A Vanadium-Based Nanoplatform Synergizing Ferroptotic-like Therapy with Glucose Metabolism Intervention for Enhanced Cancer Cell Death and Antitumor Immunity.

Ferroptosis activation has been considered a mighty weapon for cancer treatment, and growing attention is being paid to reinforcing tumor cells' sensitivity to ferroptosis. However, the existence of certain ferroptosis resistance mechanisms, especially the abnormal metabolism of tumor cells, has long been underestimated. We propose an enhanced ferroptosis-activating pattern via regulating tumor cells' glycometabolism and construct a nanoplatform named PMVL, which is composed of lonidamine (LND)-loaded tannic acid coordinated vanadium oxides with the camouflage of PD-L1 inhibiting peptide-modified tumor cell membrane. This work reveals that the mixed valence of vanadium (VIV and VV) in PMVL triggers ferroptosis due to the self-cyclic valence alteration of V, the process of which generates •OH for lipid peroxide accumulation (VIV → VV) and depletes glutathione (GSH) for glutathione peroxidase (GPX4) deactivation (VV → VIV). Notably, LND strengthens ferroptosis by dual suppression of glycolysis (decreasing ATP supply) and the pentose phosphate pathway (decreasing NADPH production), causing anabatic GSH consumption. Besides, the inhibited glycolysis generates less intracellular lactic acid and alleviates the acidity of tumor microenvironment, preventing immunosuppressive M2 macrophage polarization. In vitro and in vivo data demonstrate the glycometabolism-intervention-enhanced ferroptosis and boosted immunity activation, potentially providing opportunities and possibilities for synergetic cancer therapy.

Multifunctional biomimetic nanoplatform based on photodynamic therapy and DNA repair intervention for the synergistic treatment of breast cancer.

Photodynamic therapy (PDT) is a minimally invasive and locally effective treatment method, which has been used in the clinical treatment of a variety of superficial tumors. In recent years, PDT has received extensive attention due to its induction of immunogenic cell death (ICD). However, the repair mechanism of tumor cells and low immune response limit the further development of PDT. To this end, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) is developed to co-deliver the photosensitizer Chlorin e6 (Ce6) and Olaparib (Ola) with the function of preventing DNA repair. The nanoplatform shows efficient tumor targeting and cellular internalization properties due to cell membrane camouflage, and Ce6 and Ola produce a significant synergistic anti-tumor effect under laser irradiation. Meanwhile, the nanoplatform can also activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-interferon gene stimulator signaling (cGAS-STING) pathway to produce cytokines. The damage-associated molecular patterns induced by ICD can work with these cytokines to recruit and stimulate the maturation of dendritic cells and induce the systemic anti-tumor immune response. Overall, this multifunctional biomimetic nanoplatform integrating PDT, chemotherapy, and immunotherapy is highlighted here to boost anti-tumor therapy. STATEMENT OF SIGNIFICANCE: Self-repair of DNA damage is the most important reason for the failure of primary tumor eradication and the formation of secondary and metastatic tumors. To address this issue, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) was developed to integrate a photosensitizer Chlorine a6 and a poly (ADP-ribose) polymerase inhibitor Olaparib. With tumor targeting ability and controlled release of drugs, the MPCO was expected to enhance tumor immunogenicity and facilitate antitumor immunity through the induction of immunogenic cell death as well as the activation of the cGAS-STING pathway. This study develops a promising combination strategy against tumors and has substantial implications for the prognosis of patients with breast cancer.

Oxygen-boosted biomimetic nanoplatform for synergetic phototherapy/ferroptosis activation and reversal of immune-suppressed tumor microenvironment.

Photodynamic therapy (PDT) induces apoptosis of cancer cells by generating cytotoxic reactive oxygen species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform is fabricated for the precise delivery of photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, ferroptosis activation and CD47-SIRPα blockade. Hemin's catalase-mimetic activity alleviates TME hypoxia and enhances PDT. The nanoplatform activates ferroptosis via both classical (down-regulating glutathione peroxidase 4 pathway) and non-classical (inducing Fe2+ overload) modes. Besides the role of hemin in consuming glutathione and up-regulating heme oxygenase-1 expression, interestingly, we observe that Ce6 enhance ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity is reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 has been revealed for the first time to sensitize ferroptosis by down-regulating system Xc-. This work sheds new light on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and ferroptosis activation, laying the theoretical foundation for novel combinational modes of cancer treatment.

Advances in autophagy as a target in the treatment of tumours.

