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As a vital component of blood, platelets play crucial roles in hemostasis and maintaining vascular integrity, and actively participate in inflammation and immune regulation. The unique biological properties of natural platelets have enabled their utilization as drug delivery vehicles. The advancement and integration of various techniques, including biological, chemical, and physicochemical methods, have enabled the preparation of engineered platelets. Platelets can serve as drug delivery platforms combined with immunotherapy and chemokine therapy to enhance their therapeutic impact. This review focuses on the recent advancements in the application of unactivated platelets for drug delivery. The construction strategies of engineered platelets are comprehensively summarized, encompassing internal loading, surface modification, and genetic engineering techniques. Engineered platelets hold vast potential for treating cardiovascular diseases, cancers, and infectious diseases. Furthermore, the challenges and potential considerations in creating engineered platelets with natural activity are discussed.

Transdermal drug delivery efficacy of hyaluronic acid dissolving microneedles (HA DMNs) is limited by low loading dose and poor drug condensation in needles. HA swelling MNs (HA SMNs) could improve the efficacy, but comparisons between the formulations is missing. In this work, DMNs and SMNs were fabricated of HA and methacrylated HA, respectively. Their properties of transdermal drug delivery were systematically compared. HA SMNs exhibited enhanced mechanical strength, fast swelling performance, and extended duration of microchannels in skin. The doxorubicin (DOX) loaded by one-step loading protocol in needles and baseplate of SMNs could be transdermally delivered through the diffusing path mediated by swollen needles, conquering the limit of poor drug condensation in DMNs needles and generated a longer Tmax but higher Cmax. The relative bioavailability of DOX/SMNs towards DOX/DMNs was 200% within 12 h. The results provide theoretical references for the application of HA MNs mediated transdermal drug delivery., (Copyright © 2021. Published by Elsevier B.V.)

Tumor-draining lymph nodes (TDLN) are major metastatic sites for many solid tumor to support tumor progression and metastasis. Lymphatic delivery is regarded as a desirable route to promote adoptive immune response via vaccination, or to achieve efficient chemotherapy for tumor metastasis. In this study, a novel dissolving microneedle was fabricated using hyaluronic acid, integrated with transfersome (T) to break the limit of transdermal cargo transit. In virtue of the insertion capacity of microneedle and the lymphatic delivering ability of transfersomes, such transfersome/microneedles complex (T/MNs) was expected to enhance lymphatic delivery. The results revealed that the microneedles were able to efficiently insert into rat skin and release the doxorubicin loaded transfersome (DOX-T) in dermis via self-dissolution. DOX-T would maintain their multilayer structure as released from dissolved microneedles. DOX-T/MN could significantly promote accumulation of DOX in lymph nodes compared to epidermal diffusion, and increased its transdermal bioavailability in plasma. The results not only are promising for chemo-therapy of tumor through lymphatic drug delivery, especially for killing the metastasized tumor cells appeared in draining lymph nodes, they also provide an efficient strategy for tumor immune-therapy using transdermal administration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Uncontrolled hemorrhage leads to high death risk both in military and civilian trauma. Current hemostatic agents still have various limitations and side effects. In this study, natural diatom silica obtained from diatomite and diatom culture was purified and developed for hemorrhage control. To improve the biocompatibility and hemostatic performance of diatom silica, a series of chitosan-coated diatom (CS-diatom) was developed. The composition of CS-diatom prepared was optimized by in vitro hemocompatibility and blood coagulation evaluation for that prepared with 0.5%, 1%, 3%, and 5% chitosan. The results demonstrated that the CS-diatom prepared with 1% chitosan exhibited favorable biocompatibility (hemolysis ratio < 5%, no cytotoxicity to MEFs), great fluid absorbility (24.39 ± 1.53 times the weight of liquid), and desirable hemostasis effect (351 ± 14.73 s at 5 mg/mL, 248 ± 32.42s at 10 mg/mL). Further blood coagulation mechanism study indicated that CS-diatom could provide an ideal interface to induce erythrocyte absorption and aggregation, along with activating the intrinsic coagulation pathway and thus accelerated blood coagulation. Benefitting from the multiple hemostatic performances, CS-diatom showed the shortest clotting time (98.34 ± 26.54 s) and lowest blood loss (0.31 ± 0.11 g) in rat-tail amputation model compare to diatomite and diatom as well as gauze and commercial QuikClot zeolite. The results evidenced that the CS-diatom was a safe and effective hemostatic agent and provided a new understanding of nonsynthetic mesoporous materials for hemorrhage control.

