Phytocompounds and lipid-based drug delivery system for neurodegenerative diseases

Across the annals of time,organic molecules sourced from nature have found innumerable uses within the realms of healthcare,pharmaceuticals,and the study of living organisms.This abundant source of natural compounds has exhibited immense promise in the cure of diverse ailments,mainly neurodegenerative diseases owing to their minimum toxic and adverse effects.However,different challenges exist with phytocompounds from plants such as poor permeation,poor solubility(water/lipid),unsteadiness under extremely acidic pH conditions,and lack of targeting specificity.Furthermore,as a result of the existence of blood-brain barrier membrane and inconvenient pharmacokinetics characteristics of phytocompounds,their passage into the brain is constrained.In order to address this issue and augment the transportation of medications into the brain at a therapeutically effective level,it is imperative to formulate an innovative and pragmatic strategy.Many papers have shown that nanoformulations containing phytocompounds(resveratrol,quercetin,ferulic acid,curcumin,berberine,etc.)effectively improved many neurodegenerative diseases such as Parkinson’s,Alzheimer’s and Huntington’s diseases.This study provides an overview of phytocompounds that are used in nanosized lipid drug delivery systems.These systems are categorized according to lipid types and preparation techniques used in the formulation.Some studies regarding these systems and phytocompounds are also summarized.

Recent advances in zwitterionic nanoscale drug delivery systems to overcome biological barriers

Nanoscale drug delivery systems(nDDS)have been employed widely in enhancing the therapeutic efficacy of drugs against diseases with reduced side effects.Although several nDDS have been successfully approved for clinical use up to now,biological barriers between the administration site and the target site hinder the wider clinical adoption of nDDS in disease treatment.Polyethylene glycol(PEG)-modification(or PEGylation)has been regarded as the gold standard for stabilising nDDS in complex biological environment.However,the accelerated blood clearance(ABC)of PEGylated nDDS after repeated injections becomes great challenges for their clinical applications.Zwitterionic polymer,a novel family of antifouling materials,have evolved as an alternative to PEG due to their super-hydrophilicity and biocompatibility.Zwitterionic nDDS could avoid the generation of ABC phenomenon and exhibit longer blood circulation time than the PEGylated analogues.More impressively,zwitterionic nDDS have recently been shown to overcome multiple biological barriers such as nonspecific organ distribution,pressure gradients,impermeable cell membranes and lysosomal degradation without the need of any complex chemical modifications.The realization of overcoming multiple biological barriers by zwitterionic nDDS may simplify the current overly complex design of nDDS,which could facilitate their better clinical translation.Herein,we summarise the recent progress of zwitterionic nDDS at overcoming various biological barriers and analyse their underlyingmechanisms.Finally,prospects and challenges are introduced to guide the rational design of zwitterionic nDDS for disease treatment.

The state-of-the-art of atmospheric pressure plasma for transdermal drug delivery

Plasma-enhanced transdermal drug delivery(TDD) presents advantages over traditional methods,including painless application, minimal skin damage, and rapid recovery of permeability. To harness its clinical potential, factors related to plasma’s unique properties, such as reactive species and electric fields, must be carefully considered.This review provides a concise summary of conventional TDD methods and subsequently offers a comprehensive examination of the current state-of-the-art in plasma-enhanced TDD. This includes an analysis of the impact of plasma on HaCaT human keratinocyte cells, ex vivo/in vivo studies, and clinical research on plasma-assisted TDD. Moreover, the review explores the effects of plasma on skin physical characteristics such as microhole formation, transepidermal water loss(TEWL), molecular structure of the stratum corneum(SC), and skin resistance. Additionally, it discusses the involvement of various reactive agents in plasma-enhanced TDD, encompassing electric fields,charged particles, UV/VUV radiation, heat, and reactive species. Lastly, the review briefly addresses the temporal behavior of the skin after plasma treatment, safety considerations, and potential risks associated with plasma-enhanced TDD.

Ionic liquids as the effective technology for enhancing transdermal drug delivery: Design principles, roles, mechanisms, and future challenges

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs;as novel solvents for improving the solubility of drugs in carriers;as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs;and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

Advances in Transdermal Drug Delivery for Cancer Therapy

Transdermal drug delivery offers a promising alternative to traditional cancer therapies by providing a non-invasive,controlled,and targeted delivery of therapeutic agents.This paper explores the advancements,benefits,and challenges associated with transdermal drug delivery systems(TDDS)in cancer treatment.It highlights the mechanisms of action,key technologies,and the potential impact on patient outcomes.By examining recent studies and clinical trials,this paper aims to provide a comprehensive overview of the efficacy,safety,and prospects of transdermal drug delivery in oncology.

