Poly(cyclodextrin)-Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy.

Despite the approval of oncolytic virus therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost-intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus-based therapies. Herein, we report a nanoassembly comprised of multivalent host-guest interactions between polymerized paclitaxel (pPTX) and nitric oxide incorporated polymerized ß-cyclodextrin (pCD-pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of oncolytic virus. The resultant pPTX/pCD-pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell activation and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD-pSNO results in activation and expansion of dendritic cells systemically, but with a corresponding expansion of myeloid-derived suppressor cells and suppression of CD8+ T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen-4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD-pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo- and immunotherapeutic synergies of paclitaxel and nitric oxide and suggests the potential for virus-free nanoformulations to mimic the therapeutic action and benefits of oncolytic viruses.

Drug-loaded titanium dioxide nanoparticle coated with tumor targeting polymer as a sonodynamic chemotherapeutic agent for anti-cancer therapy.

Sonodynamic therapy utilizes ultrasound (US)-responsive generation of reactive oxygen species (ROS) from sonosensitizer, and it is a powerful strategy for anti-cancer treatment in combination with chemotherapy. Herein, we report a precisely designed sonodynamic chemotherapeutics which exhibits US-responsive drug release via ROS generation from co-loaded sono-sensitizer. Doxorubicin (DOX)-coordinated titanium dioxide nanoparticles (TNPs) were encapsulated with polymeric phenyboronic acid (pPBA) via phenylboronic ester bond between pPBA and DOX. Loaded DOX was readily released under US irradiation due to the ROS-cleavable characteristics of phenylboronic ester bond. The size of nanoparticles was around 200 nm, and DOX was released by ROS generated under US irradiation. Tumor targeting by PBA moiety, intracellular ROS generation, and combined therapeutic effect against tumor cells were confirmed in vitro. Finally, we demonstrated high tumor accumulation and efficient tumor growth inhibition in tumor-bearing mice under US irradiation, which revealed potential as a multi-functional agent for sonodynamic chemotherapy.

Self-assembled nanocomplex between polymerized phenylboronic acid and doxorubicin for efficient tumor-targeted chemotherapy.

Since the discovery that nano-scaled particulates can easily be incorporated into tumors via the enhanced permeability and retention (EPR) effect, such nanostructures have been exploited as therapeutic small molecule delivery systems. However, the convoluted synthetic process of conventional nanostructures has impeded their feasibility and reproducibility in clinical applications. Herein, we report an easily prepared formulation of self-assembled nanostructures for systemic delivery of the anti-cancer drug doxorubicin (DOX). Phenylboronic acid (PBA) was grafted onto the polymeric backbone of poly(maleic anhydride). pPBA-DOX nanocomplexes were prepared by simple mixing, on the basis of the strong interaction between the 1,3-diol of DOX and the PBA moiety on pPBA. Three nanocomplexes (1, 2, 4) were designed on the basis of [PBA]:[DOX] molar ratios of 1:1, 2:1, and 4:1, respectively, to investigate the function of the residual PBA moiety as a targeting ligand. An acid-labile drug release profile was observed, owing to the intrinsic properties of the phenylboronic ester. Moreover, the tumor-targeting ability of the nanocomplexes was demonstrated, both in vitro by confocal microscopy and in vivo by fluorescence imaging, to be driven by an inherent property of the residual PBA. Ligand competition assays with free PBA pre-treatment demonstrated the targeting effect of the residual PBA from the nanocomplexes 2 and 4. Finally, the nanocomplexes 2 and 4, compared with the free DOX, exhibited significantly greater anti-cancer effects in vitro and even in vivo. Our pPBA-DOX nanocomplex enables a new paradigm for self-assembled nanostructures with potential biomedical applications.

Injectable immunogel based on polymerized phenylboronic acid and mannan for cancer immunotherapy.

