Nanozyme Decorated Metal-Organic Framework Nanosheet for Enhanced Photodynamic Therapy Against Hypoxic Tumor.

Introduction: Photodynamic therapy (PDT) has attracted increasing attention in the clinical treatment of epidermal and luminal tumors. However, the PDT efficacy in practice is severely impeded by tumor hypoxia and the adverse factors associated with hydrophobic photosensitizers (PSs), including low delivery capacity, poor photoactivity and limited ROS diffusion. In this study, Pt nanozymes decorated two-dimensional (2D) porphyrin metal-organic framework (MOF) nanosheets (PMOF@HA) were fabricated and investigated to conquer the obstacles of PDT against hypoxic tumors. Materials and Methods: PMOF@HA was synthesized by the coordination of transition metal iron (Zr4+) and PS (TCPP), in situ generation of Pt nanozyme and surface modification with hyaluronic acid (HA). The abilities of hypoxic relief and ROS generation were evaluated by detecting the changes of O2 and 1O2 concentration. The cellular uptake was investigated using flow cytometry and confocal laser scanning microscopy. The SMMC-7721 cells and the subcutaneous tumor-bearing mice were used to demonstrate the PDT efficacy of PMOF@HA in vitro and in vivo, respectively. Results: Benefiting from the 2D structure and inherent properties of MOF materials, the prepared PMOF@HA could not only serve as nano-PS with high PS loading but also ensure the rational distance between PS molecules to avoid aggregation-induced quenching, enhance the photosensitive activity and promote the rapid diffusion of generated radical oxide species (ROS). Meanwhile, Pt nanozymes with catalase-like activity effectively catalyzed intratumoral overproduced H2O2 into O2 to alleviate tumor hypoxia. Additionally, PMOF@HA, with the help of externally coated HA, significantly improved the stability and increased the cell uptake by CD44 overexpressed tumor cells to strengthen O2 self-supply and PDT efficacy. Conclusion: This study provided a new strategy of integrating 2D porphyrin MOF nanosheets with nanozymes to conquer the obstacles of PDT against hypoxic tumors.

In situ pain relief during photodynamic therapy by ROS-responsive nanomicelle through blocking VGSC.

Pain in photodynamic therapy (PDT), resulting from the stimulation of reactive oxygen species (ROS) and local acute inflammation, is a primary side effect of PDT that often leads to treatment interruption or termination, significantly compromising the efficacy of PDT and posing an enduring challenge for clinical practice. Herein, a ROS-responsive nanomicelle, poly(ethylene glycol)-b-poly(propylene sulphide) (PEG-PPS) encapsulated Ce6 and Lidocaine (LC), (ESCL) was used to address these problems. The tumor preferentially accumulated micelles could realize enhanced PDT effect, as well as in situ quickly release LC due to its ROS generation ability after light irradiation, which owes to the ROS-responsive property of PSS. In addition, PSS can suppress inflammatory pain which is one of the mechanisms of PDT induced pain. High LC-loaded efficiency (94.56 %) owing to the presence of the thioether bond of the PPS made an additional pain relief by inhibiting excessive inflammation besides blocking voltage-gated sodium channels (VGSC). Moreover, the anti-angiogenic effect of LC offers further therapeutic effects of PDT. The in vitro and in vivo anti-tumor results revealed significant PDT efficacy. The signals of the sciatic nerve in mice were measured by electrophysiological study to evaluate the pain relief, results showed that the relative integral area of neural signals in ESCL-treated mice decreased by 49.90 % compared to the micelles without loaded LC. Therefore, our study not only develops a very simple but effective tumor treatment PDT and in situ pain relief strategy during PDT, but also provides a quantitative pain evaluation method.

Hematoporphyrin monomethyl ether-mediated photodynamic therapy for acquired port-wine stain at lower extremity: Two case reports.