A series of deoxycholate-chitosan-hydroxybutyl (DAHBCs) with different degrees of substitution (DS) of hydrophobic deoxycholate (DOCA) were successfully synthesized. The lower critical solution temperature (LCST) of various DAHBCs could be adjusted from 35.4°C to 42.1°C by controlling the graft density of DOCA. DAHBCs could self-assemble into nanoparticles (NPs) which gradually evolved from irregular aggregates to spherical particles with the decrease of the DS of DOCA groups. The size of DAHBCs NPs ranged from 100nm to 250nm and their zeta potential varied between 3.85 and 12.37mV. Hemolysis tests and protein adsorption assay exhibited DAHBCs NPs had few adverse effects on the blood components even at a concentration as high as 1mg/mL. DAHBCs NPs showed high curcumin (CUR) encapsulation efficiency up to 80%. CUR-loaded DAHBCs NPs displayed thermal-dependent drug release profiles, and the release rate of CUR (∼75%) was significantly (p<0.05) accelerated at a temperature above the LCST compared with that (∼40%) below the LCST. Cytotoxicity analysis identified no toxicity associated with DAHBCs NPs at a concentration up to 0.5mg/mL. However, when the cells were incubated with the CUR-loaded NPs, their growth was significantly inhibited at 43°C (>LCST), demonstrating the thermal-responsive release of encapsulated cargoes from the NPs. With the capacity to control the LCST of DAHBCs NPs at specific temperatures, it could be speculated that DAHBCs NPs might serve as a promising thermo-responsive nanoplatform for the delivery of antitumor drugs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We have designed and evaluated coacervate microcapsules-immobilized multilayer sodium alginate beads (CMs-M-ALG-Beads) for oral drug delivery. The CMs-M-ALG-Beads were prepared by immobilization of doxorubicin hydrochloride (DOX) loaded chitosan/carboxymethyl coacervate microcapsules (DOX:CS/CMCS-CMs) in the core and layers of the multilayer sodium alginate beads. The obtained CMs-M-ALG-beads exhibited layer-by-layer structure and rough surface with many nanoscale particles. The swelling characteristic and drug release results indicated that 4-layer CMs-M-ALG-Beads possessed favorable gastric acid tolerance (the swelling rate <5%, the cumulative drug release rate <3.8%). In small intestine, the intact DOX:CS/CMCS-CMs were able to rapidly release from CMs-M-ALG-Beads with the dissolution of ALG matrix. Ex vivo intestinal mucoadhesive and permeation showed that CMs-M-ALG-Beads exhibited continued growth for P(app) values of DOX, which was 1.07-1.15 folds and 1.28-1.38 folds higher than DOX:CS:CMCS-CMs in rat jejunum and ileum, respectively, demonstrating that CMs-M-ALG-Beads were able to enhance the absorption of DOX by controlled releasing DOX:CS/CMCS-CMs and prolonging the contact time between the DOX:CS/CMCS-CMs and small intestinal mucosa.

In cancer therapy, drug delivery is a complex process that aims to transit the cargo to the destination with as little damage to the normal tissue as possible. In the last decade, tremendous development and research on nanomedicine have been exploring an ideal system with efficient drug transportation and release property. For this end, series of barriers need to be circumvented by nanomedicine, including systemic barriers, such as biosurface adsorption, phagocytic clearance, bloodstream washing, interstitial pressure, degradation, as well as intracellular barriers, such as cell membrane reorganization and internalization, endo/lysosomal escape, cytosolic or subcellular localization. Rather than being random, these barriers follow a specific spatial-temporal sequence. Therefore, the nanocarriers have to be endowed with characteristics that are adaptive to particular biological milieu on systemic and intracellular levels. To this end, we reviewed the correlations between the spatial-temporal sequences of drug delivery and nanocarrier characteristics in cancer therapy, as well as strategies to achieve efficient drug delivery upon both systemic and intracellular levels., (© 2013.)

