Topical retinoids: Novel derivatives, nano lipid-based carriers, and combinations to improve chemical instability and skin irritation.

BACKGROUND: Retinoids, defined as synthetic or natural derivatives of vitamin A, have been extensively studied as anti-aging molecules that are widely applied in cosmetics. However, due to their physicochemical property, retinoids are highly unstable and extremely sensitive to light, oxygen, and temperature. Moreover, topical application of retinoids often leads to cutaneous irritation. These instabilities and irritant properties of retinoids limit their application in cosmetic and pharmaceutical products. AIM: Our study aimed to provide a systematic review to summarize the mechanisms underlying the instability and irritant properties of retinoids, as well as recent developments in addressing these challenges. METHODS: A comprehensive PubMed search was conducted using the following keywords: retinoids, chemical instability, skin irritation, retinoid derivatives, nano lipid-based carriers, liposomes, penetration-enhancer vesicles, ethosomes, niosomes, nanoemulsions, solid lipid nanoparticles, vitamins, soothing and hydrating agents, antioxidants and metal chelator and retinol combinations. Relevant researches published between 1968 and 2023 and studies related to these reports were reviewed. RESULTS: The development of new retinoid derivatives, the utilization of new delivery systems like nano lipid-based carriers and the combination with other compounds like vitamins, soothing agents, antioxidants and metal chelator have been explored to improve the stability, bioavailability, and toxicity of the retinoid family. CONCLUSIONS: Through advancements in formulation techniques, structure modification of retinoid derivatives and development of novel nano lipid-based carriers, the chemical instability and skin irritation of retinoids has been mitigated, ensuring their efficacy and potency over extended periods.

Cosmetically Approved Short-Chain Alcohol/Triethyl Citrate/Water Surfactant-Free Microemulsions and Potential Application to Transdermal Penetration of α-Arbutin.

Surfactant-free microemulsions (SFMEs) exhibited remarkable advantages and potential, attributed to their similarity to traditional surfactant-based microemulsions and the absence of surfactants. Herein, a novel SFME was developed utilizing cosmetically approved materials, such as short-chain alcohol as an amphi-solvent, triethyl citrate (TEC) as the nonpolar phase, and water as the polar phase. 1,2-Pentanediol (PtDO)/TEC/water combination can form the largest monophasic zone, accounting for ∼74% of the total phase diagram area, due to an optimal hydrophilic (water)-lipophilic (TEC) balance. Comparable to surfactant-based microemulsion, PtDO/TEC/water SFME can also be categorized into three types: water-in-oil, discontinuous, and oil-in-water. As TEC or water is increased, or PtDO is decreased, the nanoaggregates in PtDO/TEC/water SFME grow from <5 nm to tens of nanometers. The addition of α-arbutin (ABN) does not disrupt PtDO/TEC/water SFME, but rather enhances its formation, resulting in a larger monophasic area and consistent size (2.8-3.8 nm) through participating in interface assembly. Furthermore, ABN-loaded PtDO/TEC/water SFME exhibits remarkable resistance to dilution, exceptional stability, and minimal irritation. Notably, PtDO/TEC/water SFME significantly boosts ABN's solubility in water by 2 times, its percutaneous penetration rate by 3-4 times, and enables a slow-release DPPH• radical scavenging effect. This SFME serves as a safe and cosmetically suitable nanoplatform for the delivery of bioactive substances.

Strengthening the Combinational Immunotherapy from Modulating the Tumor Inflammatory Environment via Hypoxia-Responsive Nanogels.

Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, a TME hypoxia-responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy.

A nanomaterial targeting the spike protein captures SARS-CoV-2 variants and promotes viral elimination.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.

Applications of Magnetite Nanoparticles in Cancer Immunotherapies: Present Hallmarks and Future Perspectives.