Two cases of acquired port-wine stain (APWS) at lower extremity were treated with hematoporphyrin monomethyl ether (HMME) and 532 nm LED green light-mediated photodynamic therapy (HMME-PDT). No serious adverse reactions were observed during or post-treatment period. Five-month follow-up showed significant reduction of red patches after a single HMME-PDT treatment in both cases.

MMP-2 Inhibitor-Mediated Tumor Microenvironment Regulation Using a Sequentially Released Bio-Nanosystem for Enhanced Cancer Photo-Immunotherapy.

Combining photodynamic therapy (PDT) with natural killer (NK) cell-based immunotherapy has shown great potential against cancers, but the shedding of NK group 2, member D ligands (NKG2DLs) on tumor cells inhibited NK cell activation in the tumor microenvironment. Herein, we assembled microenvironment-/light-responsive bio-nanosystems (MLRNs) consisting of SB-3CT-containing ß-cyclodextrins (ß-CDs) and photosensitizer-loaded liposomes, in which SB-3CT was considered to remodel the tumor microenvironment. ß-CDs and liposomes were linked by metalloproteinase 2 (MMP-2) responsive peptides, enabling sequential release of SB-3CT and chlorin e6 triggered by the MMP-2-abundant tumor microenvironment and 660 nm laser irradiation, respectively. Released SB-3CT blocked tumor immune escape by antagonizing MMP-2 and promoting the NKG2D/NKG2DL pathway, while liposomes were taken up by tumor cells for PDT. MLRN-mediated photo-immunotherapy significantly induced melanoma cell cytotoxicity (83.31%), inhibited tumor growth (relative tumor proliferation rate: 1.13% of that of normal saline) in the xenografted tumor model, and enhanced tumor-infiltrating NK cell (148 times) and NKG2DL expression (9.55 and 16.52 times for MICA and ULBP-1, respectively), achieving a synergistic effect. This study not only provided a simple insight into the development of new nanomedicine for programed release of antitumor drugs and better integration of PDT and immunotherapy but also a novel modality for clinical NK cell-mediated immunotherapy against melanoma.

Emerging nanotechnological strategies to reshape tumor microenvironment for enhanced therapeutic outcomes of cancer immunotherapy.

Immunotherapy has emerged as a novel cancer treatment over the last decade, however, efficacious responses to mono-immunotherapy have only been achieved in a relatively small portion of patients whereas combinational immunotherapies often lead to concurrent side effects. It has been proved that the tumor microenvironment (TME) is responsible for tumor immune escape and the ultimate treatment failure. Recently, there has been remarkable progress in both the understanding of the TME and the applications of nanotechnological strategies, and reviewing the emerging immune-regulatory nanosystems may provide valuable information for specifically modulating the TME at different immune stages. In this review, we focus on comprehending the recently-proposed T-cell-based tumor classification and identifying the most promising targets for different tumor phenotypes, and then summarizing the nanotechnological strategies to best target corresponding immune-related factors. For future precise personalized immunotherapy, tailor-made TME modulation strategies conducted by well-designed nanosystems to alleviate the suppressive TME and then promote anti-tumor immune responses will significantly benefit the clinical outcomes of cancer patients.

Triclosan-loaded pH-responsive copolymer to target bacteria and to have long bacteriostatic efficacy.

