Molecular Mechanisms of Intracellular Delivery of Nanoparticles Monitored by an Enzyme‑Induced Proximity Labeling

Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular level.However,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date.Here,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular nanomedicines.Poly(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in macrophages.By adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles.Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over time.Based on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation timelines.More importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in cells.In summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.

Hepatocytes targeting of cationic liposomes modified with soybean sterylglucoside and polyethylene glycol

AIM: In this study, a hepatocyte-specific targeting technology was developed by modifying cationic liposomes with soybean sterylglucoside (SG) and polyethylene glycol (PEG) (C/SG/PEG-liposomes).METHODS: The liposomal transfection efficiencies in HepG22.2.15 cells were estimated with the use of fluorescein sodium (FS) as a model drug, by flow cytometry. The antisense activity of C/SG/PEG-liposomes entrapped antisense oligonucleotides (ODN) was determined as HBsAg and HBeAg in HepG2 2.2.15 cells by ELISA. The liposome uptake by liver and liver cells in mice was carried out after intravenous injection of 3H-labeled liposomes.RESULTS: C/SG-liposomes entrapped FS were effectively transfected into HepG2 2.2.15 cells in vitro. C/SG/PEGliposomes entrapped ODN, reduced the secretion of both HBsAg and HBeAg in HepG2 2.2.15 cells when compared to free ODN. After in vivo injection of 3H-labeled C/SG/PEG-liposomes, higher radiation accumulation was observed in the hepatocytes than non-parenchymal cells of the liver.CONCLUSION: C/SG/PEG-liposomes mediated gene transfer to the liver is an effective gene-delivery method for hepatocytes-specific targeting, which appears to have a potential for gene therapy of HBV infections.

Two kinds of ketoprofen enteric gel beads(CA and CS-SA) using biopolymer alginate

To obtain expected rapid-release and sustained-release of ketoprofen gel beads, this paper adopted biopolymer alginate to prepare alginate beads and chitosan-alginate gel beads. Formulation factors were investigated and optimized by the single factor test. The release of ketoprofen from calcium alginate gel beads in pH 1.0 hydrochloric acid solution was less than 10% during 2 h, then in pH6.8 was about 95% during 45 min, which met the requirements of rapid-release preparations. However, the drug release of chitosan-alginate gel beads in pH1.0 was less than 5% during 2 h, then in pH6.8 was about 50% during 6 h and reached more than 95% during 12 h, which had a good sustained-release behavior. In addition, the release kinetics of keteprofen from the calcium alginate gel beads fitted well with the Korsmeyer–Peppas model and followed a case-II transport mechanism. However, the release of keteprofen from the chitosan-alginate gel beads exhibited a non-Fickian mechanism and based on the mixed mechanisms of diffusion and polymer relaxation from chitosanalginate beads. In a word, alginate gel beads of ketoprofen were instant analgesic, while chitosan-alginate gel beads could control the release of ketoprofen during gastrointestinal tract and prolong the drug's action time.

Blends of hydrophobic and swelling agents in the swelling layer in the preparation of delayed-release pellets of a hydrophilic drug with low MW: Physicochemical characterizations and in-vivo evaluations

In this study,a hydrophobic material,ethylcellulose,which was used as its aqueous suspension Surelease^(®),was combined with a swelling agent as the swelling layer to prepare delayed-release pellets for Danshensu,which is a hydrophilic drug with low MW.A rupturable,delayed-release pellet consists of a drug core,a swelling layer containing a swelling agent(cross-linked sodium carboxymethyl cellulose)with a hydrophobic agent(Surelease^(®)),and a controlled layer composed by an insoluble,water-permeable polymeric coating(aqueous ethylcellulose dispersions)was developed in a fluidised bed.Results showed that blending Surelease^(®)into the swelling layer could effectively extend the release of Danshensu from the pellets,which may be attributed to the slowed swelling rate by reduction of water penetration and improvement of mechanical integrity of the swelling layer.Drug in the delayed pellets showed sustained release in beagle dogs after oral administration with comparable in-vivo exposure to the uncoated drug pellets.In conclusion,blends of hydrophobic and swelling agents in the swelling layer in doublemembrane pellets could achieve a delayed drug-release profile in vitro,as well as delayed and sustained absorption in vivo for highly soluble,low-MW drug.The present study highlighted the potential use of a delayed-release system for other hydrophilic,low-MW drugs to meet the formulation requirements for chronopharmacological diseases.

Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic

Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteristics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in secretory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-oriented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2). These results suggest that, in addition to the hydrophilic property of meropenem, its instability at gastric pH and secretory transport in the small intestine are possible factors involved in the inactivity of meropenem after oral administration.

Limited Effect of Intravenously Administered Indoxyl Sulfate, a Uremic Toxin, on the Hepatic Transport of Pravastatin in Normal Rats

Indoxyl sulfate (IS) is a typical uremic toxin that extensively accumulates in the plasma of patients with seriously impaired renal function. This study seeks to clarify whether IS exerts a potent modulating effect on the hepatic transport of pravastatin, which is a substrate of both organic anion transporting peptides (OATPs) and multidrug resistance-associated protein (Mrp) 2 in rats. When IS is administered intravenously to the normal rats at a dose of 120 μmol/kg;plasma IS levels are approximately 600 μM after 2 min and 100 μM after 120 min. In rats with acute renal failure (ARF) induced by cisplatin, the area under the curve (AUC) was more than 2.5-fold greater compared with that in the normal rats, indicating that IS accumulates in ARF rats. Intravenously administered pravastatin almost disappeared from the plasma by 60 min post-administration and approximately 55% of dose was excreted in the bile within 60 min. This result suggested that pravastatin was efficiently taken up from the sinusoid into hepatocytes via rat OATPs on the sinusoidal membrane and preferentially transported in the bile mediated by Mrp2 on the canalicular membrane. IS administered intravenously at a dose of 120 μmol/kg caused neither an increase in plasma pravastatin levels nor a decrease in its biliary excretion. In conclusion, the present results demonstrate that single intravenous administration of IS does not interfere with the hepatic transport of pravastatin directly in vivo, which is at variance with the results of previous in vitro studies.

Recent updates on nano-phyto-formulations based therapeutic intervention for cancer treatment

Cancer is a leading cause of death globally,with limited treatment options and several limitations.Chemotherapeutic agents often result in toxicity which long-term conventional treatment.Phytochemicals are natural constituents that are more effective in treating various diseases with less toxicity than the chemotherapeutic agents providing alternative therapeutic approaches to minimize the resistance.These phytoconstituents act in several ways and deliver optimum effectiveness against cancer.Nevertheless,the effectiveness of phyto-formulations in the management of cancers may be constrained due to challenges related to inadequate solubility,bioavailability,and stability.Nanotechnology presents a promising avenue for transforming current cancer treatment methods through the incorporation of phytochemicals into nanosystems,which possess a range of advantageous characteristics such as biocompatibility,targeted and sustained release capabilities,and enhanced protective effects.This holds significant potential for future advancements in cancer management.Herein,this review aims to provide intensive literature on diverse nanocarriers,highlighting their applications as cargos for phytocompounds in cancer.Moreover,it offers an overview of the current advancements in the respective field,emphasizing the characteristics that contribute to favourable outcomes in both in vitro and in vivo settings.Lastly,clinical development and regulatory concerns are also discussed to check on the transformation of the concept as a promising strategy for combination therapy of phytochemicals and chemotherapeutics that could lead to cancer management in the future.

On the spray drying of uniform functional microparticles

Spray drying is a typical method to produce particles in dry powder forms at industrial scale.Most spray-dried products often show a wide range of particle properties even within the same batch.At Monash University,we utilise a microfluidic spray drying approach to generate uniform microparticles with tightly controlled characteristics and sizes in a scalable,almost waste-free process.The technique is useful to correlate the effects of formulation and spray drying conditions on the properties of spray-dried particles,and can be used to test new formulations for targeted applications such as encapsulation and release of active ingredients.The synthesis route can be applied to other self-assembling systems,including mesoporous,crystalline,and hierarchically structured microparticles.As spray drying is commonly used in commercial scales,the understanding of how functional particles are formed in relation to formulations and process conditions could assist in developing a cost effective,energy and material-efficient route to produce powders with better properties and ease of handling for more advanced applications such as selective adsorption and bio-separation.

