查看更多>>摘要：Ischemia/reperfusion(I/R)injury is marked by the restriction and subsequent restoration of blood supply to an organ.This process can exacerbate the initial tissue damage,leading to further disorders,disability,and even death.Extracellular vesicles(EVs)are crucial in cell communication by releasing cargo that regulates the physiological state of recipient cells.The development of EVs presents a novel avenue for delivering therapeutic agents in I/R therapy.The therapeutic potential of EVs derived from stem cells,endothelial cells,and plasma in I/R injury has been actively investigated.Therefore,this review aims to provide an overview of the pathological process of I/R injury and the biophysical properties of EVs.We noted that EVs serve as nontoxic,flexible,and multifunctional carriers for delivering therapeutic agents capable of intervening in I/R injury progression.The therapeutic efficacy of EVs can be enhanced through various engineering strategies.Improving the tropism of EVs via surface modification and modulating their contents via preconditioning are widely investigated in preclinical studies.Finally,we summarize the challenges in the production and delivery of EV-based therapy in I/R injury and discuss how it can advance.This review will encourage further exploration in developing efficient EV-based delivery systems for I/R treatment.
查看更多>>摘要：Overcoming the poor physicochemical properties of pure alginate gel and the inherent shortcomings of pure metal-organic framework(MOF),alginate/MOF composite gel has captured the interest of many researchers as a tunable platform with high stability,controllable pore structure,and enhanced biological activity.Interestingly,different from the traditional organic or inorganic nanofillers physically trapped or chemically linked within neTtworks,MOFs crystals can not only be dispersed by crosslinking polymerization,but also support self-assembly in-situ under the help of chelating cations with alginate.The latter is influenced by multiple factors and may involve some complex mechanisms of action,which is also a topic discussed deeply in this article while summarizing different preparation routes.Furthermore,various physical and chemical levels of improvement strategies and available macroforms are summarized oriented towards obtaining composite gel with ideal performance.Finally,the application status of this composite system in drug delivery,wound healing and other biomedical fields is further discussed.And the current limitations and future development directions are shed light simultaneously,which may provide guidance for the vigorous development of these composite systems.
查看更多>>摘要：Buoyed by the discovery of small-molecule tyrosine kinase inhibitors(smTKIs),significant impact has been made in cancer chemotherapeutics.However,some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties.Almost all of these molecules exhibit significant inter-and intra-patient variations in plasma concentration-time profiles.Thus,therapeutic drug monitoring,dose adjustments and precision medicine are being contemplated by clinicians.Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release,overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes.In this context,the present review comprehensively tabulates and critically analyzes all the relevant properties(T1/2,solubility,pKa,therapeutic index,IC50,metabolism etc.)of the approved smTKIs.A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs,with a focus on strategies to enhance their pharmacokinetic profile,tumor targeting ability,and therapeutic efficacy.Various nanocarrier platforms,have been discussed,highlighting their unique features and potential applications in cancer therapy.Nanoformulations have been shown to improve bioavailability and reduce dosing frequency for several smTKIs in animal models.It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future.The review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.
查看更多>>摘要：Photodynamic therapy(PDT)brings new hope for the treatment of breast cancer due to few side effects and highly effective cell killing;however,the low bioavailability of traditional photosensitizers(PSs)and their dependence on oxygen severely limits their application.Aggregation-induced emission(AIE)PSs can dramatically facilitate the photosensitization effect,which can have positive impacts on tumor PDT.To-date,most AIE PSs lack tumor targeting capability and possess poor cell delivery,resulting in their use in large quantities that are harmful to healthy tissues.In this study,a series of AIE PSs based on pyridinium-substituted triphenylamine salts(TTPAs 1-6)with different alkyl chain lengths are synthesized.Results reveal that TTPAs 1-6 promote the generation of type Ⅰ and Ⅱ ROS,including·OH and 1O2.In particular,the membrane permeability and targeting of TTPAs 4-6 bearing C8-C10 side-chains are higher than TTPAs 1-3 bearing shorter alkyl chains.Additionally,they can assemble with albumin,thereby forming nanoparticles(TTPA 4-6 NPs)in situ in blood,which significantly facilitates mitochondrial-targeting and strong ROS generation ability.Moreover,the TTPA 4-6 NPs are pH-responsive,allowing for increased accumulation or endocytosis of the tumor and enhancing the imaging or therapeutic effect.Therefore,the in vivo distributions of TTPA 4-6 NPs are visually enriched in tumor sites and exhibited excellent PDT efficacy.This work demonstrates a novel strategy for AIE PDT and has the potential to play an essential role in clinical applications using nano-delivery systems.
