Edaravone-loaded poly(amino acid) nanogel inhibits ferroptosis for neuroprotection in cerebral ischemia injury

Neurological injury caused by ischemic stroke is a major cause of permanent disability and death. The currently available neuroprotective drugs fail to achieve desired therapeutic efficacy mainly due to short circulation half-life and poor blood−brain barrier (BBB) permeability. For that, an edaravone-loaded pH/glutathione (pH/GSH) dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to improve the neuroprotection of EDA. The nanogel was triggered by acidic and EDA-induced high-level GSH microenvironments, which enabled the selective and sustained release of EDA at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm. NG/EDA efficiently accumulated at the cerebral ischemic injury site of permanent middle cerebral artery occlusion (pMCAO) mice, showing an efficient BBB crossing feature. Notably, NG/EDA with 50 µM EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. In addition, administering NG/EDA for 7 d significantly reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. Such a pH/GSH dual-responsive nanoplatform might provide a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.

pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.

BIODEGRADABLE POLYMERS WITH A PHOSPHORYL-CONTAINING BACKBONE:TISSUE ENGINEERING AND CONTROLLED DRUG DELIVERY APPLICATIONS

This review provides a glimpse of the potential of the biodegradable phos-phoryl-containing polymers in medical applications. Undoubtedly these polymerspossess unique properties that are yet to be fully understood. Many areas warrantfurther investigation and much optimization remains to be done. The fascinatingchemistry of phosphorus poses interesting hurdles but at the same time leavesample room for polymer scientists to exercise their creativity in designinginteresting biomaterials. As the mutual understanding between basic and clinicalscientists on the need of medical devices and the capabilities of these newbiomaterials expands, imaginative application of new biomaterials to other medi-cal applications can be expected.

Synthesis of the Core-Shell Structure Materials as the Controlled-Release Drug Carrier

We have developed a controlled-release drug carrier. Smartly controlled-release polymer nanoparticles were firstly synthesized through RAFT polymerization as the controlled-release core. The structural and particle properties of polymer nanoparticles were characterized by nuclear magnetic resonance spectroscopy (1H-NMR), scanning electron microscope (SEM) and X-ray spectroscopy (EDX). Mesoporous materials were selected as the shell materials to encapsulate the smart core as the stable shell. The mesoporous shell was characterized by transmission electron microscopy (TEM) and scanning electron microscope (SEM). All the results showed that a well-defined core-shell structure with mesoporous structure was obtained, and this controllable delivery system will have the great potential in nanomedicine.

Biointerface engineering nanoplatforms for cancer-targeted drug delivery

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.

PEGylated PLGA Nanoparticles as Tumor Ecrosis Factor-α Receptor Blocking Peptide Carriers:Preparation,Characterization and Release in vitro

To assess the merits of PEGylated poly （lactic-co-glycolic acid） （PEG-PLGA） nanoparticles as drug carriers for tumor necrosis factor-α receptor blocking peptide （TNFR-BP）, PEG-PLGA copolymer, which could be used to prepare the stealth nanoparticles, was synthesized with methoxypolyethyleneglycol, DL-lactide and glycolide. The structure of PEG-PLGA was confirmed with ^1H-NMR and FT-IR spectroscopy, and the molecular weight （MW） was determined by gel permeation chromatography. Fluorescent FITC-TNFR- BP was chosen as model protein and encapsulated within PEG-PLGA nanoparticles using the double emulsion method. Atomic force microscopy and photon correlation spectroscopy were employed to characterize the stealth nanoparticles fabricated for morphology, size with polydispersity index and zeta potential. Encapsulation efficiency （EE） and the release of FITC-TNFR-BP in nanopartieles in vitro were measured by the fluorescence measurement. The stealth nanoparticles were found to have the mean diameter less than 270 nm and zeta potential less than -20 mV. In all nanoparticle formulations, more than 45% of EE were obtained. FITC-TNFR-BP release from the PEG-PLGA nanoparticles exhibited a biphasic pattern, initial burst release and consequently sustained release. The experimental results show that PEG-PLGA nanoparticles possess the potential to develop as drug carriers for controlled release applications of TNFR-BP.

Self-assembled Nanoparticles based on Folic Acid Modifi ed Carboxymethyl Chitosan Conjugated with Targeting Antibody

Nanoparticles conjugated with antibody were designed as active drug delivery system to reduce the toxicity and side effects of drugs for acute myeloid leukemia（AML）.Moreover,methotrexate（MTX）was chosen as modeldrug and encapsulate within folic acid modified carboxymethylchitosan（FACMCS）nanoparticles through self-assembling.The chemicalstructure,morphology,release and targeting of nanoparticles were characterized by routine detection.It is demonstrated that the mean diameter is about 150 nm,the release rate increases with the decreasing of p H,the binding rate of CD33 antibody and FA-CMCS nanoparticles is about 5：2,and nanoparticles can effectively bind onto HL60 cells in vitro.The experimentalresults indicate that the FA-CMCS nanoparticles conjugated with antibody may be used as a potentialp Hsensitive drug delivery system with leukemic targeting properties.