Current immuno-oncotherapeutic protocols that inhibit tumor immune evasion have demonstrated great clinical success. However, the therapeutic response is limited only to a percentage of patients, and the immune-related adverse events can compromise the therapeutic benefits. Therefore, improving cancer immunotherapeutic approaches that pursue high tumor suppression efficiency and low side effects turn out to be a clinical priority. Novel magnetite nanoparticles (MNPs) exhibit great potential for therapeutic and imaging applications by utilizing their properties of superparamagnetism, good biocompatibility, as well as the easy synthesis and modulation/functionalization. In particular, the MNPs can exert magnetic hyperthermia to induce immunogenic cell death of tumor cells for effective antigen release and presentation, and meanwhile polarize tumor-associated macrophages (TAMs) to M1 phenotype for improved tumor killing capability, thus enhancing the anti-tumor immune effects. Furthermore, immune checkpoint antibodies, immune-stimulating agents, or tumor-targeting agents can be decorated on MNPs, thereby improving their selectivity for the tumor or immune cells by the unique magnetic navigation capability of MNPs to promote the tumor killing immune therapeutics with fewer side effects. This mini-review summarizes the recent progress in MNP-based immuno-oncotherapies, including activation of macrophage, promotion of cytotoxic T lymphocyte (CTL) infiltration within tumors and modulation of immune checkpoint blockade, thus further supporting the applications of MNPs in clinical therapeutic protocols.

Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.

Reinforcing the Combinational Immuno-Oncotherapy of Switching "Cold" Tumor to "Hot" by Responsive Penetrating Nanogels.

Although immuno-oncotherapy in clinic has gained great success, the immunosuppressive tumor microenvironment (TME) existing in the "cold" tumor with insufficient and exhausted lymphocytes may result in a lower-than-expected therapeutic efficiency. Therefore, a properly designed synergistic strategy that can effectively turn the "cold" tumor to "hot" should be considered to improve the therapeutic effects of immuno-oncotherapy. Herein, TME-responsive penetrating nanogels (NGs) were developed, which can improve the delivery and penetration of the co-loaded resiquimod (R848) and green tea catechin (EGCG) in tumors by a nano-sized controlled releasing system of the soluble cyclodextrin-drug inclusion complex. Consequently, the NGs effectively promoted the maturation of dendritic cells, stimulated the cytotoxic T lymphocytes (CTLs), and decreased the PD-L1 expression in tumors. The combination of NGs with the OX40 agonist (αOX40) further synergistically enhanced the activation and infiltration of CTLs into the deep tumor and inhibited the suppression effects from the regulatory T cells (Tregs). As a result, an increased ratio of active CTLs to Tregs in tumors (20.66-fold) was achieved with a 91.56% tumor suppression effect, indicating a successful switch of "cold" tumors to "hot" for an immunologically beneficial TME with significantly improved anti-tumor immune therapeutics. This strategy could be tailored to other immuno-oncotherapeutic approaches to solve the urgent efficiency concerns of the checkpoint-based treatment in clinic.

Cdk5 knocking out mediated by CRISPR-Cas9 genome editing for PD-L1 attenuation and enhanced antitumor immunity.

Blocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells via specifically knocking out Cyclin-dependent kinase 5 (Cdk5) gene in vivo. The expression of PD-L1 on tumor cells was significantly attenuated by knocking out Cdk5, leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer. Importantly, we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8+ T cells was significantly increased while regulatory T cells (Tregs) was decreased. It may be the first case to exhibit direct in vivo PD-L1 downregulation via CRISPR-Cas9 genome editing technology for cancer therapy. It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.

Intracellularly Generated Immunological Gold Nanoparticles for Combinatorial Photothermal Therapy and Immunotherapy against Tumor.

Gold nanoparticle (AuNP) has been widely used in cancer photothermal therapy (PTT) for ablating accessible tumor, while it is insufficient for inhibiting tumor metastasis and relapse in current stage. Here, we first developed a novel immunological AuNP through intracellular generation and exocytosis for combinatorial PTT and immunotherapy. Melanoma B16F10 cells were employed to generate AuNPs first and then shed nanoparticle trapped vesicles to extracellular environment with retained tumor antigens (AuNP@B16F10). By further introducing the nanoparticles into dendritic cells (DCs), DC-derived AuNPs (AuNP@DCB16F10) were generated with enhanced biosafety, which can induce hyperthermia and provoke antitumor immune responses. This immunological nanoplatform demonstrated efficient inhibition or even eradication of primary tumor, tumor metastasis, as well as tumor relapse, with significantly improved overall survival of mice. With our design, the intracellularly generated AuNPs with immunological property could act as an effective treatment modality for cancer.

