain (SR-g-PNVCL)-g-P2MBA. The degree of functionalization depended on the concentrations of monomers and the irradiation dose. The films were characterized by attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy/energy-dispersive X-ray spectrometry (SEM–EDX), thermogravimetric analysis (TGA), and contact angle. An upper critical solution temperature (UCST) of the films was demonstrated by the swelling degree as a temperature function. (SR-g-PNVCL)-g-P2MBA films demonstrated hydrolysis-mediated drug release from the polymeric prodrug, pH, and temperature sensitivity. GC–MS confirmed the presence of the drug (salicylic acid), after polymer hydrolysis. The concentration of the drug in the release media was quantified by HPLC. Cytocompatibility and thermo-/pH sensitivity of functionalized medical silicone were demonstrated in cancer and non-cancer cells.