It is important to reduce side effects and to explore novel usage for hydrophobic broad-spectrum antibacterial agent triclosan (TCS). In this study, a new amphiphilic copolymer with tertiary amine groups, monomethyl ether poly(ethylene glycol)-b-poly{α-[4-(diethylamino)methyl-1,2,3-triazol]-caprolactone-co-caprolactone} (mPEG-PDCL) was designed and synthesized, and its micelles were applied as carries of TCS to enhance antimicrobial and bacteriostatic action. mPEG-PDCL and its contrastive copolymer mPEG-PCL could form uniform spherical micelles with sizes 50-110 nm. The zeta potential of mPEG-PDCL micelles was positive and changed from 7.00 ± 0.67 mV at pH 7.5 to 24.67 ± 1.23 mV at pH 5.5. Both TCS-loaded micelles displayed quite high drug loading content (approx. 15%) and drug loading efficiency (more than 85%). In comparison with pH 7.4, TCS released faster in acidic environment which was induced by bacteria metabolism. MIC values of both TCS-loaded micelles against S. aureus and E. coli were as low as free TCS. TCS-loaded micelles showed much better antibacterial activity than free TCS, especially, mPEG-PDCL/TCS micelles displayed long bacteriostatic efficacy in 60 h against S. aureus and in 54 h against E. coli. mPEG-PDCL micelles preferred targeting to both S. aureus and E. coli due to positive zeta potential. In in vivo experiment, the purulence of the infected wound almost disappeared for SD rats treated with mPEG-PDCL/TCS micelles. Therefore, mPEG-PDCL micelles may be used as good carriers for antimicrobial agents, and the TCS-loaded micelles possess long antimicrobial/bacteriostatic efficacy.

Biocompatible Polyphosphorylcholine Hydrogels with Inherent Antibacterial and Nonfouling Behavior Effectively Promote Skin Wound Healing.

Hydrogels with inherent antibacterial activity and nonfouling behavior can not only provide better environment for skin wounds to avoid infection but also accelerate wound healing. Herein, 2-(methacryloyloxy) ethyl 2-(trimethylammonio) ethyl phosphate (MPC) copolymers with epoxy groups, referred to as P(MPC-co-GMA), are designed and synthesized for preparing hydrogel wound dressing with inherent antibacterial and nonfouling properties. The P(MPC-co-GMA) hydrogel network is fabricated by a ring-opening reaction of the epoxy group with nontoxic and antibacterial cystamine under mild conditions. The hydrogel shows an appropriate swelling ratio, elastic behavior, and good cytocompatibility on L929 and RBCs. Bacteria scarcely adhered on the hydrogel surfaces, and the adhered bacteria could be killed by the hydrogels. Furthermore, curcumin (Cur) could be loaded into and released from the three-dimensional network structure of the hydrogels. P(MPC-co-GMA) hydrogel and its Cur-loaded hydrogel can accelerate wound healing of full-thickness skin injury compared to control groups. Conclusively, this polyphosphorylcholine hydrogel displays a potential application for skin wound healing on account of inherent antibacterial activity, antibacterial adhesion behavior, and drug release ability.

Tracing Difference: In Vitro and in Vivo Antitumor Property Comparison of pH-Sensitive Biomimetic Phosphorylcholine Micelles with Insensitive Micelles.

Although smart polymer micelles able to respond to the tumor acid microenvironment are potential anticancer drug carriers, fruitful clinical application of these carriers is inadequate. For the purpose of finding the origin of the unsatisfactory therapeutic efficacy of pH-sensitive drug carriers with tertiary amine groups, we newly designed and synthesized poly{α-[4-(diethylamino)methyl-1,2,3-triazol]-caprolactone-co-caprolactone}-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PDCL-PMPC), a biomimetic phosphorylcholine polymer with pH-ensitive groups. PDCL-PMPC self-assembles into small and uniform micelles as its counterpart poly(caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PCL-PMPC) without pH-sensitive groups. The in vitro and in vivo properties of PDCL-PMPC and PCL-PMPC micelles are investigated in detail. PDCL-PMPC micelles display obvious pH sensitivity by micelle change and fast drug release at pH 5, but the insensitive micelles do not. The internalization of PDCL-PMPC micelles by tumor cells is stronger than that of PCL-PMPC micelles. However, in comparison with the insensitive micelles, the pH-sensitive micelles present much shorter blood circulation time in pharmacokinetics and demonstrate worse accumulation in the tumor site in vivo study. As a result, DOX loaded PCL-PMPC micelles demonstrate much better antitumor efficiency than pH-sensitive micelles. Furthermore, DOX loaded PCL-PMPC micelles show similar therapeutic efficacy to DOX·HCl but with considerably lower side effects.