Chitosan based nanogels with pH/redox sensitivities tunable to stepwise response to intracellular delivery kinetics were developed. The nanogels were simply constructed by ionic gelation first, between O-Carboxymethyl-chitosan (CMCS) and thiolated chitosan (TCS), and then oxidation to form disulfide bonds for CMCS-TCS nanogels (CTNGs). Doxorubicin loaded nanogels (DOX/CTNGs) exhibited desirable stability under physiological pH with a mean size of 150.5 nm, and quickly aggregated at pH 5.5 (mimic endo/lysosomes) due to protonation of the carboxyl groups on CMCS. DOX/CTNGs would maintain their TCS skeleton in acidic pH and compromised as treated with 10 mM glutathione (mimic cytosol). In agreement with the structural variation, release of DOX was dramatically enhanced by the synergetic effects of acidic pH and reductive potential. Stepwise responses to intracellular delivery kinetics were evidenced by laser confocal images showing that DOX/CTNGs underwent efficient cellular internalization through endocytosis, endo/lysomse escape via self-precipitation, cleavage of disulfide linkage in cytosol and disintegration in nucleus, achieving enhanced nuclear delivery and rapid release of doxorubicin. DOX/CTNGs exerted comparable or higher anticancer efficacies than that of free DOX against hela cells. The simple construction of the nanogels and their capacity of enhancing anticancer activities of DOX are potential for translational applications in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Drug delivery mediated by hydrogel has shown great promise in controlled drug release field. We report here the development of a hydroxybutyl chitosan (HBC) thermo-sensitive gel to deliver doxorubicine hydrochloride (DOX·HCl) for cancer treatment. Concentrated HBC aqueous solution could transform into hydrogel within 30 s after injection under physiological temperature in non-chemical fashion. The properties of the HBC gels including chemical structure, surface morphology, and rheologic properties were studied. Gelation temperature and gelation time of HBC could be adjusted by HBC concentrations. The gel erosion rate in vivo was faster than solubilization rate in vitro. The mild inflammatory response caused by implantation of the hydrogel was acceptable. The DOX·HCl (1 mg/ml) loaded HBC gels displayed slow release rates that were independent of the HBC concentration, and significantly reduced viability of 4T-1 cells compared with the HBC gels after 1 day incubation. These results indicate that thermo-sensitive HBC hydrogels have promising potential as an injectable drug carrier for pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Abstract: To develop a functional nanosized transdermal drug delivery system for tumor therapy, amphiphilic hyaluronic acid (HA) based niosome was constructed combining transdermal and tumor targeting ability in one entity. HA esterified with monostearin, the conjugate labeled as HA–GMS self-assembled onto niosome surface and formed HA–niosome. The multilayer vesicle had small size (around 40nm), good stability and desirable drug encapsulating efficacy, and well compatible with blood. It exhibited better endocytosis to mouse breast tumor cell (4T1) than the control chitosan nanoparticle, which was verified qualitatively and quantitatively. Skin permeation of HA–niosome was proven to be efficient using in vitro stratum corneum model and in vivo fluorescence observation. Histological section study confirmed the security and efficiency of transdermal permeation. The results evidence HA–niosome to be exciting and promising for tumor therapy through trandermal administration. [Copyright &y& Elsevier]

