Drug Loading Content Research Articles

Investigating How All-Trans Retinoic Acid Polycaprolactone (atRA-PCL) Microparticles Alter the Material Properties of 3D Printed Fibrin Constructs.

The 3D printing of human tissue constructs requires carefully designed bioinks to support the growth and function of cells. Here it is shown that an additional parameter is how drug-releasing microparticles affect the material properties of the scaffold. A microfluidic platform is used to create all-trans retinoic acid (atRA) polycaprolactone (PCL) microparticles with a high encapsulation efficiency (85.9 ± 5.0%), and incorporate them into fibrin constructs to investigate their effect on the material properties. An encapsulation that is around 25-35% higher than the current state of the art batch methods is achieved. It is also found that the drug loading concentration affects the microparticle size, which can be controlled using the microfluidic platform. It is shown that the release of atRA is slower in fibrin constructs than in buffer, and that the presence of atRA in the microparticles modulates both the degradation and the rheological properties of the constructs. Finally, it is shown that the fibrin material exhibits a stronger solid-like state in the presence of atRA-PCL microparticles. These findings establish a basis for understanding the interplay between drug-releasing microparticles and scaffold materials, paving the way for bioinks that achieve tailored degradation and mechanical properties, together withsustained drug delivery for tissue engineeringapplications.

Polymerizable Cholinium-Based Antibiotics for Polymer Carriers: Systems with Combined Load of Cloxacillin and Ampicillin.

Single and dual-drug delivery systems (DDSs) based on linear choline polymers were designed through the controlled polymerization of a pharmaceutically functionalized monomer, i.e., [2-(methacryloyloxy)ethyl]trimethylammonium, with counterions of cloxacillin (TMAMA/CLX), or its copolymerization with [2-(methacryloyloxy)ethyl]trimethylammonium with ampicillin (TMAMA/AMP), providing antibiotic properties. This strategy was effective in attaining well-defined linear copolymers with 38-93 mol. % of TMAMA content, which were regulated by the initial ratio of TMAMA to methyl methacrylate comonomer. The polymer compositions were controlled by the total monomer conversion (40-75%), resulting in a variable degree of polymerization (DPn = 160-300) and pharmaceutical anion contents (CLX- 51-80% and AMP- 78-87%). In aqueous solution, the polymers formed particles with sizes ranging between 274 and 380 nm for CLX- systems and 288-348 nm for CLX-/AMP- systems. In vitro drug release, driven by the exchange of pharmaceutical anions with phosphate ions in phosphate-buffered saline (PBS), imitating a physiological fluid, demonstrated release efficiencies of 58-76% for CLX- (10.5-13.6 µg/mL) in single systems, and 91-100% for CLX- (12.9-15.1 µg/mL) and 97-100% for AMP- (21.1-23.3 µg/mL) in dual systems. Compared to conventional systems delivering antibiotics without a polymer carrier, the choline-based polymer DDS attained satisfactory levels of drug loading content and (co-)release from the polymer carriers, offering a promising alternative for antibiotic delivery.

Exploring Micelles and Nanospheres as Delivery Systems for Phenothiazine Derivatives in Cancer Therapy.

Objectives: Cancer remains one of the leading causes of death worldwide, and thus, there is a need for the development of innovative and more effective treatment strategies. The aim of the study was to evaluate two types of nanoparticles-nanospheres and micelles-obtained from PLA-based polymers to discover their potential for delivering four types of phenothiazine derivatives. Methods: The morphology, drug-loading properties, cytocompatibility, hemolytic properties and anticancer activity were analyzed. Results: The micelles exhibited significantly higher drug-loading properties, release process and cytotoxic activity against cancer cells compared to the nanospheres. The micelles containing 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride with an OH group as a substituent in the 10-position of the quinobenzothiazine ring showed the highest drug-loading content, the most efficient drug release, the lowest hemolytic activity and the most significant cytotoxic effect against HeLa cells. Conclusions: The conducted study enabled the development of a delivery system for the new anticancer compound and showed that the choice of drug carrier has a crucial effect on its cytotoxic potential against cancer cells.

