Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Pathogenesis, diagnosis, and treatment of epilepsy: electromagnetic stimulation-mediated neuromodulation therapy and new technologies

Epilepsy is a severe,relapsing,and multifactorial neurological disorder.Studies regarding the accurate diagnosis,prognosis,and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy.The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression,protein expression,ion channel activity,energy metabolites,and gut microbiota composition.Satisfactory results are lacking for conventional treatments for epilepsy.Surgical resection of lesions,drug therapy,and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy.Non-pharmacological treatments,such as a ketogenic diet,gene therapy for nerve regeneration,and neural regulation,are currently areas of research focus.This review provides a comprehensive overview of the pathogenesis,diagnostic methods,and treatments of epilepsy.It also elaborates on the theoretical basis,treatment modes,and effects of invasive nerve stimulation in neurotherapy,including percutaneous vagus nerve stimulation,deep brain electrical stimulation,repetitive nerve electrical stimulation,in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation.Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures.Additionally,many new technologies for the diagnosis and treatment of epilepsy are being explored.However,current research is mainly focused on analyzing patients’clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level,which has led to a lack of consensus regarding the mechanisms related to the disease.

Advances of nanoparticles in transmucosal drug delivery

Transmucosal drug administration represents a potential strategy for enhancing treatment efficacy and reducing side effects by avoiding the first-pass effect into the systemic circulation and delivering therapeutics directly to the target disease site.However,many challenges still remain in its clinical application,including low drug availability and limited retention time in the mucosa.The burgeoning advancement of nanotechnologies offers great potential to overcome the above limitations,leveraging their distinct advantages of high drug-loading capacity and strong permeability.In this review,the latest developments of nanoparticles(NPs)in transmucosal drug delivery as well as their clinical applications are discussed.

Recent advances of bioresponsive polymeric nanomedicine for cancer therapy

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes,and can exert its therapeutic efficacy within a confined space.These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues.Moreover,bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage.In this review,recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized.We mainly discuss three categories,including acidity-sensitive,redox-responsive,and enzyme-triggered polymeric nanosystems.The important issues regarding clinical translation such as reproducibility,manufacture,and probable toxicity,are also commented.

Macroencapsulation Devices for Cell Therapy

Macroencapsulation has been widely used in cell therapy due to its capability to provide immune-privileged sites for implanted allogeneic or xenogeneic cells.Macroencapsulation also serves to provide mechanical and physiochemical support for maintaining cell expansion and promoting therapeutic func-tions.Macroencapsulation devices such as membrane-controlled release systems,hydrogels,micronee-dle(MN)array patches,and three-dimensional(3D)stents have shown promising in-lab and preclinical results in the maintenance of long-term cell survival and the strengthening of treatment effi-cacy.Recent studies focus on expanding the applications of these devices to new cell-based areas such as chimeric antigen receptor(CAR)-T cell delivery,cardiovascular disease therapy,and the exploration of new materials,construction methods,and working principles to augment treatment efficacy and prolong therapy duration.Here,we survey innovative platforms and approaches,as well as translation outcomes,for advancing the performance and applications of macrodevices for cell-based therapies.A discussion and critique regarding future opportunities and challenges is also provided.

Research Article Ferric iron coordinated cisplatin prodrug reprograms the immunecold tumor microenvironment through tumor hypoxia relief for enhanced cancer photodynamic-immunotherapy

The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxia and reverse immunosuppression of cold tumors.In this study,the oxygen(O_(2))self-replenishing nano-enabled coordination platform can be used to induce potent antitumor immune response in cold tumors.The nanoplatform can produce O_(2)by catalyzing hydrogen peroxide(H_(2)O_(2))in tumor site effectively,showing excellent photodynamic therapy(PDT)performance.Meanwhile,it can further trigger immunogenic cell death(ICD),enhance T cell infiltration,reverse immunosuppression,and reprogram the immune-cold tumor microenvironment.In vitro and in vivo results demonstrate that the nanoplatform has potential for eradicating tumors and long-term immunological memory effect.The nanoplatform opens up a strategy for reprograming the immunosuppressive microenvironment in cold tumors.

Engineering SIRPα cellular membrane-based nanovesicles for combination immunotherapy

Immune checkpoint inhibitors(ICIs)have revolutionized cancer treatment for their unprecedented clinical efficacy.Signal regulatory proteinα(SIRPα)is a phagocytic checkpoint expressed on macrophages,dendritic cells,other myeloid cells.Cancer cells inhibit macrophage phagocytosis through the interaction of the CD47-SIRPαaxis.Disrupting the CD47-SIRPαaxis has therefore been a promising strategy in restoring the immune attack against cancer.Herein,we engineered cellular membrane nanovesicles(NVs)presenting SIRPαreceptors for phagocytosis checkpoint blockade to augment the antitumor immune response.Furthermore,zebularine(Zeb),an inhibitor of DNA methyltransferase,was encapsulated into SIRPαNVs to reprogram the immunosuppressive tumor microenvironment together with blockade of phagocytosis checkpoint.It is demonstrated that SIRPα@Zeb can improve tumor immunogenicity,the polarization of tumor-associated macrophages to the M1 phenotype,increase the infiltration of CD8^(+)T lymphocytes in tumors.The robust antitumor immune response induced by SIRPα@Zeb significantly suppressed tumor growth and extended mice-bearing melanoma xenograft survival.

Biomedical polymers: synthesis, properties, and applications

Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.

Materials and Carriers Development for Glucose-Responsive Insulin

CONSPECTUS:Insulin replacement therapy is an essential and effective treatment strategy for controlling the blood glucose level(BGL)of people without sufficient endogenous insulin production.However,insulin therapy faces challenges such as daily multiple injections and hypoglycemia risk arising from its narrow therapeutic index,which together leads to poor BGL control.Thus,glucose-responsive insulin delivery systems that can mimicβ-cell function are developed to improve BGL control and reduce injection frequency.Glucose-responsive materials-based insulin delivery systems are competent in tightly controlling the BGL with an additional benefit of reducing the hypoglycemia risk.