Place of intravitreal dexamethasone implant in the treatment armamentarium of diabetic macular edema

Diabetic macular edema(DME)is a very important and well-known cause of visual loss in diabetics.Blood-retina barrier disruption and consequent intraretinal fluid accumulation may lead to retinal thickening at the posterior pole namely DME.Even though it is not clearly understood,current evidence suggests that chronic low-grade inflammation characterized with various cytokines has a major role in the occurrence of DME.Clinical trials are continuously shaping our treatment approaches for the eyes with DME.Today,vascular endothelial growth factor(VEGF)inhibitor and steroid administrations are the main alternatives in DME treatment.Dexamethasone(DEX)implant(Ozurdex®;Allergan,Inc.,Irvine,CA,United States)was approved by the United States Food&Drug Administration in 2014 for DME treatment.The implant is made up of a biodegradable solid copolymer that is broken down by releasing its active ingredient into the vitreous cavity over time.Biphasic release feature of this sustained-release drug delivery system ensures its efficacy for up to 6 mo with an acceptable and manageable safety profile.DEX implant provides a favorable anatomical and functional outcome in DME as shown in several randomized-controlled studies but has a relatively higher ocular side-effect profile such as increased risk of cataract formation and raised intraocular pressure when compared to the gold standard anti-VEGF agents.Thus,DEX implant becomes the second-line treatment option demonstrating inadequate clinical response to anti-VEGF therapy.However,it can be preferred as the first-line treatment in vitrectomized and pseudophakic eyes.Even in some selected conditions DEX implant is favored over anti-VEGF agents where the use of VEGF-inhibitors is either inappropriate or contraindicated such as the patients with a recent history of a major cardiovascular or cerebrovascular event,pregnancy and noncompliant to frequent visits.This mini-review briefly overviews the efficacy,safety profile and complications of DEX implant and summarizes the outcome of DEX implant administration in major clinical studies on DME treatment.

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment

The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins.In recent years,toxins have been widely used as warheads for antibody-drug conjugates(ADCs)due to their eff-cient killing activity against various cancer cells.Although ADCs confer certain targeting properties to the toxins,low drug loading capacity,possible immunogenicity,and other drawbacks also limit the po-tential application of ADCs.Recently,non-ADC delivery strategies for toxins have been extensively investigated.To further understand the application of toxins in anti-tumor,this paper provided an over-view of prodrugs,nanodrug delivery systems,and biomimetic drug delivery systems.In addition,toxins and their combination strategies with other therapies were discussed.Finally,the prospect and challenge of toxins in cancertreatmentwerealso summarized.

Unlocking the potential of amorphous calcium carbonate: A star ascending in the realm of biomedical application

Calcium-based biomaterials have been intensively studied in the field of drug delivery owing to their excellent biocompatibility and biodegradability.Calcium-based materials can also deliver contrast agents,which can enhance real-time imaging and exert a Ca^(2+)-interfering therapeutic effect.Based on these characteristics,amorphous calcium carbonate(ACC),as a brunch of calcium-based biomaterials,has the potential to become a widely used biomaterial.Highly functional ACC can be either discovered in natural organisms or obtained by chemical synthesis However,the standalone presence of ACC is unstable in vivo.Additives are required to be used as stabilizers or core-shell structures formed by permeable layers or lipids with modified molecules constructed to maintain the stability of ACC until the ACC carrier reaches its destination.ACC has high chemical instability and can produce biocompatible products when exposed to an acidic condition in vivo,such as Ca^(2+) with an immune-regulating ability and CO_(2) with an imaging-enhancing ability.Owing to these characteristics,ACC has been studied for selfsacrificing templates of carrier construction,targeted delivery of oncology drugs,immunomodulation,tumor imaging,tissue engineering,and calcium supplementation.Emphasis in this paper has been placed on the origin,structural features,and multiple applications of ACC.Meanwhile,ACC faces many challenges in clinical translation,and long-term basic research is required to overcome these challenges.We hope that this study will contribute to future innovative research on ACC.

Imaging-Guided Cancer Therapy Based on Multifunctional Magnetic Nanoparticles

In recent years,magnetic nanoparticles(MNPs)have received great attention within the field of biomedicine,especially for cancer therapy.This is because MNPs have many excellent physical and chemical properties to provide sufficient imaging information along with satisfactory therapeutic efficacy.Moreover,by virtue of various modification strategies,the obtained multifunctional MNPs can further achieve synergized multimodal cancer theranostic,which is worthy of further study.In this review,we summarize the recent developments in imaging-guided strategies and synergistic cancer therapy based on multifunctional MNPs.Then,we discuss the challenge and perspective of the next generation of MNPs-based imaging-guided cancer therapy,hoping to provide guidance in potential applications.