Synthesis and Antioxidant Effects of Edaravone-Loaded MPEG-2000-DSPE Micelles in Rotenone-Induced PC12 Cell Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder globally that lacks any disease-modifying drug for prevention or treatment. Oxidative stress has been identified as one of the key pathogenic drivers of Parkinson's disease (PD). Edaravone, an approved free-radical scavenger, has proven to have potential against PD by targeting multiple key pathologies, including oxidative stress, focal mitochondria, and neuroinflammation. However, its bioavailability is potentially restricted due to its poor solubility and short half-life. This study aims to develop a simple and effective drug delivery system for edaravone to enhance its solubility, stability, and bioavailability to improve its neuroprotective efficacy. An MPEG-2000-DSPE-edaravone (MDE) micelle was prepared via solvent evaporation using MPEG-2000-DSPE as a carrier to encapsulate edaravone. The morphology, particle size, zeta potential, chemical structure, and edaravone loading of MDE were evaluated. We then investigated whether such targeted edaravone delivery could provide enhanced neuroprotection. A cell model of PD was established in PC12 cells through exposure to rotenone. The effects of MDE on PC12 cells treated with or without rotenone were evaluated using a cell counting kit-8, calcein acetoxymethyl ester (AM)-propidine iodide (PI) staining, and flow cytometry. Cell migration was evaluated using a wound healing assay. Additionally, the intracellular antioxidant study was performed using an ROS-level-detecting DCFH-DA probe, and the mitochondrial membrane potentials were evaluated using a JC-1 assay. MDE with a drug-loading content of 17.6% and an encapsulation efficiency of 92.8% was successfully prepared. The resultant MDE had a mean particle size of 112.97 ± 5.54 nm with a zeta potential of -42 mV. Cytotoxicity assays confirmed that the MDE (≤200 ug/mL) exhibited promising cytocompatibility with no significant effect on cell viability, cell cycle regulation, or apoptosis levels. Likewise, compared with the free edaravone, no effect on cell migration was noted for MDE. MDE might be able to target edaravone delivery into PC12 cells, increasing the mitochondrial membrane potential and providing a significant local antioxidant effect. The results demonstrated that MPEG-2000-DSPE could be a promising material for enhancing edaravone's aqueous solubility, stability, and antioxidant effects. MDE could be a potential drug formulation for treating PD and other diseases in which oxidative stress plays a key role in pathogenesis.

Platelet-mimicking nanoparticles loaded with diallyl trisulfide for Mitigating Myocardial Ischemia-Reperfusion Injury in rats.

Hydrogen sulfide (H2S) shows promise in treating myocardial ischemia-reperfusion injury (MIRI), but the challenge of controlled and sustained release hinders its clinical utility. In this study, we developed a platelet membrane-encapsulated mesoporous silica nanoparticle loaded with the H2S donor diallyl trisulfide (PM-MSN-DATS). PM-MSN-DATS demonstrated optimal encapsulation efficiency and drug-loading content. Comprehensive in vitro and in vivo assessments confirmed the biosafety of PM-MSN-DATS. In vitro, PM-MSN-DATS adhered to inflammation-activated endothelial cells and exhibited targeted accumulation in MIRI rat hearts. In vivo experiments revealed significant reductions in reactive oxygen species (ROS) and myocardial fibrosis area, improving cardiac function. Our findings highlight successfully creating a targeted H2S delivery system through platelet membrane-coated MSN nanoparticles. This well-designed drug delivery platform holds significant promise for advancing MIRI treatment strategies.

Enhanced transcytosis and therapeutic efficacy of paclitaxel nanoparticles: Pyridylboronic acid modification and sialic acid targeting

Efficient drug delivery and deeper penetration into tumors have become a primary focus of anti-tumor nanomedicine. In this study, pyridylboronic acid (BPA), as a targeting ligand for sialic acid, which is highly expressed on the surface of tumor cells, was conjugated with DSPE-PEG2k-NH2 to synthesize DSPE-PEG2k-BPA and used to encapsulate PTX. The resultant PTX@DSPE-PEG2k-BPA nanoparticles (DPB NPs) showed a mean particle size of 189.0 ± 3.5 nm, with a high drug loading content of 48.75 % and a rod-like morphology. In contrast to PTX@DSPE-mPEG2k nanoparticles (DP NPs), DPB NPs displayed enhanced cellular uptake and targetability to 4T1 tumor cells. Interestingly, BPA modification could also enhance transcytosis through the endoplasmic reticulum-Golgi pathway, thus improving penetration and accumulation of nanoparticles in tumors. An in vivo study on 4T1 tumor-bearing mice demonstrated that DPB NPs achieved a faster and more accumulation in tumors than DP NPs after intravenous administration, led to significantly improved therapeutic efficacy with a higher tumor inhibition rate (74.27 % vs 50.58 %, p < 0.01). In conclusion, the modification of BPA presents a strategy for the development of drug delivery systems that exhibit dual functionalities: active targeting and transcytosis.