Modular Hydrogels for Drug Delivery

The development of novel drug delivery systems is an essential step toward controlled site-specific administration of therapeutics within the body. It is desirable for delivery vehicles to be introduced into the body through minimally invasive means and, these vehicles should be capable of releasing drug to their intended location at a controlled rate. Furthermore, it is desirable to develop drug delivery systems that are capable of in vivo to suffer degradation and to deliver the drug completely, avoiding the need to surgically remove the vehicle at the end of its useful lifetime. Hydrogels are of particular interest for drug delivery applications due to their ability to address these needs in addition to their good biocompatibility, tunable network structure to control the diffusion of drugs and, tunable affinity for drugs. However, hydrogels are also limited for drug delivery applications due to the often quick elution of drug from their highly swollen polymer matrices as well as the difficulty inherent in the injection of macroscopic hydrogels into the body. This paper presents an overview to the advances in hydrogels based drug delivery. Different types of hydrogels can be used for drug delivery to specific sites in the gastrointestinal tract ranging from the oral cavity to the colon. These novel systems exhibit a range of several peculiar properties which make them attractive as controlled drug release formulations. Moreover, such materials are biocompatible and can be formulated to give controlled, pulsed, and triggered drug release profiles in a variety of tissues.

Preparation and Characterization of pH-Sensitive Polyvinyl Alcohol Hydrogel for Cancer Therapy

Hydrogel has emerged as an excellent carrier platform for smart drug delivery and effective cancer treatment due to its high water content, good biocompatibility and sufficient mechanical properties. In this work,the DOX-loaded polyvinyl alcohol( PVA)hydrogel was prepared by freeze-thawing technique. The swelling test and the mechanical properties of the pure PVA hydrogels were performed. In addition, the in vitro drug release profiles were examined and the in vitro antitumor efficiency against He La cells was also estimated. The results indicated that the resulting PVA hydrogels contained significant amounts of water and possessed good mechanical properties,and DOX-loaded PVA hydrogel exhibited a sustained and p H-responsive DOX release. The MTT assays also demonstrated that the released DOX could effectively inhibit the proliferation of He La cells. Thus,the cross-linked PVA hydrogel can be further developed as a promising platform for cancer therapy.

An overview of management of narcotics and psychotropic drugs in China

Narcotics and psychotropic drugs are known as controlled drugs with special management and super vision due to their psychic and physiological dependence. Based on the literature review, experts interview and policy comparative analysis, our study summarized and reviewed the status of related legislation and regulations since the enactment of the Narcotics and Psychotropic Drugs Regulations in 2005. We found the problems of legal loopholes, the complexity of supervision system and the irrational use of narcotics in the treatment of chronic non-cancer. Our analysis suggested that China should reinforce legislation, strengthen the cooperation among departments, establish the information network and improve the guideline of narcotics and psychotropic drugs for clinical treatment as quickly as possible.

Unconventional Fluorescent and Multi-responsive Polysiloxane:Synthesis,Characterization and Biological Applications

Owing to their high significance in fundamental study and diverse applications,stimuli-responsive and fluorescent polymers,particularly those with cluster-triggered emission(CTE)featured by non-conjugated chromophores,have drawn tremendous attention in recent years.In this work,fluorescent and multi-responsive polysiloxane(FRPS)was synthesized by hydrolytic condensation polymerization of 3-aminopropyl methyl diethoxysilane(APMS)with 3-(N-isopropyl propionamide)iminopropyl methyl diethoxysilane(APMS-NIP),which was formed in situ through aza-Michael addition between APMS and N-isopropyl acrylamide.FRPS was not only highly sensitive to temperature,pH and CO_(2) in water,but also showed an enhanced and stimuli-adjustable fluorescence emission.The effects of monomer feeding,pH and CO_(2) on its lower critical solution temperature and fluorescent property were investigated.FRPS fluorescence emission was ascribed to CTE mechanism.In addition,FRPS was shown to be highly potential as physiological indicator for cell imaging,and for controlled release and trace detection of doxorubicin.This study provides therefore a type of stimuli-responsive and fluorescent material for potential applications in biomedical fields,and it is also of great significance for understanding of the fluorescence mechanism of polysiloxane-based stimuli-responsive polymers.