The recent development and prospects of cancer immunotherapy have led to diversification of the types of therapeutic agents used. By simultaneously administering various agents, a more effective therapeutic effect can be expected due to the synergistic effects of multiple therapeutics. In particular, if a substance with adjuvanticity and tumor antigen is delivered at the same time, enhanced cancer immunotherapy can be achieved through high cross-presentation and antigen-presenting cell (APC) maturation. To this end, we developed a polymerized phenylboronic acid (pPBA)-based immunogel for the simultaneous delivery of mannan, which has adjuvanticity and tumor antigen. The immunogel was formed by simple mixing of the polysaccharide mannan with pPBA through the formation of phenylboronic ester between the diol of mannose monomers and phenylboronic acids of pPBA. The immunogel was slowly degraded by hydrolysis to release the loaded tumor antigen. In addition, the released mannan played a key role in both APC maturation in vitro and the upregulation of cross-presentation. Finally, the pPBA-mannan immunogel exhibited a significant anticancer effect in the 4 T1 cell-inoculated mouse model, implying the potential of a codelivery system of antigens and adjuvants for effective cancer immunotherapy.

Immunostimulation of tumor microenvironment by targeting tumor-associated macrophages with hypoxia-responsive nanocomplex for enhanced anti-tumor therapy.

Tumor-associated macrophages (TAMs), which dampen the therapeutic efficacy of cancer immunotherapy, are the key players in the immunosuppressive tumor microenvironment (TME). Therefore, reprogramming TAMs into tumoricidal M1 macrophages possesses considerable potential as a novel immunotherapy. However, the low bioavailability of polarization agents and limited accumulation of TAMs restrict their anti-tumor efficacy. In this study, we developed a polymer-based hypoxia-responsive nanocomplex to target TAMs in hypoxia for enhanced cancer immunotherapy. We synthesized a hypoxia-cleavable polymer poly(ethylene glycol)-azo-poly(l-lysine) (PEG-azo-PLL) and formulated a nanocomplex by simple mixing PEG-azo-PLL and poly(I:C). By mimicking in vitro hypoxia conditions, PEG-azo-PLL/poly(I:C) complexes could transform the physicochemical properties to enhance the delivery efficiency of poly(I:C) to tumor hypoxia, where M2-like TAMs are accumulated. Furthermore, PEG-azo-PLL/poly(I:C) could successfully reduce the population of M2-like TAMs in hypoxic tumors and promoted infiltration of CD8+ T cells in vivo, resulting in the favorable conversion of immunosuppressive TME. Finally, PEG-azo-PLL/poly(I:C) could elicit a significant in vivo anti-tumor effect in B16F10-bearing mice in addition to a prolonged survival time, demonstrating that the hypoxia-responsive nanocomplex PEG-azo-PLL/poly(I:C) is a promising approach for TAM reprogramming immunotherapy for solid tumors.

Facile preparation of poly(N-isopropylacrylamide)/graphene oxide nanocomposites for chemo-photothermal therapy.

Carbon-based nanomaterials, such as carbon nanotubes, fullerenes, nanodiamonds, and graphene, have been investigated for various biomedical applications, including biological imaging, photothermal therapy, drug/gene delivery, cancer therapy, biosensors, and electrochemical sensors. Graphene oxide (GO) has unique physicochemical properties and can be used to restore conductivity through oxidation. In this study, we developed poly(N-isopropylacrylamide) (PNIPAM)-based nanogel systems containing GO for controlled in vitro drug delivery. The photothermal effects of the PNIPAM/GO- and PNIPAMAAM/GO-based nanogel systems were enhanced. The release of DOX from the PNIPAM/GO-based nanogel was achieved using the photothermal effect of near-infrared irradiation. Using a Cell Counting Kit-8 assay, the cytotoxicity of all conditions demonstrated that the PNIPAM composite-based nanogels were biocompatible with no significance.

Harnessing the Formation of Natural Killer-Tumor Cell Immunological Synapses for Enhanced Therapeutic Effect in Solid Tumors.

The formation of an immunological synapse (IS) on recognition of a cancer cell is the main mechanism underlying the natural killer (NK)-cell-mediated killing of tumor cells. Herein, an integrative strategy for cancer therapy against solid tumors is reported, in which alterations in the cleft of IS, following the secretion of acidic granular content, are utilized as a trigger for the delivery of chemotherapeutic drugs. NK cells are decorated with the IS-environment-responsive micellar system to ensure the release of the payload when they attack cancer cells. Using this strategy, the immunological cytotoxic killing effect of NK cells against solid tumors is reinforced with the site-specific diffusion of chemotherapeutic agents. Harnessing the intrinsic mechanism for the recognition of abnormal cells and the tumor-homing effect of NK cells limit the adverse systemic effects of chemotherapeutic drugs. This approach may provide a pragmatic platform for the universal and effective utilization of IS formation.