查看更多>>摘要：Total resection of glioblastoma(GB)tumors is nearly impossible,and systemic administration of temozolomide(TMZ)is often inadequate.This study presents a hybrid layered composite nanofiber network(LHN)designed for localized treatment in GB tumor bed.The LHN,consisting of polyvinyl alcohol and core-shell polylactic acid layers,was loaded with TMZ and rutin.In vitro analysis revealed that LHNTMZ and LHNrutin decelerated epithelial-mesenchymal transition and growth of stem-like cells,while the combination,LHNTMZ+rutin,significantly reduced sphere size compared to untreated and LHNTMZ-treated cells(P＜0.0001).In an orthotopic C6-induced GB rat model,LHNTMZ+rutin therapy demonstrated a more pronounced tumor-reducing effect than LHNTMZ alone.Tumor volume,assessed by magnetic resonance imaging,was significantly reduced in LHNTMZ+rutin-treated rats compared to untreated controls.Structural changes in tumor mitochondria,reduced membrane potential,and decreased PARP expression indicated the activation of apoptotic pathways in tumor cells,which was further confirmed by a reduction in PHH3,indicating decreased mitotic activity of tumor cells.Additionally,the local application of LHNs in the GB model mitigated aggressive tumor features without causing local tissue inflammation or adverse systemic effects.This was evidenced by a decrease in the angiogenesis marker CD31,the absence of inflammation or necrosis in H&E staining of the cerebellum,increased production of IFN-γ,decreased levels of interleukin-4 in splenic T cells,and lower serum AST levels.Our findings collectively indicate that LHNTMZ+rutin is a promising biocompatible model for the local treatment of GB.
查看更多>>摘要：Cationic polymers such as polyethylenimine have been considered promising carriers for mRNA vaccines.However,their application is hindered by their inherent toxicity and a lack of targeted delivery capability.These issues need to be addressed to develop effective cancer vaccines.In this study,we investigated whether dendritic cell membrane-coated polyethylenimine/mRNA nanoparticles(DPN)could effectively deliver mRNA to dendritic cells and induce immune responses.For comparison,we employed red blood cell membrane-coated polyethylenimine/mRNA(RPN)and plain polyethylenimine/mRNA polyplex(PN).The dendritic cell membrane coating altered the zeta potential values and surface protein patterns of PN.DPN demonstrated significantly higher uptake in dendritic cells compared to PN and RPN,and it also showed greater mRNA expression within these cells.DPN,carrying mRNA encoding luciferase,enhanced green fluorescent protein,or ovalbumin(OVA),exhibited higher protein expression in dendritic cells than the other groups.Additionally,DPN exhibited favorable mRNA escape from lysosomes post-internalization into dendritic cells.In mice,subcutaneous administration of DPN containing ovalbumin mRNA(DPNOVA)elicited higher titers of anti-OVA IgG antibodies and a greater population of OVA-specific CD8+T cells than the other groups.In a B16F10-OVA tumor model,DPNovA treatment resulted in the lowest tumor growth among the treated groups.Moreover,the population of OVA-specific CD8+T cells was the highest in the DPNOVA-treated group.While we demonstrated DPN's feasibility as an mRNA delivery system in a tumor model,the potential of DPN can be broadly extended for immunotherapeutic treatments of various diseases through mRNA delivery to antigen-presenting cells.