Unconventional Fluorescent and Multi-responsive Polyethyleneimine with LCST and UCST Behavior:Synthesis,Characterization and Biological Applications

Non-aromatic fluorescent and multi-responsive materials,exhibiting inherent fluorescence emission and controlled phase change,have garnered significant attention in recent years.However,the underlying interaction between their fluorescent properties and phase transition remains unclear.In this study,we synthesized a series of catalyst-free aza-Michael addition-based polyethyleneimine(RFPEI)materials by reacting polyethyleneimine(PEI)with N-isopropyl acrylamide(NIPAM).The resulting RFPEI was comprehensively characterized,and demonstrated dual-phase transition behavior(LCST and UCST)in water,which could be finely tuned by adjusting its composition or external factors such as pH.Notably,upon UV irradiation(365 nm),RFPEI exhibited strong fluorescence emission.We further investigated the effects of NIPAM grafting percentage to PEI,polymer concentration,and pH on the LCST/UCST and fluorescent properties of RFPEI aqueous solutions.Moreover,we showcased the great potential of RFPEI as a versatile tool for physiological cell imaging,trace detection,and controlled release of doxorubicin.Our study presents a novel class of stimuli-responsive fluorescent materials with promising applications in the field of biomedicine.

Targeted nanostrategies eliminate pre-metastatic niche of cancer

Establishing a pre-metastatic niche(PMN)in secondary organs is a prerequisite for cancer metastases.Despite advances in cancer therapy,the efficient inhibition of PMN formation remains a clinical challenge.Recent advances in understanding the specific characteristics of PMN and advances in nanotechnology have provided hope for manipulating their microenvironments.A series of nanostrategies have been designed to eliminate the PMN,including the removal of pro-metastatic exosomes from the bloodstream for excretion via the intestines,the targeting and scavenging of myeloid-derived suppressor cells,fibroblasts,and critical extracellular matrix components,and the elimination of circulating tumor cells prior to colonization in distant organs.This review summarizes the underlying mechanisms of PMN formation,highlights the anti-PMN efficacy of currently reported nanostrategies,and underlines the unresolved questions.

高度灵活可控的多孔MOF膜用于高效药物释放

具有生物力学和生化活性的敷料在伤口护理和皮肤组织再生中起着至关重要的作用.然而,机械失配和药物释放管理所涉及的问题限制了当前敷料的有效使用.在本工作中,我们报道了一种简单的策略,即采用聚偏二氟乙烯(PVDF)作为底物,通过嵌入不同尺寸的沸石咪唑酸盐框架(ZIF-8)种子,以推动具有均匀蜂窝结构的高柔性金属有机框架(MOF)复合膜的受控生长,用于药物负载和释放.以嵌入的种子为控制中心,形成的多孔膜具有约0.7-3μm的宽孔隙.这种可调节的微尺度孔与ZIF-8中的固有纳米孔不仅可以有效地提高抗炎类药物的负载(姜黄素,CCM),而且还能够快速并可控地释放药物,大大提高了抗菌活性,同时促进细胞生长.其中,在40 nm种子上生长的0.7μm多孔膜的表现优于其他蜂窝膜,与2μm多孔膜(相当于裸PVDF基质)相比,细胞增殖能力提高了约2倍,针对金黄色葡萄球菌(S.aureus)和大肠杆菌(E.coli)的抗菌活性分别提高了5倍和2.4倍,是基底抗菌活性的5倍,这是因为这种最佳孔几何结构具有CCM和Zn2+释放特性的平衡效应.这种可控分层孔阵列膜的独特性质有望真正用于伤口愈合,同时也为生物医学设计提供了新的指导.

Biochemical hallmarks-targeting antineoplastic nanotherapeutics

Tumor microenvironments(TMEs)have received increasing attention in recent years as they play pivotal roles in tumorigenesis,progression,metastases,and resistance to the traditional modalities of cancer therapy like chemotherapy.With the rapid development of nanotechnology,effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed.The appropriate design and fabrication endow nanomedicines with the abilities for active targeting,TMEs-responsiveness,and optimization of physicochemical properties of tumors,thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits.This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments,such as tumor acidosis,hypoxia,and dysregulated metabolism.Finally,this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.

Poly(β-cyclodextrin)-mediated Polylactide-cholesterol Stereocomplex Micelles for Controlled Drug Delivery

A series of host-guest interaction-adjusted polylactide stereocomplex micelles was prepared via the self-assembly of 4-armed poly（ethylene glycol）-block-poly（L-lactide/D-lactide）-cholesterol （4-armed PEG-b-PLLA/PDLA-CHOL） and poly（β-cyclodextrin） （PCD） with the molar ratios of CHOL/β-CD at 1：0.5, 1 ：l, and 1：2 in an aqueous environment. The hydrodynamic diameters of the micelles ranged from 84.1 nm to 107 nm depending on the molar ratio of CHOL/β-CD. It was shown that the micelle with the largest proportion of PCD possessed excellent abilities in drug release, cell internalization as well as proliferation inhibitory effect toward human A549 lung cancer cells. The results demonstrated that the stereocomplex and host-guest interactions-mediated PLA micelles exhibited great potential in sustained drug delivery.