Autophagy is a multi-step lysosomal degradation process, which regulates energy and material metabolism and has been used to maintain homeostasis. Autophagy has been shown to be involved in the regulation of health and disease. But at present, there is no consensus on the relationship between autophagy and tumour, and we consider that it plays a dual role in the occurrence and development of tumour. That is to say, under certain conditions, it can inhibit the occurrence of tumour, but it can also promote the process of tumour. Therefore, autophagy could be used as a target for tumour treatment. The regulation of autophagy plays a synergistic role in the radiotherapy, chemotherapy, phototherapy and immunotherapy of tumour, and nano drug delivery system provides a promising strategy for improving the efficacy of autophagy regulation. This review summarised the progress in the regulatory pathways and factors of autophagy as well as nanoformulations as carriers for the delivery of autophagy modulators.

NIR-triggerable ROS-responsive cluster-bomb-like nanoplatform for enhanced tumor penetration, phototherapy efficiency and antitumor immunity.

The restricted tumor penetration has been regarded as the Achilles' Heels of most nanomedicines, largely limiting their efficacy. To address this challenge, a cluster-bomb-like nanoplatform named CPIM is prepared, which for the first time combines size-transforming and transcytosis strategies, thus enhancing both passive and active transport. For passive diffusion, the "cluster-bomb" CPIM (135 nm) releases drug-loaded "bomblets" (IR780/1-methyl-tryptophan (1 MT) loaded PAMAM, <10 nm) in response to the high reactive-oxygen-species (ROS) concentration in tumor microenvironment (TME), which promotes intratumoral diffusion. Besides, IR780 generates ROS upon NIR irradiation and intensifies this responsiveness; therefore, there exists a NIR-triggered self-destructive behavior, rendering CPIM spatiotemporal controllability. For active transport, the nanoplatform is proven to be delivered via transcytosis with/without NIR irradiation. Regarding the anti-cancer performance, CPIM strengthens the photodynamic therapy (PDT)/photothermal therapy (PTT) activity of IR780 and IDO pathway inhibition effect of 1 MT, thus exhibiting a strongest inhibitory effect on primary tumor. CPIM also optimally induces immunogenic cell death, reverses the "cold" TME to a "hot" one and evokes systemic immune response, thus exerting an abscopal and anti-metastasis effects. In conclusion, this work provides a facile, simple yet effective strategy to enhance the tumor penetration, tumor-killing effect and antitumor immunity of nanomedicines.

Progress in the study of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) reversing multidrug resistance.

Currently, multidrug resistance (MDR) is one of the major reasons for failure in clinical cancer chemotherapy. Overexpression of the ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which significantly increases the efflux of anticancer drugs from tumor cells, enhances MDR. In the past few decades, four generations of P-gp inhibitors have appeared. However, they are limited in clinical application due to their severe toxic side effects. As a P-gp inhibitor and carrier for loading chemotherapy agents, TPGS has received increasing attention due to its advantages and unique properties of reversing MDR. TPGS is an amphipathic agent that increases the solubility of most chemotherapy drugs and decreases severe side effects. In addition, TPGS is an excellent carrier with P-gp-inhibiting ability. In this review, we summarize the latest articles on TPGS-based nanodelivery systems to prevent MDR.

A review of stimuli-responsive polymeric micelles for tumor-targeted delivery of curcumin.

Despite a potential drug with multiple pharmacological activities, curcumin has disadvantages of the poor water solubility, rapid metabolism, low bioavailability, which considerably limit its clinical application. Currently, polymeric micelles (PMs) have gained widespread concern due to their advantageous physical and chemical properties, easy preparation, and biocompatibility. They can be used to improve drug solubility, prolong blood circulation time, and allow passive targeted drug delivery to tumor through enhanced penetration and retention effect. Moreover, studies focused on tumor microenvironment offer alternatives to design stimulus-responsive smart PMs based on low pH, high levels of glutathione, altered enzyme expression, increased reactive oxygen species production, and hypoxia. There are various external stimuli, such as light, ultrasound, and temperature. These endogenous/exogenous stimuli can be used for the research of intelligent micelles. Intelligent PMs can effectively load curcumin with improved solubility, and intelligently respond to release the drug at a controlled rate at targeted sites such as tumors to avoid early release, which markedly improves the bioavailability of curcumin. The present review is aimed to discuss and summarize recent developments in research of curcumin-loaded intelligent PMs based on endogenous and exogenous stimuli, and facilitates the development of novel delivery systems for future research.

Galactosamine-modified PEG-PLA/TPGS micelles for the oral delivery of curcumin.