Therapeutic co-assemblies for synergistic NSCLC treatment through dual topoisomerase I and tubulin inhibitors

Camptothecin (CPT) and podophyllotoxin (PPT) function as topoisomerase (TOP) I and tubulin inhibitors, respectively, with potent anticancer effects in a variety of cancers. Despite its promise, the clinical applicability of the combination of CPT and PPT faces challenges, including potential side effect and limited therapeutic efficacy. In this study, we designed co-assembly nanomedicines with the different weight (w/w) ratios of amphiphilic Evans blue conjugated CPT prodrug (EB-ss-CPT) and PPT molecules, denoted as ECT Nano. The co-assembly of EB-ss-CPT and PPT without other excipients has nearly 100% drug loading efficiency and high drug loading content of PPT of up to 74.29 ± 0.90 wt%. Notably, the ECT Nano (1:2) equipped with the ability to inhibit TOP I activity and tubulin polymerization, which provided a highly efficient strategy to improve synergistic efficacy and decrease side toxicity in non-small cell lung cancer mouse model. This work represents a step forward to the development of practical applications for dual TOP I and tubulin inhibitors and especially hopeful to the rational design of combination nanomedicine for therapeutic purposes.

Albumin and Polysorbate-80 Coated Sterile Nanosuspensions of Mebendazole for Glioblastoma Therapy.

The scarcity of existing and novel therapies for brain cancer has significantly affected the survival rate of glioblastoma patients. Mebendazole (MBZ), an antiparasitic agent demonstrated promising activity against brain cancer. However, poor solubility, multiple polymorphs, and insufficient permeability through blood-brain barrier (BBB) restricts its therapeutic efficacy through parenteral administration. The current study aimed to develop, optimize, and characterize sterile, injectable nanosuspension of mebendazole using parenterally acceptable stabilizers. Albumin and polysorbate 80 (PS-80) coated MBZ Nanosuspension (NS) was prepared using wet media milling technique. Design of experiment (DoE) approach was used to understand effect of drug loading versus stabilizer concentration. The optimized MBZ NS showed hydrodynamic diameter of 208.36 ± 0.24 nm with a poly dispersibility index (PDI) of 0.210 ± 0.03 and zeta potential of -20.41 ± 0.36 mV. The IC50 value of MBZ NS in U-87 MG and LN-229 cell lines were found to be 0.49 ± 0.02 μM and 0.48 ± 0.05 μM, respectively. Additionally, MBZ NS demonstrated a 2.65-fold decrease in colony-forming efficiency and a 1.16-fold reduction in migration of the bridging area compared to MBZ. In 3D spheroids of the U-87 MG glioma cell line, MBZ NS exhibited a 50% reduction in tumor growth and increased cell apoptosis compared to the control. MBZ NS formulations were sterilized by gamma irradiation and tested as per the USP sterility test. Albumin-PS 80 coated NS is rendered to be useful parenteral delivery of mebendazole for the treatment of brain cancer.

A Modular Approach to Obtain HER2-Targeting DM1-Loaded Nanoparticles for Gastric Cancer Therapy.

Antibody-based tumor-targeting nanomedicines, despite their high efficacy, present significant challenges in preparation and long-term storage. We introduce a novel approach for the synthesis of durable, ready-to-use, antibody-coupled nanomedical drugs. Our research centers on the development of HER2-targeting DM1-loaded nanoparticles for gastric cancer treatment using a modular methodology. We synthesized Fc-PLG-Mal, conjugated DM1 through a "click" reaction, and subsequently bound the resultant compound with the HER2 antibody trastuzumab. The nanoparticles demonstrated a high drug loading content, stable particle size, and effective HER2 targeting. HER2-PLG-DM1 exhibited significant cytotoxicity against NCI-N87 gastric cancer cells, with an IC50 of 0.35 nM. Biodistribution revealed rapid and substantial tumor accumulation, 6-fold higher than that of nontargeting IgG-PLG-DM1. HER2-PLG-DM1 significantly inhibited tumor growth in NCI-N87 tumor-bearing mice, achieving a 90.8% tumor inhibition rate, and displayed dose-dependent effects without significant liver and kidney toxicity. These studies offer an efficient and stable method for the preparation of antibody-coupled drugs.