Drug-nanoencapsulated PLGA microspheres prepared by emulsion electrospray with controlled release behavior

The development of modern therapeutics has raised the requirement for controlled drug delivery system which is able to efficiently encapsulate bioactive agents and achieve their release at a desired rate satisfying the need of the practical system.In this study,two kind of aqueous model drugs with different molecule weight,Congo red and albumin from bovine serum(BSA)were nanoencapsulated in poly(DL-lactic-co-glycolic acid)(PLGA)microspheres by emulsion electrospray.In the preparation process,the aqueous phase of drugs was added into the PLGA chloroform solution to form the emulsion solution.The emulsion was then electrosprayed to fabricate drugnanoencapsulated PLGA microspheres.The morphology of the PLGA microspheres was affected by the volume ratio of aqueous drug phase and organic PLGA phase(V_(w)/V_(o))and the molecule weight of model drugs.Confocal laser scanning microcopy showed the nanodroplets of drug phase were scattered in the PLGA microspheres homogenously with different distribution patterns related to V_(w)/V_(o).With the increase of the volume ratio of aqueous drug phase,the number of nanodroplets increased forming continuous phase gradually that could accelerate drug release rate.Moreover,BSA showed a slower release rate from PLGA microspheres comparing to Congo red,which indicated the drug release rate could be affected by not only V_(w)/V_(o)but also the molecule weight of model drug.In brief,the PLGA microspheres prepared using emulsion electrospray provided an efficient and simple systemto achieve controlled drug release at a desired rate satisfying the need of the practices.

Progress on intelligent hydrogels based on RAFT polymerization:Design strategy, fabrication and the applications for controlled drug delivery

Although intelligent hydrogels have shown bright potential application in biomedical fields,they were prepared by conventional methods and still face many serious challenges,such as uncontrollable stimulus-response and low response sensitivity.Recently,RAFT polymerization provides a versatile strategy for the fabrication of intelligent hydrogels with improved stimulus-response properties,owing to the ability to efficiently construct hydrogel precursors with well-defined structure,such as block copolymer,graft copolymer,star copolymer.In this review,we summarized the recent progress on intelligent hydrogels based on RAFT polymerization with emphasis on their fabrication strategies and applications for controlled drug delivery.

In situ synthesis of gold nanostars within liposomes for controlled drug release and photoacoustic imaging

This report describes the design and synthesis of gold nanostars(AuNSs) containing liposomes by the in situ reduction of gold precursor,HAuCU(pre-encapsulated within the liposomes) through HEPES diffusion and reduction.Compared with the conventional process that encapsulates the pre-synthesized gold nanoparticles into liposomes during the thin-film hydration step,this facile and convenient method allows the formation and simultaneous encapsulation of AuNSs within liposomes.The absorption spectra of AuNSs can be tuned between visible and near infra-red(NIR) regions by controlling the size and morphology of AuNSs through varying the concentrations of HAuCU and HEPES.As a proof of concept,we demonstrate the synthesis of AuNSs with a maximum absorbance at 803 nm within the temperature-sensitive liposomes.These liposomes can produce stronger photoacoustic signals(1.5 fold) in the NIR region than blood.Furthermore,when there are drugs(i.e.,doxorubicin) within these liposomes,the irradiation with the NIR pulse laser will disrupt the liposomes and trigger the 100%release of these pre-encapsulated drugs within 10 seconds.In comparison,there is neglectable contrast enhancement or minor release(10%) of drugs for the pure liposomes under the same conditions.Finally,cell experiment shows the potential therapeutic application of this system.

Amphiphilic poly(ethylene glycol)-b-poly(ethylene brassylate)copolymers: One-pot synthesis, self-assembly, and controlled drug release

A set of amphiphilic poly（ethylene glycol）-b-poly（ethylene brassylate）（PEG-b-PEB） copolymers based on the PEB hydrophobic block was first synthesized by ring-opening polymerization of ethylene brassylate with an organic catalyst. The EB/PEG molar ratios and reaction times were adjusted to achieve different chain lengths of PEB. Block copolymers that were characterized by1 H NMR and GPC could selfassemble into multimorphological aggregates in aqueous solution, which were characterized by DLS and TEM. The hydrophobic doxorubicin（DOX） was chosen as a drug model and successfully encapsulated into the nanoparticles. The release kinetics of DOX were investigated.