Prognostic value of ECOG performance status and Gleason score in the survival of castration-resistant prostate cancer:a systematic review

Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of consistency regarding their prognostic or predictive value for OS.Therefore,we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories.A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019.The data from 8247 patients in 34 studies,including clinical trials and real-world data,were included in our meta-analysis.Of these,twenty studies reported multivariate results and were included in our main analysis.CRPC patients with higher ECOG performance statuses(≥2)had a significantly increased mortality risk than those with lower ECOG performance statuses(<2),hazard ratio(HR):2.10,95%confidence interval(CI):1.68-2.62,and P<0.001.The synthesized HR of OS stratified by Gleason score was 1.01,with a 95%CI of 0.62-1.67(Gleason score≥8 vs<8).Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy(docetaxel and cabazitaxel)and androgen-targeting therapy(abiraterone acetate and enzalutamide)or for patients with different chemotherapy histories.ECOG performance status was identified as a significant prognostic factor in CRPC patients,while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.

中药复方冠心Ⅱ的群体药物动力学研究(英文)

目的:以群体药物动力学原理分析复方冠心Ⅱ不同组成条件对主要组分芍药苷及阿魏酸体内过程的影响。方法:将大鼠随机分组后分别静脉注射芍药苷(PPE)或阿魏酸(FA)提取物水溶液、灌胃给予PPE或FA水溶液及不同组成的水煎液,HPLC法测定血浆中芍药苷和阿魏酸浓度,以非线性混合效应模型(NONMEM)法分别对芍药苷和阿魏酸的血药浓度数据进行群体药物动力学解析。结果:芍药苷的体内药物动力学过程可用吸收相包含一级降解过程的二室口服吸收模型进行表述,参数CL1、V1、CL2、V2、Ka0和Ka1分别为0.509 L/h, 0.104 L,0.113 L/h,0.123 L,0.135/h及0.0135/h;阿魏酸的体内过程可用二室口服吸收模型表述,参数CL1、V1、CL2、V2,、Ka及F分别为0.295 L/h、0.025 L、0.0331 L/h、0.0518 L、0.110/h及0.40。模型化中对个体间差异进行了估计,并以给药组方因素(DF)作为固定效应对参数进行了校正。结论:群体药物动力学方法可以用于分析中药复方冠心Ⅱ中组方变化对其中指标成分的体内吸收和分布产生的影响,较以往的方法有一定的优越性。

In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes

TM208 and TM209,dithiocarbamate derivatives with potential anti-cancer effects,were evaluated in reversible and time-dependent cytochrome P450(CYP)3A inhibition assays in rat liver microsomes using testosterone as probe substrate.Both compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat CYP3A.For reversible inhibition on rat CYP3A,the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM,respectively.For time-dependent inhibition,the inactivation constants(K_(l))were 31.93±12.64 and 32.91±15.58 μM,respectively,and the maximum inactivation rates(kinact)were 0.0349770.0069 and 0.0725970.0172 min^(-1) respectively.These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209。

建立中国癫痫儿童丙戊酸钠的群体药动学/药效学结合模型

AIM: To establish a population pharmacokinetic/pharmacodynamic (PK/PD) model for valproate (VPA) in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS: Sparse data of VPA serum concentrations from 417 pediatric children were collected. These patients were divided into three groups: Population PK-Index group, n=317; Population PK-Valid group, n=100; 115 of the total 417 subjects were also included in the Population PD group. Population PK parameters of VPA were estimated based on the data from population PK-Index group. In the validation procedure, the serum concentrations of VPA from the population PK-Valid group were predicted by base and final models respectively. To assess the accuracy and precision of the predictions, mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight-residues (WRES) and its 95% confidence intervals (95%CI) were all calculated, then compared between the two models. For population PD group, all of the 115 patients were VPA monotherapy. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased (PSFD%). The value of PSFD% 100%, 75%-100%, 50%-75%, 25%-50%, or less than 25% are corresponding to grade 1 to 5. For population PD group, the quantitative relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by logistic regression. RESULTS: Population PK of VPA was described by one-compartment model with first order absorption. In the final model, Ka, V/F, CL/F are 0.251+2.24·(1-HS) (/h), 2.88+0.157·WT (L), 0.1060.98·CO+0.0157·AGE (L/h), respectively. The final model was validated internally and externally. Logistic regression showed that VPA serum concentrations and corresponding peak probability for its efficacy were (25 μg/mL, grade 5, 50%), (32 μg/mL, grade 4, 32.3%), (50 μg/mL, grade 3, 26.3%), (67 μg/mL, grade 2, 36.5%), and (78 μg/mL, grade 1, 50%), respectively. CONCLUSION: The population PK/PD model of VPA in children with epilepsy in China is successfully established by NONMEM, and the probability of efficacy for a given concentration is satisfactorily estimated as well.