Abstract: Oleoyl-carboxymethyl-chitosan (OCMCS) was synthesized and were soluble at neutral pH. The critical micelle concentration (CMC) of OCMCS in deionized water was 0.021mg/ml. OCMCS nanoparticles were successfully prepared via self-assembly with mean diameter of 215.34nm, zeta potential of 19.26mV and an almost spherical shape as determined by electron microscopy. The OCMCS nanoparticles showed low erythrocyte membrane-damaging effect. The MTT survival assay indicated no significant cytotoxicity to Caco-2 cells and MEFs cells. The uptake of FITC labeled OCMCS nanoparticles by Caco-2 cells was confirmed via confocal laser scanning microscope (CLSM). In vivo toxicity assays were performed via histopathological evaluation, and no specific anatomical pathological changes or tissue damage was observed in the tissues of carps. The extent of tissue distribution and retention following oral administration of FITC-OCMCS nanoparticles was analyzed for 3 days. After 3 days, the nanoparticles remained detectable in the muscle, heart, kidney, liver, intestine, and spleen. The results showed that 34.32% of the particles were localized in the liver, 18.79% in the kidney, and 17.36% in the heart. The lowest percentage was observed in the muscle. These results implied that OCMCS nanoparticles had great potential to be applied as safe carriers for the oral administration of protein drugs. [Copyright &y& Elsevier]

In this study, a folate-modified-chitosan-coated liposome (FCCL) was prepared for tumor-targeted drug delivery. The folate-chitosan conjugates were characterized using H NMR and infrared spectrum analysis. The properties of folate-chitosan-coated liposomes (FCCLs) were studied and compared with those of traditional liposomes and chitosan-coated liposomes (CCLs). FCCLs were spherical in shape with a classic core-shell structure. Compared with conventional liposomes, FCCLs had larger size (average diameter: 182.0 nm), higher zeta potential (10.1 mV), prolonged drug release behaviors (55.76 % after 24 h), and better physical stability when stored at 25 °C, all similar to the properties of CCLs. With fluorescein as a model drug, fluorescein-loaded liposomes, CCLs, and FCCLs were prepared and their tumor targeting ability was evaluated according to the in vitro cellular uptake of fluorescein loaded nanoparticles by MCF-7 and HUVEC cells. Results demonstrated that FCCLs had a significant higher uptake by folate receptor positive cells (MCF-7) as compared to traditional liposomes and CCLs, which indicated that the FCCLs were promising nano-carriers for tumor-targeted drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: An alcohol-free oil/water hyaluronic acid nanoemulsion was developed to be applied as transdermal carrier for active lipophilic ingredient. In vitro hemolysis, skin penetration and histological examinations were carried out using α-tocopherol as model ingredient to assess skin permeability and bioavailability. Without any chemical enhancers, nanoemuslion performed desirable skin permeable capacity, being able to penetrate across stratum corneum and diffuse deeper into dermis compared with the control group (ethanol solution) via follicular and intercellular pathway. Penetration mechanism was preliminarily studied and suggested to be closely concerned with transmembrane concentration gradient, carrier characteristics and penetration enhancers. No irritation has been found in dermis and skin surface indicated hyaluronic acid nanoemulsions could be successfully used as purcutaneous delivery carrier of active lipophilic ingredient and favorable for drug and cosmetic applications. [Copyright &y& Elsevier]

The article focuses on a study which prepared chitosan-based thermosensitive hydrogels for drug delivery. Study authors showed how pH, ionic strength and CS/αΒ-GP ratio affect the thermosensitive characteristics, appearance and structure of the hydrogels. They concluded that chitosan-based thermosensitive hydrogels can be used in a sustained drug delivery system.