Extracellular vesicles based self-grown gold nanopopcorn for combinatorial chemo-photothermal therapy.

Here, we generated a popcorn-like gold nanostructure exploiting extracellular vesicles (EVs). EVs can first serve as the vehicle for chemotherapeutic drug doxorubicin (DOX). Taking advantages of EVs, gold nanoparticles can be then self-grown surrounding the EVs, assembling into popcorn-like nanostructure. The formulated nanopopcorn, consisting of self-grown gold nanoparticles and EVs encapsulated with DOX, retained the photothermal transduction from gold nanoparticle assemblies and cytotoxicity of DOX. Under external near infrared irradiation, gold nanopopcorn can produce hyperthermia to induce tumor ablation and trigger drug release, achieving combinatorial chemo-photothermal therapy. The nanoplatform demonstrated improved cellular internalization, controlled drug release, enhanced antitumor efficacy with tumor inhibitory rate up to 98.6% and reduced side effects. Our design of popcorn-like nanostructure will contribute a novel modality for facile and green synthesis of complex metal nanostructures exploiting natural properties of EVs for combinational therapy.

Co-delivery of Doxorubicin and Interferon-γ by Thermosensitive Nanoparticles for Cancer Immunochemotherapy.

A dual-sensitive nanoparticle delivery system was constructed by incorporating an acid sensitive hydrazone linker into thermosensitive nanoparticles (TSNs) for co-encapsulating doxorubicin (DOX) and interferon γ (IFNγ) and to realize the co-delivery of chemotherapy and immunotherapy agents against melanoma. DOX, a chemotherapeutic drug, was conjugated to TSNs by a pH-sensitive chemical bond, and IFNγ, a potent immune-modulator, was absorbed into TSNs through the thermosensitivity and electrostatics of nanoparticles. Consequently, the dual sensitive drug-loaded TSN delivery systems were successfully built and showed an obvious core-shell structure, good encapsulation efficiency of drugs, sustained and sensitive drug release, prolonged circulation time, as well as excellent synergistic antitumor efficiency against B16F10 tumor bearing mice. Moreover, the combinational antitumor immune responses of hydrazone bearing DOX/IFNγ-TSN (hyd) were strengthened by activating Th1-type CD4+ T cells, cytotoxic T lymphocytes, and natural killer cells, downregulating the expression levels of immunosuppressive cytokines, such as IL10 and TGFß, and upregulating the secretion of IL2 and TNFα. Taken together, the multifunctional TSNs system provides a promising strategy for multiple drugs co-delivery with distinct properties.

Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

Immunochemotherapy mediated by thermosponge nanoparticles for synergistic anti-tumor effects.

The efficacy of immunotherapy was demonstrated to be compromised by reduced immunogenicity of tumor cells and enhanced suppressive properties of the tumor microenvironment in cancer treatment. There is growing evidence that low-dose chemotherapy can modulate the immune system to improve the anti-tumor effects of immunotherapy through multiple mechanisms, including the enhancement of tumor immunogenicity and reversal of the immunosuppressive tumor microenvironment. Here, we fabricated thermosponge nanoparticles (TSNs) for the co-delivery of chemotherapeutic drug paclitaxel (PTX) and immunostimulant interleukin-2 (IL-2) to explore the synergistic anti-tumor effects of chemotherapy and immunotherapy. The distinct temperature-responsive swelling/deswelling character facilitated the effective post-entrapment of cytokine IL-2 in nanoparticles by a facile non-solvent mild incubation method with unaffected bioactivity and favorable pharmacokinetics. PTX and IL-2 co-loaded TSNs exhibited significant inhibition on tumor growth and metastasis, and prolonged overall survival for tumor-bearing mice compared with the corresponding monotherapies. The synergistic effect was evidenced from the remodeled tumor microenvironment in which low-dose chemotherapeutics disrupted the immunosuppressive tumor microenvironment and enhanced tumor immunogenicity, and immunostimulant cytokine promoted the anti-tumor immune response of immune effector cells. The immunochemotherapy mediated by this thermosponge nanoplatform may provide a promising treatment strategy against cancer.