Purpurolide C-based microneedle promotes macrophage-mediated diabetic wound healing via inhibiting TLR4-MD2 dimerization and MYD88 phosphorylation

Delayed wound healing in diabetes is a global challenge,and the development of related drugs is a clinical problem to be solved.In this study,purpurolide C(PC),a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum,was found to promote diabetic wound healing.To investigate the key regulation targets of PC,in vitro RNA-seq,molecular docking calcula-tions,TLR4-MD2 dimerization SDS-PAGE detection,and surface plasmon resonance(SPR)were per-formed,indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation.Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing.Furthermore,a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC(PC@MLIP MN)was developed,which overcame the poor water solubility and weak skin permeability of PC,so that successfully punctured the skin and delivered PC to local tissues,and accurately regulated macrophage polarization in diabetic wound management.Overall,PC is an anti-inflammatory small molecule compound with a well-defined structure and dualtarget regulation,and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.

Plant-derived nanovesicles: Further exploration of biomedical function and application potential

Extracellular vesicles(EVs)are phospholipid bilayer vesicles actively secreted by cells,that contain a variety of functional nucleic acids,proteins,and lipids,and are important mediums of intercellular communication.Based on their natural properties,EVs can not only retain the pharmacological effects of their source cells but also serve as natural delivery carriers.Among them,plant-derived nanovesicles(PNVs)are characterized as natural disease therapeutics with many advantages such as simplicity,safety,eco-friendliness,low cost,and low toxicity due to their abundant resources,large yield,and low risk of immunogenicity in vivo.This review systematically introduces the biogenesis,isolation methods,physical characterization,and components of PNVs,and describes their administration and cellular uptake as therapeutic agents.We highlight the therapeutic potential of PNVs as therapeutic agents and drug delivery carriers,including anti-inflammatory,anticancer,wound healing,regeneration,and antiaging properties as well as their potential use in the treatment of liver disease and COVID-19.Finally,the toxicity and immunogenicity,the current clinical application,and the possible challenges in the future development of PNVs were analyzed.We expect the functions of PNVs to be further explored to promote clinical translation,thereby facilitating the development of a new framework for the treatment of human diseases.

Smart drug delivery systems for precise cancer therapy

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.

Construction of Nanocarriers Based on Endogenous Cell Membrane and Their Application in Nanomedicine

Inspired by the adaptation of cells to the surrounding environment,the combination of cell membrane and nanomaterials has gradually become a new type of biomimetic nanocomposite.The construction of endogenous membrane biomimetic nanocarriers(EMBNs)not only retains the structure of membrane surface protein,but also has the properties of nanoparticles(NPs),also provides the ability of natural interaction between nanomaterials and organisms,thus overcoming the severe challenges faced by traditional nanodelivery systems in clinical application.In this paper,the construction methods of EMBNs are reviewed,focusing on a simple method to prepare membrane proteins.Secondly,EMBNs were classified according a variety of cell membranes.Finally,the unique advantages of EMBNs in nanomedicine are introduced,including improving biocompatibility,homologous targeting ability,prolonging blood circulation time and immune escape abilty.In nanomedicine,such as targeted delivery,phototherapy,immunotherapy and tumor imaging,multifaceted biological interfaces through membrane masking provide a new approach for the development of multifunctional NPs.

Development of new ionic gelation strategy： Towards the preparation of new monodisperse and stable hyaluronic acid/ β-cyclodextrin-grafted chitosan nanoparticles as drug delivery carriers for doxorubicin

In the present study, β-cyclodextrin-grafted chitosan nanoparticles （β-CD- g-CS NPs） were prepared using a new ionic gelation strategy involving a synergistic effect of NaCI （150 mmol/L）, 4-（2-hydroxyethyl）-1-piperazineethanesulfonic acid （HEPES, 10 mmol/L）, and water bath sonication. This new strategy afforded smaller and more monodisperse β-CD-g-CS NPs vs. the classical ionic gelation method. New HA8β-CD-g-CS NPs were also prepared using the above-mentioned strategy by adding hyaluronic acid （HA） to the β-CD-g-CS copolymer at different weight ratios until the ZP values conversion. The best result was obtained with the weight ratio of w（HA）：w（β-CD-g-CS） = 2：1 and furnished new spherical and smooth HA/β-CD-g-CS NPs. Furthermore, the stability of β- CD-g-CS NPs and HA/β-CD-g-CS NPs at 4℃ in physiological medium （pH 7.4） was compared for 3 weeks period and showed that HA/β-CD-g-CS NPs were more stable all maintaining their monodispersity and high negative ZP values compared to β-CD-g-CS NPs. Finally, preliminary study of HA/β-CD-g-CS NPs as carrier for the controlled release of the anticancer drug doxorubicin was investigated. These new HA/β-CD-g-CS NPs can potentially be used as drug delivery and targeting systems for cancer treatment.