New Synthetic Route of Two Active Isomeric Metabolites of Erlotinib and Their Bioactivity Studies against Several Tumor Cell Lines

合成和 erlotinib 的二活跃同质异构的代谢物的微分 antiproliferative 活动被调查。这个合成过程示威了避免不稳定的 4-chloroquinazoline 中介和长过程。新中介和最后的混合物被 1H NMR， 13C NMR 和 ESI-TOF MS 识别，并且他们的纯净被高效液体层析决定。在 vitroproliferative，试金显示这二代谢物在细胞的水平作为与 erlotinib 控制，和他们的 antitumor 活动相比对一些常规肿瘤房间线和 EGFR 酷氨酸 kinase 在表示上肿瘤房间线拥有了 antiproliferative 活动首先这里被报导。

肾移植病人应用环孢菌素A群体药物动力学研究的临床应用

A population pharmacokinetic model of cyclosporine (CsA) for clinical renal transplant patients was constructed to adjust CsA’s administration individually. A total of 2,548 retrospective drug monitoring data were collected from 120 Chinese renal transplant patients receiving CsA. Population modeling was performed with NONMEM by a one-compartment model with first-order absorption and elimination. Six significant covariates were included in the final model. It is postoperative days (POD), total bilirubin level (TBIL), current body weight (CBW), age, concurrent metabolic inhibitors of CsA (INHI), and hematocrit (HCT). The population means for CL/F (28.5 L/h), V/F (volume of distribution, 133 L), and inter-patient variability (CV%=19.7%) for CL/F were estimated. The model was further validated internally and externally, and was demonstrated to be effective and robust. Moreover, in order to put the result of population pharmacokinetic studies into clinical practice, a database with the name of C-TDM for post renal transplantation patients based on the population model was established. Up on the availability of the information from clinic, the precision of the plasma concentration predicted with C-TDM was classified into 3 levels, they are population, sub-population and individual. C-TDM’s interface is user-friend, and the median value, the 90% confidence interval are simulated accompanied with comprehensive graphs, to facilitate the individualized application of CsA.

A genome-wide association study identifies novel genetic loci that modify pharmacokinetic-pharmacodynamic responses to clopidogrel

OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.

Self-adjuvant Astragalus polysaccharide-based nanovaccines for enhanced tumor immunotherapy:a novel delivery system candidate for tumor vaccines

The study of tumor nanovaccines(NVs)has gained interest because they specifically recognize and eliminate tumor cells.However,the poor recognition and internalization by dendritic cells(DCs)and insufficient immunogenicity restricted the vaccine efficacy.Herein,we extracted two molecular-weight Astragalus polysaccharides(APS,12.19 k D;APSHMw,135.67 k D)from Radix Astragali and made them self-assemble with OVA257–264directly forming OVA/APS integrated nanocomplexes through the microfluidic method.The nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve stability.APS in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor immunotherapy.The optimal APS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline solution.The FITC-OVA in APS-NVs could be effectively taken up by DCs,and APS-NVs could stimulate the maturation of DCs,improving the antigen cross-presentation efficiency in vitro.The possible mechanism was that APS can induce DC activation via multiple receptors such as dectin-1 and Toll-like receptors 2 and 4.Enhanced accumulation of APS-NVs both in draining and distal lymph nodes were observed following s.c.injection.Smaller APS-NVs could easily access the lymph nodes.Furthermore,APS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic T cells.In addition,APS-NVs achieve a better antitumor effect in established B16-OVA melanoma tumors compared with the OVA+Alum treatment group.The antitumor mechanism correlated with the increase in cytotoxic T cells in the tumor region.Subsequently,the poor tumor inhibitory effect of APS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by NVs.Therefore,this study developed a promising APS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.