Hypoxia-Triggered Transforming Immunomodulator for Cancer Immunotherapy via Photodynamically Enhanced Antigen Presentation of Dendritic Cell.

A key factor for successful cancer immunotherapy (CIT) is the extent of antigen presentation by dendritic cells (DCs) that phagocytize tumor-associated antigens (TAA) in the tumor site and migrate to tumor draining lymph nodes (TDLN) for the activation of T cells. Although various types of adjuvant delivery have been studied to enhance the activity of the DCs, poor delivery efficiency and depleted population of tumor infiltrating DCs have limited the efficacy of CIT. Herein, we report a hypoxia-responsive mesoporous silica nanocarrier (denoted as CAGE) for an enhanced CIT assisted by photodynamic therapy (PDT). In this study, CAGE was designed as a hypoxia-responsive transforming carrier to improve the intracellular uptake of nanocarriers and the delivery of adjuvants to DCs. Furthermore, PDT was exploited for the generation of immunogenic debris and recruitment of DCs in a tumor site, followed by enhanced antigen presentation. Finally, a significant inhibition of tumor growth was observed in vivo, signifying that the PDT would be a promising solution for DC-based immunotherapy.

A cyotosol-selective nitric oxide bomb as a new paradigm of an anticancer drug.

We have reported rational design of a polymeric NO delivery micelle as a cytosol-selective NO bomb. Protected NO-donors are released from the micelle under endolysosomal conditions, and then deprotected by cytosolic glutathione. Cytosol-selective NO delivery facilitates significant tumor regression without the aid of other therapeutic modalities even in intravenous administrations.

Andrographolide-loaded polymerized phenylboronic acid nanoconstruct for stimuli-responsive chemotherapy.

Along with the successful discovery of paclitaxel as an anticancer drug, natural products have drawn great attention in drug discovery. Recently, andrographolide (AND) from Andrographis paniculata was reported to provide several benefits, including an anticancer effect. However, the extremely low solubility of the compound in an aqueous medium was an obstacle to overcome for the systemic administration and clinical application of AND. Based on our previous report, we formulated a water-soluble nanoconstruct by forming a boronic ester between the cis-1,3-diol of AND with hydrophilically polymerized phenylboronic acid (pPBA). The release of loaded AND was controlled by intracellular conditions, specifically, by low pH and high ATP concentrations, due to the pH- and diol-dependent affinity of the boronic ester. Because of the intrinsic property of the PBA moiety, the pPBA-AND nanoconstruct exhibited an excellent tumor targeting ability both in vitro and in vivo. Finally, a significant inhibition of tumor growth was observed in vivo. Taken together, our strategy, which is based on the formulation of a soluble nanoconstruct using hydrophilically polymerized PBA and a cis-diol, is plausible and provides a delivery system for a wide variety of chemotherapeutics. This strategy has applications not only in cancer therapy but also broader fields such as anti-inflammation or immunotherapy.

Nitric oxide-releasing polymer incorporated ointment for cutaneous wound healing.

This work demonstrates the development of nitric oxide-releasing ointment and its potential on efficient wound healing. Nitric oxide-releasing polymer was successfully synthesized, which is composed of biocompatible Pluronic F127, branched polyethylenimine and 1-substituted diazen-1-ium-1,2-diolates. The synthesized nitric oxide-releasing polymer was incorporated into the PEG-based ointment which not only facilitated nitric oxide release in a slow manner, but also served as a moisturizer to enhance the wound healing. As compared to control groups, the nitric oxide-releasing ointment showed the accelerated wound closure with enhanced re-epithelialization, collagen deposition, and blood vessel formation in vivo. Therefore, this nitric oxide-based ointment presents the promising potential for the efficient strategy to heal the cutaneous wound.