Tumor Microenvironment Responsive Nanogel for the Combinatorial Antitumor Effect of Chemotherapy and Immunotherapy.

A biomimetic nanogel with tumor microenvironment responsive property is developed for the combinatorial antitumor effects of chemotherapy and immunotherapy. Nanogels are formulated with hydroxypropyl-ß-cyclodextrin acrylate and two opposite charged chitosan derivatives for entrapping anticancer drug paclitaxel and precisely controlling the pH responsive capability, respectively. The nanogel supported erythrocyte membrane can achieve "nanosponge" property for delivering immunotherapeutic agent interleukin-2 without reducing the bioactivity. By responsively releasing drugs in tumor microenvironment, the nanogels significantly enhanced antitumor activity with improved drug penetration, induction of calreticulin exposure, and increased antitumor immunity. The tumor microenvironment is remodeled by the combination of these drugs in low dosage, as evidenced by the promoted infiltration of immune effector cells and reduction of immunosuppressive factors.

Lipid-enveloped zinc phosphate hybrid nanoparticles for codelivery of H-2K(b) and H-2D(b)-restricted antigenic peptides and monophosphoryl lipid A to induce antitumor immunity against melanoma.

Nanoimmunotherapy, the application of nanotechnology for sustained and targeted delivery of antigens to dendritic cells (DCs), has attracted much attention in stimulating antigen-specific immune response for antitumor therapy. In order to in situ deliver antigens to DCs for efficient antigen presentation and subsequent induction of strong cytotoxic T lymphocytes (CTL) response, here we developed a multi-peptide (TRP2180-188 and HGP10025-33) and toll-like receptor 4 agonist (monophosphoryl lipid A) codelivery system based on lipid-coated zinc phosphate hybrid nanoparticles (LZnP NPs). This delivery system equips with the chelating property of zinc to realize the high encapsulation efficiency with antigenic peptides and the influence on immune system with adjuvant-like feature. The combination of H-2K(b) and H-2D(b)-restricted peptides could provide multiple epitopes as the target of specific MHC alleles, making tumor more difficult to escape from the surveillance of immune system. The formulated LZnP nano-vaccine with the size of 30nm and outer leaflet lipid exhibited antitumor immunity as the secretion of cytokines in vitro and increased CD8(+) T cell response from IFN-γ ELISPOT analysis ex vivo. The antitumor effects were further evidenced from the prophylactic, therapeutic and metastatic melanoma tumor models compared with free antigens and single peptide-loaded nano-vaccines. These results validate the benefit of LZnP-based vaccine for antitumor immunity and indicate that co-delivery of tumor antigens along with adjuvant may be an optimized strategy for tumor immunotherapy.

Radiosensitization of TPGS-emulsified docetaxel-loaded poly(lactic-co-glycolic acid) nanoparticles in CNE-1 and A549 cells.

Docetaxel is among the most effective radiosensitizers. It is widely used as radiosensitizer in many tumors, including head and neck carcinoma. Nevertheless, poor solubility and severe hypersensitivity limit its clinical use and its therapeutic effect remains to be improved. In this study, docetaxel-loaded polymeric nanoparticles were prepared by nanoprecipitation method to be new radiosensitizer with lower side effects and higher efficacy. The physiochemical characteristics of the nanoparticles were studied. Two human tumor cell lines which are resistant to radiotherapy were used in this research. We have compared the radioenhancement efficacy of docetaxel-loaded nanoparticles with docetaxel in A549 and CNE-1 cells. Compared with docetaxel, radiosensitization of docetaxel-loaded nanoparticles was improved significantly (sensitization enhancement ratio in A549 increased 1.24-fold to 1.68-fold when the radiation was applied 2 h after the drug, p < 0.01, sensitization enhancement ratio in CNE-1 increased 1.32-fold to 1.61-fold, p < 0.05). We explored the mechanisms for the radiosensitization efficiency and the difference between docetaxel and docetaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The improved radiosensitization efficacy was associated with enhanced G2/M arrest, promoted apoptosis and the role of D-alpha-tocopheryl polyethylene glycol 1000 succinate which will enhance the cell uptake and inhibit the multiple drug resistance. Moreover, the radiosensitization efficacy of docetaxel-loaded nanoparticles was more prominent than docetaxel. In conclusion, tocopheryl polyethylene glycol 1000 succinate-emulsified docetaxel-loaded PLGA nanoparticles were more efficacious and fewer adverse effects were observed than with the commercial docetaxel formulation. Thus, PLGA nanoparticles hold promise as a radiosensitizing agent.