Multifunctional Temperature-Sensitive Lipid-Protein-Polymer Conjugates: Tailored Drug Delivery and Bioimaging.

In this study, we introduce a protein-polymer bioconjugate comprising bovine serum albumin (BSA) and a lipid-based thermoresponsive block copolymer. These amphiphilic BSA-polymer conjugates can autonomously be organized into vesicular compartments for codelivery of glucose oxidase (GOx) and doxorubicin (DOX), demonstrating high drug loading content and remarkable antitumor activity via synergistic cancer therapy combining chemo-starvation strategies. Through the incorporation of a hydrophilic BSA block, the lower critical solution temperature (LCST) of the bioconjugates is tuned to around 40 °C, facilitating their targeted drug delivery to tumor cells. Consequently, these smart protein-polymer conjugates present greater promise compared to traditional drug delivery vehicles, particularly in the realm of anticancer therapy. Moreover, these bioconjugates displayed enhanced intracellular fluorescence intensity with increasing temperature, attributed to the clustering-triggered emission of the nonconventional chromophore moieties within poly(vinylcaprolactam) (PNVCL). The active aggregation-induced emission (AIE) characteristic and excellent biocompatibility suggest an opportunity to further apply these bioconjugates for biosensing and cellular imaging.

Comparative efficacy of Knema retusa extract delivery via PEG-b-PCL, niosome, and their combination against Acanthamoeba triangularis genotype T4: characterization, inhibition, anti-adhesion, and cytotoxic activity.

Acanthamoeba spp. is a waterborne, opportunistic protozoan that can cause amebic keratitis and granulomatous amebic encephalitis. Knema retusa is a native tree in Malaysia, and its extracts possess a broad range of biological activities. Niosomes are non-ionic surfactant-based vesicle formations and suggest a future targeted drug delivery system. Copolymer micelle (poly(ethylene glycol)-block-poly(ɛ-caprolactone); PEG-b-PCL) is also a key constituent of niosome and supports high stability and drug efficacy. To establish Knema retusa extract (KRe) loading in diverse nanocarriers via niosome, PEG-b-PCL micelle, and their combination and to study the effect of all types of nanoparticles (NPs) on Acanthamoeba viability, adherent ability, elimination of adherence, and cytotoxicity. In this study, we characterized niosomes, PEG-b-PCL, and their combination loaded with KRe and tested the effect of these NPs on Acanthamoeba triangularis stages. KRe-loaded PEG-b-PCL, KRe-loaded niosome, and KRe-loaded PEG-b-PCL plus niosome were synthesized and characterized regarding particle size and charge, yield, encapsulation efficiency (EE), and drug loading content (DLC). The effect of these KRe-loaded NPs on trophozoite and cystic forms of A.triangularis was assessed through assays of minimal inhibitory concentration (MIC), using trypan blue exclusion to determine the viability. The effect of KRe-loaded NPs was also determined on A.triangularis trophozoite for 24-72 h. Additionally, the anti-adhesion activity of the KRe-loaded niosome on trophozoites was also performed on a 96-well plate. Cytotoxicity activity of KRe-loaded NPs was assessed on VERO and HaCaT cells using MTT assay. KRe-loaded niosome demonstrated a higher yielded (87.93 ±6.03%) at 286nm UV-Vis detection and exhibited a larger size (199.3 ±29.98 nm) and DLC (19.63±1.84%) compared to KRe-loaded PEG-b-PCL (45.2 ±10.07 nm and 2.15±0.25%). The EE (%) of KRe-loaded niosome was 63.67 ±4.04, which was significantly lower than that of the combination of PEG-b-PCL and niosome (79.67±2.08). However, the particle charge of these NPs was similar (-28.2 ±3.68 mV and -28.5 ±4.88, respectively). Additionally, KRe-loaded niosome and KRe-loaded PEG-b-PCL plus niosome exhibited a lower MIC at 24 h (0.25 mg/mL), inhibiting 90-100% of Acanthamoeba trophozoites which lasted 72 h. KRe-loaded niosome affected adherence by around 40-60% at 0.125-0.25 mg/mL and removed Acanthamoeba adhesion on the surface by about 90% at 0.5 mg/mL. Cell viability of VERO and HaCaT cells treated with 0.125 mg/mL of KRe-loaded niosome and KRe-loaded PEG-b-PCL plus niosome exceeded 80%. Indeed, niosome and niosome plus PEG-b-PCL were suitable nanocarrier-loaded KRe, and they had a greater nanoparticle property to test with high activities against A. triangularis on the reduction of adherence ability and demonstration of its low toxicity to VERO and HaCaT cells.