Ionizable drug delivery systems for efficient and selective gene therapy

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.

Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer:A review

The complication of diabetes,which is known as diabetic foot ulcer(DFU),is a significant concern due to its association with high rates of disability and mortality.It not only severely affects patients’quality of life,but also imposes a substantial burden on the healthcare system.In spite of efforts made in clinical practice,treating DFU remains a challenging task.While mesenchymal stem cell(MSC)therapy has been extensively studied in treating DFU,the current efficacy of DFU healing using this method is still inadequate.However,in recent years,several MSCs-based drug delivery systems have emerged,which have shown to increase the efficacy of MSC therapy,especially in treating DFU.This review summarized the application of diverse MSCs-based drug delivery systems in treating DFU and suggested potential prospects for the future research.

Interpeduncular cistern intrathecal targeted drug delivery for intractable postherpetic neuralgia: A case report

BACKGROUND Intractable postherpetic neuralgia(PHN)can be difficult to manage even with aggressive multimodal therapies.Patients who experience uncontrolled refractory cranial PHN despite conservative treatment may benefit from an intrathecal drug delivery system(IDDS).For craniofacial neuropathic pain,the traditional approach has been to place the intrathecal catheter tip below the level of the cranial nerve root entry zones,which may lead to insufficient analgesia.CASE SUMMARY We describe a 69-year-old man with a 1-year history of PHN after developing a vesicular rash in the ophthalmic division of cranial nerve V(trigeminal nerve)distribution.The pain was rated 7-8 at rest and 9-10 at breakthrough pain(BTP)on a numeric rating scale.Despite receiving aggressive multimodal therapies including large doses of oral analgesics(gabapentin 150 mg q12 h,oxycodone 5 mg/acetaminophen 325 mg q6 h,and lidocaine 5%patch 700 mg q12 h)and sphenopalatine ganglion block,there was no relief of pain.Subsequently,the patient elected to have an implantable IDDS with the catheter tip placed at the interpeduncular cistern.The frequency of BTP episodes decreased.The patient’s continuous daily dose was adjusted to 0.032 mg/d after 3 mo of follow-up and stopped 5 mo later.He did not report pain or other discomfort at outpatient follow-up 6 mo and 1 year after stopping intracisternal hydromorphone.CONCLUSION The use of interpeduncular cistern intrathecal infusion with low-dose hydromorphone by IDDS may be effective for severe craniofacial PHN.

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

Drug delivery via intra-articular(IA)injection has proved to be effective in osteoarthritis(OA)therapy,limited by the drug efficiency and short retention time of the drug delivery systems(DDSs).Herein,a series of modified cross-linked dextran(Sephadex,S0)was fabricated by respectively grafting with linear alkyl chains,branched alkyl chains or aromatic chain,and acted as DDSs after ibuprofen(Ibu)loading for OA therapy.This DDSs expressed sustained drug release,excellent anti-inflammatory and chondroprotective effects both in IL-1βinduced chondrocytes and OA joints.Specifically,the introduction of a longer hydrophobic chain,particularly an aromatic chain,distinctly improved the hydrophobicity of S0,increased Ibu loading efficiency,and further led to significantly improving OA therapeutic effects.Therefore,hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.

Preparation and evaluation of controllable drug delivery system:A light responsive nanosphere based on β-cyclodextrin/mesoporous silica

A novel light responsive nanosphere was constructed,and it was used as a drug carrier to investigate the loading and release properties of the Quercetin(QU).In this paper,mesoporous silica nanoparticles(MSN)were used as a substrate,and 3-aminopropyl triethyoxysilane was used as a surface modification agent to introduce—NH_(2),and the azobenzene-4,4’-dicarboxylic acid(AZO)was used as light responsive agent to introduce the group of—N=N—,and thenβ-cyclodextrin(β-CD)was combined with AZO through host-guest interaction to construct light responsive nanoparticles(MSN@β-CD).The structure and properties of the carrier were analyzed by FTIR,BET,XPS,TGA,XRD,SEM and TEM.In vitro drug release studies showed the release rate of QU@MSN@β-CD(dark)was 12.19%within 72 h,but the release rate of QU@MSN@β-CD(light 10 min)was 26.09%,exhibiting a light-responsive property.The CCK8 tests demonstrated that MSN@β-CD could significantly decrease the toxicity of QU.Therefore,the controllable light-responsive drug delivery system has great application prospects.