To develop more effective anticancer mucoadhesive drug delivery system for the treatment of colorectal cancer, chitosan based nanogels (NGs) were prepared by electrostatic interaction between chitosan (CS) and carboxymethyl-chitosan (CMCS). By respectively using tripolyphosphate (TPP) and CaCl 2 as ionic crosslinker, two well-characterized doxorubicin hydrochloride (DOX) loaded NGs with opposite zeta potential (DOX:CS/CMCS/TPP NGs, −32.6 ± 1.1 mV and DOX:CS/CMCS/Ca 2+ NGs, +31.8 ± 0.9 mV) were obtained. Compared with DOX:CS/CMCS/TPP NGs, DOX:CS/CMCS/Ca 2+ NGs were taken up to a greater extent by colorectal cancer cells, resulting in greater reduction in percentage of cell viability. Owing to high binding capability to mucin and inhibited paracellular transport by colon, DOX:CS/CMCS/Ca 2+ NGs exhibited improved mucoadhesion and limited permeability. This is beneficial to prolong the contact time of formulation onto intestinal mucosa and improved local drug concentration. The results provided evidence DOX:CS/CMCS/Ca 2+ NGs to be exciting and promising for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract: Two types of poly-lactic-co-glycolic acid (PLGA) based nanoparticles were prepared by surface modification (C-NPs) and homogeneous modification (G-NPs) with chitosan. The naked PLGA NPs were served as control. These nanoparticles all showed regularly spherical shape with mean diameters as 191.3±3.6nm, 211.9±13.2nm and 187.5±17.6nm for PLGA NPs, C-NPs and G-NPs, respectively. Their zeta potentials were −22.4±1.31mV, −8.7±0.45mV, −3.1±0.12mV, respectively. Both C-NPs (15.3% PLGA remained after 2 weeks) and G-NPs (3.7% PLGA remained after 2 weeks) had higher hydrolysis rate than PLGA NPs (18.4% PLGA remained after 6 weeks), with G-NPs showing the highest rate in hydrolysis due to the incorporation of chitosan and its self-assembled structure. Self-assembling properties and controllable biodegradability of G-NPs indicated that it could be a promising drug delivery carrier for tumor drug delivery. [Copyright &y& Elsevier]

The primary constraints for efficient oral delivery of anticancer drugs include the efflux pump function of the multidrug transporter P-glycoprotein (P-gp) for anticancer drugs and the barriers to drug absorption in gastrointestinal (GI) tract. To improve bypassing P-gp drug efflux pumps and oral bioavailability of doxorubicin hydrochloride (DOX), Multilayer micro-dispersing system (MMS) was constructed by co-immobilization of DOX loaded chitosan/carboxymethyl chitosan nanogels (DOX:CS/CMCS-NGs), along with quercetin (Qu) in the core of multilayer sodium alginate beads (DOX:NGs/Qu-M-ALG-Beads). The obtained DOX:NGs/Qu-M-ALG-Beads possessed layer-by-layer structure and porous core with many nanoscale particles. The swelling characteristic and drug release results indicated that DOX:NGs/Qu-M-ALG-Beads exhibited favorable gastric acid tolerance and targeting release of intact DOX:CS/CMCS-NGs and Qu in small intestine. After oral administration of DOX:NGs/Qu-M-ALG-Beads in rats, DOX was effectively delivered into systemic circulation due to P-gp inhibitory properties of Qu. The absolute bioavailability reached 55.75%, about 18.65 folds higher than oral DOX. Tissue distribution results showed that the liver exhibited the highest DOX level, followed by kidney, heart, lung, and spleen. These results implied that DOX:NGs/Qu-M-ALG-Beads had great potential to be applied as dual drug delivery for oral chemotherapy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the efficacy of nanoparticles based on chitosan as a vehicle for oral antigen delivery in fish vaccination. Carboxymethyl chitosan/chitosan nanoparticles (CMCS/CS-NPs) loaded extracellular products (ECPs) of Vibrio anguillarum were successfully developed by ionic gelation method. The prepared ECPs-loaded CMCS/CS-NPs were characterized for various parameters including morphology, particle size (312 ± 7.18 nm), zeta potential (+17.4 ± 0.38 mV), loading efficiency (57.8 ± 2.54%) and stability under the simulated gastrointestinal (GI) tract conditions in turbot. The in vitro profile showed that the cumulative release of ECPs from nanoparticles was higher in pH 7.4 (58%) than in pH 2.0 (37%) and pH 4.5 (29%) after 48 h. Fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) was used as model protein antigen and encapsulated in CMCS/CS-NPs for investigating the biodistribution of antigen after oral delivery to turbot in 24 h. Oral immunization of ECPs-loaded CMCS/CS-NPs group in turbot showed elevated specific antibody and higher concentrations of lysozyme activity and complement activity in fish serum than ECPs solution. CMCS/CS-NPs loaded with ECPs could enhance both adaptive and innate immune responses than the group treated with ECPs solution and suggested to be a potential antigen delivery system. [ABSTRACT FROM AUTHOR]