An enzyme-responsive and transformable PD-L1 blocking peptide-photosensitizer conjugate enables efficient photothermal

Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic efficacy.However,it remains a challenge to facilely integrate the two therapies and make it potential for clinical translation.This work designed a peptide-photosensitizer conjugate(PPC),which consisted of a PD-L1 antagonist peptide(CVRARTR),an MMP-2 specific cleavable sequence,a self-assembling motif,and the photosensitizer Purpurin 18.The single-component PPC can self-assemble into nanospheres which is suitable for intravenous injection.The PPC nanosphere is cleaved by MMP-2 when it accumulates in tumor sites,thereby initiating the cancer-specific release of the antagonist peptide.Simultaneously,the nanospheres gradually transform into co-assembled nanofibers,which promotes the retention of the remaining parts within the tumor.In vivo studies demonstrated that PPC nanospheres under laser irradiation promote the infiltration of cytotoxic T lymphocytes and maturation of DCs,which sensitize 4T1 tumor cells to immune checkpoint blockade therapy.Therefore,PPC nanospheres inhibit tumor growth efficiently both in situ and distally and blocked the formation of lung metastases.The present study provides a simple and efficient integrated strategy for breast cancer photoimmunotherapy.

Hot-melt extrusion promotes dissolution,extends“spring-parachute”process and inhibits crystallization in supersaturating microparticle systems

Despite the potential advantages of amorphism-induced supersaturation,the merit of new amorphiza-tion formation methods on the properties of the amorphous drug including the stability of the amor-phous state,dissolution/solubility,supersaturation,and"spring-parachute"process is still poorly understood,particularly for certain amorphous supersaturating drug delivery systems(aSDDS).The present work aimed to explore the detailed merit of current attractive amorphization manufacturing methods(i.g.,hot-melt extrusion(HME)technique)on the property improvement of aSDDS in form of amorphous solid dispersion microparticles by employing a model Bcs II drug nitrendipine and a polyvinylpyrrolidone-based model polymer copovidone.Many asDDS systems were developed by various methods,and their physicochemical properties were characterized by SEM,PXRD and DSC.HME-triggered amorphization induced superior supersaturation by the observation of the highest dissolution and solubility.HME induced the optimal supersaturation duration by the observed greatest extension of"spring-parachute"process(e.g,maximum AUCspring-parachute).HME technique is comparable with other techniques for the stabilization of amorphous state during storage.All aSDDS systems by HME and other methods showed improved long-term stability of the amorphous state in comparison to the pure amorphous drug.Fourier transformation infrared spectroscopy,Noyes-Whitney equation,nucleation theory and Gibbs free energy of transfer(△G)were used to analyze the underlying mechanisms.Mo-lecular mechanism studies indicated that HME caused a stronger crystallization inhibition effect in the asDDS systems than other methods,but molecular interaction is not a dominant mechanism for property enhancement caused by HME.For the mechanism associated with the polymer itself(PVPVA64),it could inhibit the drug recrystallization,solubilize the drug spontaneously and cause the improved molecular interactions in all aSDDS systems.This study provided a deep insight into detailed advantage of HME-triggered supersaturation/amorphization and facilitated the applications of the technique both in the field of particuology and in pharmaceutical industry.

Virus-inspired surface-nanoengineered antimicrobial liposome:A potential system to simultaneously achieve high activity and selectivity

Enveloped viruses such as SARS-CoV-2 frequently have a highly infectious nature and are considered effective natural delivery systems exhibiting high efficiency and specificity.Since simultaneously enhancing the activity and selectivity of lipopeptides is a seemingly unsolvable problem for conventional chemistry and pharmaceutical approaches,we present a biomimetic strategy to construct lipopeptide-based mimics of viral architectures and infections to enhance their antimicrobial efficacy while avoiding side effects.Herein,a surface-nanoengineered antimicrobial liposome(SNAL)is developed with the morphological features of enveloped viruses,including a moderate size range,lipid-based membrane structure,and highly lipopeptide-enriched bilayer surface.The SNAL possesses virus-like infection to bacterial cells,which can mediate high-efficiency and high-selectivity bacteria binding,rapidly attack and invade bacteria via plasma membrane fusion pathway,and induce a local“burst”release of lipopeptide to produce irreversible damage of cell membrane.Remarkably,viral mimics are effective against multiple pathogens with low minimum inhibitory concentrations(1.6-6.3μg mL1),high bactericidal efficiency of>99%within 2 h,>10-fold enhanced selectivity over free lipopeptide,99.8%reduction in skin MRSA load after a single treatment,and negligible toxicity.This bioinspired design has significant potential to enhance the therapeutic efficacy of lipopeptides and may create new opportunities for designing next-generation antimicrobials.