Smart stimuli-responsive drug delivery systems in spotlight of COVID-19

The world has been dealing with a novel severe acute respiratory syndrome(SARS-CoV-2)since the end of 2019,which threatens the lives of many peopleworldwide.COVID-19 causes respiratory infection with different symptoms,from sneezing and coughing to pneumonia and sometimes gastric symptoms.Researchers worldwide are actively developing novel drug delivery systems(DDSs),such as stimuli-responsive DDSs.The ability of these carriers to respond to external/internal and even multiple stimuli is essential in creating“smart”DDS that can effectively control dosage,sustained release,individual variations,and targeted delivery.To conduct a comprehensive literature survey for this article,the terms“Stimuli-responsive”,“COVID-19”and“Drug delivery”were searched on databases/search engines like“Google Scholar”,“NCBI”,“PubMed”,and“Science Direct”.Many different types of DDSs have been proposed,including those responsive to various exogenous(light,heat,ultrasound andmagnetic field)or endogenous(microenvironmental changes in pH,ROS and enzymes)stimuli.Despite significant progress in DDS research,several challenging issues must be addressed to fill the gaps in the literature.Therefore,this study reviews the drug release mechanisms and applications of endogenous/exogenous stimuli-responsive DDSs while also exploring their potential with respect to COVID-19.

Contact lens as an emerging platform for ophthalmic drug delivery:A systematic review

The number of people with eye diseases has increased with the use of electronics.However,the bioavailability of eye drops remains low owing to the presence of the ocular barrier and other reasons.Although many drug delivery systems have been developed to overcome these problems,they have certain limitations.In recent years,the development of contact lenses that can deliver drugs for long periods with high bioavailability and without affecting vision has increased the interest in using contact lenses for drug delivery.Hence,a review of the current state of research on drug delivery contact lenses has become crucial.This article reviews the key physical and chemical properties of drug-laden contact lenses,development and classification of contact lenses,and features of the commonly used materials.A review of the methods commonly used in current research to create contact lenses has also been presented.An overview on how drug-laden contact lenses can overcome the problems of high burst and short release duration has been discussed.Overall,the review focuses on drug delivery methods using smart contact lenses,and predicts the future direction of research on contact lenses.

Recent progress of respiratory inhalation drug delivery systems

With the influence of many factors such as the aging of the population,the younger smokers,and the serious air pollution,the incidence of chronic respiratory diseases is increasing year by year.In the treatment of respiratory diseases,clinical intervention is still mainly based on drug control of pulmonary symptoms.However,systemic drugs have disadvantages such as many adverse reactions and severe systemic side effects.In recent years,the research and development of local drug delivery systems for the respiratory tract has brought new changes to the treatment of respiratory diseases.Locally delivered drugs can directly act on the airways and have the characteristics of fast onset,good curative effect and small side effects.It is a simple,efficient and safe treatment method,which has a very significant effect,and has become a hot topic of current research and promotion.This paper briefly reviews the development track and latest research progress of respiratory local drug delivery systems at home and abroad,in order to provide reference for clinical workers in drug selection and application.

Nasal implants for drug delivery:Advancements and applications

Nasal implants have emerged as a pioneering technology for nasal drug delivery systems.These are breakthrough options made of biocompatible materials that are temporarily inserted into the nasal passages for both functional and cosmetic purposes.Drug-eluting nasal implants are beneficial for improving patient compliance,reducing the need for repeated drug administration,and achieving controlled release of therapeutic agents.This article offers a comprehensive insight into nasal implants and their applications,and addresses a patent perspective in the same context.Important considerations for clinically approved implants,such as Propel,Sinuva,Sinu-Foam,and Relieva Stratus,have also been discussed.

Characteristics and Transdermal Drug Delivery of Triamcinolone-Acetonide-Acetate-Loaded Solid Lipid Nanoparticles Carbomer Gel