查看更多>>摘要：Cervical cancer stands is a formidable malignancy that poses a significant threat to women's health.Calcium overload,a minimally invasive tumor treatment,aims to accumulate an excessive concentration of Ca2+within mitochondria,triggering apoptosis.Copper sulfide(CuS)represents a photothermal mediator for tumor hyperthermia.However,relying solely on thermotherapy often proves insufficient in controlling tumor growth.Curcumin(CUR),an herbal compound with anti-cancer properties,inhibits the efflux of exogenous Ca2+while promoting its excretion from the endoplasmic reticulum into the cytoplasm.To harness these therapeutic modalities,we have developed a nanoplatform that incorporates hollow CuS nanoparticles(NPs)adorned with multiple CaCO3 particles and internally loaded with CUR.This nanocomposite exhibits high uptake and easy escape from lysosomes,along with the degradation of surrounding CaCO3,provoking the generation of abundant exogenous Ca2+in situ,ultimately damaging the mitochondria of diseased cells.Impressively,under laser excitation,the CuS NPs demonstrate a photothermal effect that accelerates the degradation of CaCO3,synergistically enhancing the antitumor effect through photothermal therapy.Additionally,fluorescence imaging reveals the distribution of these nanovehicles in vivo,indicating their effective accumulation at the tumor site.This nanoplatform shows promising outcomes for tumor-targeting and the effective treatment in a murine model of cervical cancer,achieved through cascade enhancement of calcium overload-based dual therapy.
查看更多>>摘要：The structures of solid dosage forms determine their release behaviors and are critical attributes for the design and evaluation of the solid dosage forms.Here,the 3D structures of doxazosin mesylate sustained-release tablets were parallelly assessed by micro-computed tomography(micro-CT).There were no significant differences observed in the release profiles between the RLD and the generic formulation in the conventional dissolution,but the generic preparation released slightly faster in media with ethanol during an alcohol-induced dose-dumping test.With their 3D structures obtained via micro-CT determination,the unique release behaviors of both RLD and the generic were investigated to reveal the effects of internal fine structure on the release kinetics.The structural parameters for both preparations were similar in conventional dissolution test,while the dissolutions in ethanol media showed some distinctions between RLD and generic preparations due to their static and dynamic structures.Furthermore,the findings revealed that the presence of ethanol accelerated dissolution and induced changes in internal structure of both RLD and generic preparations.Moreover,structure parameters like volume and area of outer contour,remaining solid volume and cavity volume were not equivalent between the two formulations in 40％ethanol.In conclusion,the structure data obtained from this study provided valuable insights into the diverse release behaviors observed in various modified-release formulations in drug development and quality control.
查看更多>>摘要：Parkinson's disease(PD)poses a significant therapeutic challenge,mainly due to the limited ability of drugs to cross the blood-brain barrier(BBB)without undergoing metabolic transformations.Levodopa,a key component of dopamine replacement therapy,effectively enhances dopaminergic activity.However,it encounters obstacles from peripheral decarboxylase,hindering its passage through the BBB.Furthermore,levodopa metabolism generates reactive oxygen species(ROS),exacerbating neuronal damage.Systemic pulsatile dosing further disrupts natural physiological buffering mechanisms.In this investigation,we devised a ROS-responsive levodopa prodrug system capable of releasing the drug and reducing ROS levels in the central nervous system.The prodrug was incorporated within second near-infrared region(NIR-Ⅱ)gold nanorods(AuNRs)and utilized angiopep-2(ANG)for targeted delivery across the BBB.The processes of tight junction opening and endocytosis facilitated improved levodopa transport.ROS scavenging helped alleviate neuronal oxidative stress,leading to enhanced behavioral outcomes and reduced oxidative stress levels in a mouse model of PD.Following treatment,the PD mouse model exhibited enhanced flexibility,balance,and spontaneous exploratory activity.This approach successfully alleviated the motor impairments associated with the disease model.Consequently,our strategy,utilizing NIR-Ⅱ AuNRs and ANG-mediated BBB penetration,coupled with the responsive release of levodopa,offers a promising approach for dopamine supplementation and microenvironmental regulation.This system holds substantial potential as an efficient platform for delivering neuroprotective drugs and advancing PD therapy.
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