In this study, galactosamine-modified poly(ethylene glycol)-poly(lactide) (Gal-PEG-PLA) polymers were synthesized and Gal-PEG-PLA/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles named as GPP micelles were designed to promote the oral absorption of a hydrophobic drug, curcumin (CUR). CUR-loaded Gal-PEG-PLA/TPGS micelles (CUR@GPP micelles) were fabricated using the thin-film dispersion method. CUR@GPP micelles had a size of about 100 nm, a near-neutral zeta potential, drug loading (DL) of 14.6%, and sustained release properties. GPP micelles with high Gal density (GPP3 micelles) were superior in facilitating uptake in epithelial cells and improving intestinal permeation. In situ intestinal absorption studies suggested that the jejunum and ileum were the best absorption segments in the intestinal tract. Additionally, biodistribution results revealed that GPP3 micelles could be remarkably taken up by the jejunum and ileum. Pharmacokinetics revealed that the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) for CUR@GPP3 micelles were both significantly increased, and that the relative bioavailability of CUR@GPP3 micelles to CUR-loaded mPEG-PLA/TPGS micelles (CUR@PP micelles) was 258.8%. Furthermore, CUR-loaded micelles could reduce damage to the liver and intestinal tissues. This study highlights the importance of Gal content in the design of targeting nanocarrier Gal-modified micelles, which have broad prospects for oral delivery of hydrophobic drugs. Therefore, they could serve as a promising candidate for targeted delivery to the liver.

Chondroitin sulfate derived theranostic and therapeutic nanocarriers for tumor-targeted drug delivery.

The standard chemotherapy is facing the challenges of lack of cancer selectivity and development of drug resistance. Currently, with the application of nanotechnology, the rationally designed nanocarriers of chondroitin sulfate (CS) have been fabricated and their unique features of low toxicity, biocompatibility, and active and passive targeting made them drug delivery vehicles of the choice for cancer therapy. The hydrophilic and anionic CS could be incorporated as a building block into- or decorated on the surface of nanoformulations. Micellar nanoparticles (NPs) self-assembled from amphiphilic CS-drug conjugates and CS-polymer conjugates, polyelectrolyte complexes (PECs) and nanogels of CS have been widely implicated in cancer directed therapy. The surface modulation of organic, inorganic, lipid and metallic NPs with CS promotes the receptor-mediated internalization of NPs to the tumor cells. The potential contribution of CS and CS-proteoglycans (CSPGs) in the pathogenesis of various cancer types, and CS nanocarriers in immunotherapy, radiotherapy, sonodynamic therapy (SDT) and photodynamic therapy (PDT) of cancer are summarized in this review paper.

Recent progress of functionalised graphene oxide in cancer therapy.

In recent years, graphene oxide (GO) nanomaterials have attracted wide attention due to their large surface area, strong light sensitivity and good biocompatibility in cancer treatment. The rich oxygen-containing functional groups on the surface provide it with the opportunity to be modified by many functional molecules to expand biological applications and reduce toxicity. In this review, the properties of GO and the methods of surface modification are presented, and the toxicity of GO is analysed. In addition, the current applications of GO in cancer diagnoses and treatments including biological imaging, drug and gene delivery, phototherapy and imaging-mediated combination therapy are summarised. Finally, the prospects and challenges of GO in cancer treatment are discussed.

Current development in the formulations of non-injection administration of paclitaxel.

Paclitaxel (PTX) belongs to a class of taxane anti-tumor drug used for the clinic treatment of breast cancer, ovarian cancer, non-small-cell lung cancer, and so on. PTX has poor water solubility and oral bioavailability. It is generally administered via intravenous (i.v.) infusion. Traditional PTX injectable preparations contain Cremophor-EL and ethanol to improve its solubility, which would result in adverse reactions like severe hypersensitivity, neutropenia, etc. Adverse reactions can be reduced only by complicated pretreatment with glucocorticoid and antihistamines drugs and followed by PTX slow infusion for three hours, which has brought significant inconvenience to the patients. Though, a new-generation PTX formulation, Abraxane, free of Cremophor-EL and ethanol, is still being administrated by frequent i.v. infusions and extremely expensive. Therefore, non-injection administration of PTX is urgently needed to avoid the side effects as well as reduce inconvenience to the patients. Recently, a variety of non-injection drug delivery systems (DDSs) of PTX have been developed. This review aims to discuss the progress of non-injectable administration systems of PTX, including oral administration systems, vaginal administration systems, implantable DDSs, transdermal DDSs and intranasal administration for the future study and clinical applications.