Synthesis of Carboxylate-Dialdehyde Cellulose to Use as a Component in Composite Thin Films for an Antibacterial Material in Wound Dressing.

Wound infections can lead to life-threatening infection and death. Antibacterial materials from biopolymers in the form of films are a promising strategy for wound dressings. Carboxylate-dialdehyde cellulose (CDAC) is a proper candidate for use as an antibacterial material due to its biocompatibility, nontoxicity, and antibacterial property. Additionally, CDAC can be synthesized from cellulose through environmentally friendly and nontoxic methods. Thus, this study aims to synthesize CDAC from microcrystalline cellulose (MCC) PH102 and use it in composite films for an antibacterial application. The CDAC was synthesized using Fe2+/H2O2, followed by NaIO4 oxidation. The obtained CDAC was characterized in terms of carboxylate and aldehyde content as well as FTIR and XRD spectra. The CDAC was mixed with HPMC in different ratios to prepare films. To determine the optimal formulation for clindamycin HCl loading, the films were evaluated for morphology, mechanical properties, and swelling ratio. Finally, the films containing clindamycin HCl were evaluated for drug loading content, in vitro drug release, and antibacterial activity. This study found that CDAC contained 2.1 ± 0.2 carboxylate and 4.15 ± 0.2 mmol/g of aldehyde content. The FTIR spectra confirmed the successful synthesis. X-ray diffractograms indicated that CDAC was less crystalline than MCC. The film, consisting of CDAC and HPMC E50 in the ratio of 2:1 (D2H1), was identified as the most suitable for clindamycin HCl loading due to its superior appearance, mechanical strength, and swelling properties compared to other formulations. D2H1 exhibited a high drug loading capacity (91.49 ± 5.48%) and demonstrated faster drug release than the film composed only of HPMC because of the higher swelling ratio and lower mechanical strength. This formulation was effective against Staphylococcus aureus (MSSA), S. aureus (MRSA), and Pseudomonas aeruginosa. Furthermore, the D2H1 film containing clindamycin HCl showed a larger inhibition zone against these bacteria, likely due to a synergistic effect. This study found that CDAC has the potential to be applied as an antibacterial material for wound dressing.

Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu2+ depletes intracellular GSH and is reduced to Cu+ simultaneously, which reacts with local H2O2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

Berberine-Loaded PVCL-PVA-PEG Self-Assembled Micelles for the Treatment of Liver Fibrosis.

Liver fibrosis is a necessary pathological process in many chronic liver diseases. Studies have shown that the progression of chronic liver disease can be slowed by rational intervention in hepatic fibrosis. Berberine (BBR), a natural extract of Phellodendron amurense, inhibits the development of liver fibrosis through several mechanisms. However, the clinical application of BBR is limited due to its low solubility. Drug delivery systems have been developed to improve the solubility of hydrophobic drugs and increase their efficacy in treating the liver fibrosis. In this study, a biocompatible nanomicelle was constructed by thin-film dispersion method using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) as a carrier to encapsulate BBR (PVCL-PVA-PEG/BBR-MCs) to improve the solubility of BBR and reduce the systemic side effects. The ability to inhibit HSC-T6 cell activation of PVCL-PVA-PEG/BBR-MCs was evaluated in vitro. The anti-hepatic fibrosis effects of PVCL-PVA-PEG/BBR-MCs were investigated in vivo. PVCL-PVA-PEG/BBR-MCs have a uniform spherical shape with a mean particle size of 60.04 ± 0.027 nm and a potential of 1.49 ± 0.32 mV. It had an encapsulation efficiency of 98.52% ± 0.70 and drug loading content of 6.16% ± 0.04. Compared to free BBR, PVCL-PVA-PEG/BBR-MCs significantly inhibited HSC-T6 cell activation and TGF-β1-induced HSC-T6 cell migration in vitro. In vivo biodistribution experiments showed significantly improved hepatic distribution of PVCL-PVA-PEG/DiD-MCs compared to free DiD, suggesting that PVCL-PVA-PEG micelles enhance the ability of BBR to enter the liver and improve therapeutic efficacy. After treatment, PVCL-PVA-PEG/BBR-MCs significantly improved fibrotic liver structure and reduced collagen deposition in comparison to the CCl4-treated group; the treatment outcome was more effective than that of the free BBR group. Our results demonstrate the advantages of encapsulating BBR in PVCL-PVA-PEG micelles and highlight the potential of PVCL-PVA-PEG/BBR-MCs as a therapeutic strategy for the treatment of liver fibrosis.