Here we described nano-polyplexes (NPs) made of oleoyl-carboxymethy-chitosan (OCMCS)/hyaluronic acid (HA) as novel potential carriers for oral gene vaccines delivery. Aerolysin gene (aerA) of Aeromonas hydrophila as microbial antigen was efficiently loaded to form OCMCS-HA/aerA (OHA) NPs. OHA NPs performed the optimal parameters, i.e. smallest (154.5 ± 9.4 nm), positive charged (+7.9 ± 0.5 mV) and monodispersed system with the N/P ratio of 5 and OCMCS/HA weight ratio of 4. Upon the introduction of HA, OHA NPs was beneficial for the DNA release in intestinal environments in comparison to OA NPs. The mean fluorescence intensity detected in Caco-2 cells incubated with OHA NPs was about 2.5-fold higher than that of OA NPs; however, it decreased significantly in the presence of excess free HA. The OHA NPs and OA NPs decreased the transepithelial electric resistance (TEER) of Caco-2 monolayers obviously and induced increasing the apparent permeability coefficient ( P app ) of DNA by 5.45–6.09 folds compared with free DNA. Significantly higher (P < 0.05) antigen-specific antibodies were detected in serum after orally immunized with OHA NPs than that immunized with OA NPs and DNA alone in carps. These results enable the OHA NPs might resolve challenges arising from gastrointestinal damage to gene antigens, and offer an approach applicable for oral vaccination. [ABSTRACT FROM AUTHOR]

To develop efficient and safe anticancer drug doxorubicin hydrochloride (DOX) delivery system for oral chemotherapy, chitosan based nanoparticles (CS/CMCS–NPs) composed of chitosan (CS) and o-carboxymeymethy chitosan (CMCS) were immobilized in multilayer sodium alginate beads (NPs–M–Beads). Two kinds of NPs–M–Beads, with or without porous core, were respectively prepared by internal or external ionic gelation method. In the small intestine, the intact CS/CMCS–NPs were able to escape from porous-beads and sustained release the loading DOX. In vivo results showed that the DOX could be efficiently absorbed by small intestine of SD rat and the higher concentration of the DOX in major organs of rats were found after oral administration of Porous-Beads, which were about 2–4 folds higher than that of non-porous-beads. These results suggested that the NPs–M–Beads with porous core to be exciting and promising for oral delivery of DOX. [ABSTRACT FROM AUTHOR]

Abstract: The present study investigated the ability of a polyelectrolyte complex (CS/CMCS-NPs), composed of chitosan (CS) and o-carboxymeymethy chitosan (CMCS) as a pH responsive carrier for oral delivery of doxorubicin hydrochloride (DOX). The obtained CS/CMCS-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency and stability under the simulated GI tract conditions. The pH responsive stability of the DOX-loaded CS/CMCS nanoparticles (DOX:CS/CMCS-NPs) determined the drug release rate, which was lower in acidic pH than the neutral. Ex vivo intestinal adhesion and permeation indicated DOX:CS/CMCS-NGs were able to enhance absorption of DOX throughout the entire small intestine, especially in jejunum and ileum. Oral administration of DOX:CS/CMCS-NPs was effective to deliver DOX into blood, giving an absolute bioavailability of 42%. The tissue distribution and toxicity of DOX:CS/CMCS-NPs in rats showed low level of DOX in heart and kidney, and obviously decreased cardiac and renal toxicities. These results indicated CS/CMCS-NPs were highly efficient and safe as an oral delivery system for DOX. [Copyright &y& Elsevier]