RGD-decorated redox-responsive d-α-tocopherol polyethylene glycol succinate-poly(lactide) nanoparticles for targeted drug delivery.

Developing multifunctional nanoparticles (NPs) to improve therapeutic efficacy is highly desirable in cancer therapy. In an attempt to respond to such a challenge, a novel copolymer, d-α-tocopherol polyethylene glycol succinate-SS-poly(lactide) (TPGS-SS-PLA) with a disulfide linkage between the TPGS and PLA units, was synthesized for paclitaxel (PTX) delivery. PTX-loaded NPs were fabricated using a nanoprecipitation method to form a particle size of ∼130 nm with good in vitro stability, which can be disassociated under intracellular reductive conditions to release PTX rapidly. The detached TPGS can further promote the drug retention and cytotoxicity through its P-glycoprotein inhibiting property. Integrin-specific targeting peptide, cyclic RGD (cRGD), was further conjugated to the surface of the NPs for targeting the drug delivery. The RGD-decorated NPs exhibited enhanced cellular uptake, PTX accumulation and cell cytotoxicity as compared to non-targeted NPs on murine melanoma B16F10 cells, PTX-sensitive human ovarian A2780 cells and PTX-resistant A2780/T cells. In vivo evaluation of the targeted NPs further showed an extended half-life, increased AUC (area under the concentration-time curve), and significant tumor growth inhibition in mouse sarcoma S180- and B16F10-tumor bearing mice, with reduced side effects as compared to Taxol® and non-targeted NPs. These results indicate that the RGD decorated redox-sensitive NPs could deliver chemotherapies specifically inside the cell via receptor-mediated endocytosis with enhanced efficacy, especially in integrin αvß3/αvß5-rich tumor cells. Such a targeted nanocarrier against receptor clustering prepared from a non-cytotoxic and biodegradable copolymer might have great potential in cancer treatment.

Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma.

Cancer immunotherapy is mainly focused on manipulating patient's own immune system to recognize and destroy cancer cells. Vaccine formulations based on nanotechnology have been developed to target delivery antigens to antigen presenting cells (APCs), especially dendritic cells (DCs) for efficiently induction of antigen-specific T cells response. To enhance DC targeting and antigen presenting efficiency, we developed erythrocyte membrane-enveloped poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles for antigenic peptide (hgp10025-33) and toll-like receptor 4 agonist, monophosphoryl lipid (MPLA). A Mannose-inserted membrane structure was constructed to actively target APCs in the lymphatic organ, and redox-sensitive peptide-conjugated PLGA nanoparticles were fabricated which prone to cleave in the intracellular milieu. The nanovaccine demonstrated the retained protein content in erythrocyte and enhanced in vitro cell uptake. An antigen-depot effect was observed in the administration site with promoted retention in draining lymph nodes. Compared with other formulations after intradermal injection, the nanovaccine prolonged tumor-occurring time, inhibited tumor growth, and suppressed tumor metastasis in prophylactic, therapeutic, and metastatic melanoma models, respectively. Additionally, we revealed that nanovaccine effectively enhanced IFN-γ secretion and CD8(+) T cell response. Taken together, these results demonstrated the great potential in applying an erythrocyte membrane-enveloped polymeric nanoplatform for an antigen delivery system in cancer immunotherapy.

Nitric oxide releasing d-α-tocopheryl polyethylene glycol succinate for enhancing antitumor activity of doxorubicin.

Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when codelivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized d-α-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release ∼90% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO3 could also serve as an enhancer for the common chemotherapeutic drug doxorubicin (DOX). Codelivering TNO3 with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (∼6.25-fold lower IC50). Moreover, for DOX-based chemotherapy in tumor-bearing mice, coadministration with TNO3 significantly extended the blood circulation time of DOX (14.7-fold t1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO3, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.