Aim To prepare triamcinolone-acetonide-acetate (TAA)-loaded solid lipidnanoparticles (SLN) carbomer gel with tripalmitin glyceride (TPG), and investigate theircharacteristics and transdermal drug delivery. Methods SLN suspension was prepared by high-pressurehomogenization technique, and then mixed with carbomer gel matrix to get SLN gel. The morphology,particle size with polydispersi-ty index (PI) and zeta potential were examined by atomic forcemicroscopy (AFM) and photon correlation spectroscopy (PCS). The entrapment efficiency, stability andin vitro drug release were also studied. The transdermal drug delivery through porcine ear skin wasevaluated using modified Franz diffusion cells. Results The SLN had a spherical shape with theaverage size of (95.5 - 186.2) nm, the zeta potential of (-26.3- -15.7) mV and the entrapmentefficiency of 67.4%-90.3% for different TAA encapsulated compounds. TAA-SLN carbomer gel had goodstability, the release profile in vitro fitted Higuchi equation. In comparison with conventionalhydrogels, TAA-SLN carbomer gel resulted in higher drug permeation amount and drug deposition withinporcine ear skin after 24 h penetration experiment. Conclusion TAA-SLN carbomer gel is preparedwith stable physicochemical properties. The release profile and improved drug permeation into skinmake it be a promising vehicle for transdermal drug delivery.

Preparation and characterization of icariin/PHBV drug delivery coatings on anodic oxidized titanium

A composite material was fabricated by applying a biodegradable drug delivery coating,consisting of poly（3-hydroxyburyrate-co-3-hydroxyvalerate）（PHBV） and icariin,to an anodic oxidized titanium plate.The coating was prepared by evaporating chloroform solution containing PHBV and icariin on the titanium plate under vacuum condition.Icariin/PHBV coated titanium plates significantly enhance the proliferation of MG-63 cells compared with the PHBV coated and anodic oxidized ones.Increased icariin contained in the coating displays an elevated influence on cell proliferation.The results show that icariin gradually releases from the coating to cells mainly through the phospholipid-based cellular membrane instead of the culture medium.The overall results suggest that the novel icariin/PHBV coating can be used to enhance the bioactivity of titanium based orthopedic implants.

Design and preparation of a new multi-targeted drug delivery system using multifunctional nanoparticles for co-delivery of siRNA and paclitaxel

Drug resistance is a great challenge in cancer therapy using chemotherapeutic agents. Administration of these drugs with siRNA is an efficacious strategy in this battle. Here, the present study tried to incorporate siRNA and paclitaxel(PTX) simultaneously into a novel nanocarrier. The selectivity of carrier to target cancer tissues was optimized through conjugation of folic acid(FA) and glucose(Glu) onto its surface. The structure of nanocarrier was formed from ternary magnetic copolymers based on FeCopolyethyleneimine(FeCo-PEI) nanoparticles and polylactic acid-polyethylene glycol(PLA-PEG) gene delivery system. Biocompatibility of FeCo-PEI-PLA-PEG-FA(NPsA), FeCo-PEI-PLA-PEG-Glu(NPsB) and FeCo-PEI-PLA-PEG-FA/Glu(NPsAB) nanoparticles and also influence of PTX-loaded nanoparticles on in vitro cytotoxicity were examined using MTT assay. Besides, siRNA-FAM internalization was investigated by fluorescence microscopy. The results showed the blank nanoparticles were significantly less cytotoxic at various concentrations. Meanwhile, siRNA-FAM/PTX encapsulated nanoparticles exhibited significant anticancer activity against MCF-7 and BT-474 cell lines. NPsAB/siRNA/PTX nanoparticles showed greater effects on MCF-7 and BT-474 cells viability than NPsA/siRNA/PTX and NPsB/siRNA/PTX.Also, they induced significantly higher anticancer effects on cancer cells compared with NPsA/siRNA/PTX and NPsB/siRNA/PTX due to their multi-targeted properties using FA and Glu. We concluded that NPsAB nanoparticles have a great potential for co-delivery of both drugs and genes for use in gene therapy and chemotherapy.

Enhanced intestinal lymphatic absorption of saquinavir through supersaturated self-microemulsifying drug delivery systems

The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus(HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated selfmicroemulsifying drug delivery system(S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS.Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper selfmicroemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS.Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.

Alginate-Coated Fe3O4 Hollow Microspheres for Drug Delivery

Novel hollow Fe3O4 nanoparticles for drug delivery were synthesized via a one-step template- free approach. These nanoparticles were obtained by modifing the Fe3O4 nanoparticles with 3-aminopropyltrimethoxy silane, and then grafting alginate onto the surface of amine magnetic. The hollow structure of Fe3O4 spheres was characterized by TEM, XRD, and XPS. The M-H hysteresis loop indicated that the magnetic spheres exhibit snperparamagnetic characteristics at room temperature. Daunorubicin acting as a model drug was loaded into the carrier, and the maximum percent of envelop and load were 28.4% and 14.2% respectively. The drug controlled releasing behaviors of the carriers were compared in different pH media.