Synthesis and characterization of Fe3O4@MIL-100 nanoparticles as an SSI-assisted drug carrier

In this study, core–shell structured Fe3O4@MIL-100 nanoparticles were synthesized through an in-situ growth method. The resulting magnetic composite exhibited significant magnetic responsivity, with a magnetization saturation (Ms) of 37.24 emu/g and a magnetocaloric temperature rise of 42.1 ℃ within 6 min at 20 A. Supercritical solution impregnation (SSI) technology was used for CUR loading, achieving an outstanding drug loading content of 4.36 wt% compared to ethanol impregnation. These results show the potential of the present magnetic materials with SSI process in biomedical applications.

ROS-responsive nanomicelles encapsulating celastrol ameliorate pressure overload-induced cardiac hypertrophy by regulating the NF-κB signaling pathway

Celastrol (CEL) belongs to the group of non-steroidal immunosuppressants with the potential to improve cardiac hypertrophy (CH). However, the poor biocompatibility and low bioavailability of CEL limit its in vivo application. This study was aimed to develop a targeted drug delivery system that can efficiently and safely deliver CEL to target tissues, providing a research basis for the application of CEL in CH therapy. A novel ROS-sensitive drug-loaded nanomicelle, dodecanoic acid (DA)-phenylboronic acid pinacol ester-dextran polymer encapsulating CEL (DBD@CEL), was synthesized using chemical synthesis. Then, the morphology, particle size, drug-loaded content, and ROS-responsive release behavior of DBD@CEL were studied. Pharmacokinetics and biocompatibility were evaluated using healthy mice. Finally, the ability and mechanism of DBD@CEL in improving CH in vivo were investigated using a mouse CH model. DBD@CEL was successfully prepared with a drug loading of 18.9%. It exhibited excellent stability with an average particle size of 110.0 ± 1.7 nm. Within 48 h, DBD@CEL released only 19.4% in the absence of H2O2, while in the presence of 1 mM H2O2, the release rate increased to 71.5%. Biocompatibility studies indicated that DBD@CEL did not cause blood cell hemolysis, had no impact on normal organs, and did not result in abnormal blood biochemical indicators, demonstrating excellent biocompatibility. In vivo studies revealed that DBD@CEL regulated the activation of NF-κB signaling, inhibits pyroptosis and oxidative stress, and thereby ameliorates CH. The ROS-responsive DBD@CEL nanodrug delivery system enhances the therapeutic activity of CEL for CH, providing a promising drug delivery system for the clinical treatment of CH.

ROS sensitive micelles of carbon dioxide based amphiphilic polymer for delivery of avermectin

A novel amphiphilic polymer, methoxy polyethylene glycols (mPEG)-3, 3′-(propane-2, 2-diylbis (sulfanediyl)) dipropionic acid (TK)-poly (propylene oxide-co-carbon dioxide-co-allyl glycidyl ether) (PPAG) (mPEG2000-TK-PPAG), was successfully synthesized for delivery of avermectin (AVE). The chemical structure was characterized by FTIR. In aqueous medium, mPEG2000-TK-PPAG could self-assembled into micelles. The AVE loaded mPEG2000-TK-PPAG micelles showed a considerable drug-loading content of 19 %. The prepared micelles were spherical morphology with average hydrodynamic diameter 469.4 nm and zeta potential of around –33.6 mv. AVE was released slowly from the AVE loaded mPEG2000-TK-PPAG micelles in a neutral condition and was released rapidly under stimulation of reactive oxygen species (ROS). Therefore, this ROS responsive micelle formulation achieves target control of pests and provides an efficient micelle platform for green agriculture.

Novel RGD-decorated micelles loaded with doxorubicin for targeted breast cancer chemotherapy

Nanotechnology has emerged as a promising innovative avenue for therapeutic intervention in cancer research. However, achieving satisfactory accumulation of nanoparticles in the tumor and fabricating optimized nanoparticles remain challenging. In this work, we developed a novel polymeric micelle system to actively target integrin receptors, which are usually overexpressed in breast cancer. We first synthesized a targeted peptide-modified cyclic (Arg-Gly-Asp-D-Phe-Cys) (c(RGDfc))-polyethylene glycol-acitretin amphipathic conjugate (RPA) and prepared doxorubicin (DOX)-loaded RPADm (RPA@DOX) micelles with a high drug loading content of more than 11 %. Compared with unmodified DOX-containing micelles, RPADm demonstrated increased cytotoxicity and cellular uptake by MCF-7 cells. Importantly, competitive binding experiments confirmed that the observed enhancement effect was attributed to the modification of c(RGDfc) on the surface of the micelles. Furthermore, due to its active tumor-targeting ability, compared with the other DOX-based formulations, the RPADm exhibited the highest tumor distribution and strongest therapeutic efficacy in MCF-7 tumor-bearing nude mice. Additionally, the safety evaluation experiments revealed that the DOX-loaded micelles had no obvious systemic toxicity. These results suggest that the developed micelles modified with c(RGDfc) are promising candidates for tumor-active targeting therapies.

A comparative study of PEO-PBO content on the targeting and anti-glioma activity of annonaceous acetogenins-loaded nanomicelles

Annonaceous acetogenins (ACGs) have great potential in the treatment of gliomas, but are extremely insoluble and difficult for delivery in vivo. Poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) is an amphiphilic polymer and can reduce the clearance of nanoparticles by mononuclear phagocyte system. To explore an efficient and safe nanomedicine for glioma, ACGs-loaded nanomicelles (ACGs/EB-NCs) was constructed using PEO-PBO as a carrier, and the effect of PEO-PBO content on the targeting and anti-glioma activity were also compared. ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs, the three nanomicellels prepared with different ACGs/EB feeding ratios, had average particle sizes of 148.8±0.5 nm, 32.7±4.1 nm, and 27.1±0.3 nm, respectively. The three ACGs/EB-NCs were spherical in shape, with drug loading content close to the theoretical drug loading content, encapsulation efficiency greater than 97 %, and good stability in physiological media. The cumulative release rates of ACGs/EB5-NCs, ACGs/EB10-NCs and ACGs/EB20-NCs were 78.2 %, 63.4 %, and 56.3 % within 216 hours, respectively. The inhibitory effects of three ACGs/EB-NCs on U87 MG cells were similar and stronger than free ACGs (P<0.05), with half inhibitory concentration of 0.17, 0.18, and 0.16 ng/mL (P>0.05), respectively. In U87 MG tumor‑bearing mice, ACGs/EB5-NC, ACGs/EB10-NCs and ACGs/EB20-NCs showed a similar tumor inhibition rate of 61.1±5.9 %, 56.2±8.6 % and 64.3±9.4 % (P>0.05), with good safety. Three ACGs/EB-NCs exhibited excellent liver escape ability and tumor targeting ability, with the tumor targeting index greater than 1.5. Three ACGs/EB-NCs were successfully prepared with strong anti-glioma activity and tumor targeting properties, which are expected to provide new options for the clinical treatment of gliomas. The content of PEO-PBO in micelles did not have a significant effect on the tumor targeting and anti-glioma activity of ACGs/EB-NCs.

Celastrol Derivative/DOX Co-Assembled Nanodrug for Enhanced Antitumor Therapy.

Multidrug resistance (MDR) is a key challenge in clinical chemotherapy. The combination of drugs can effectively reverse multi-drug resistance. In this study, doxorubicin (DOX) was capsulated into nanoparticles formed by an amphiphilic PEGylated-poly (α-lipoic acid)-methanamide analogue of celastrol (mPEG-PαLA-CEN) prodrug polymer. CEN was linked to the branched chain of poly (α-lipoic acid) by forming ester bonds. DOX was physically trapped inside the nanoparticles via electrostatic interaction. Both drugs can be simultaneously released in response to low pH and high GSH in order to overcome DOX resistance. The chemical structure of the mPEG-PαLA-CEN-DOX NPs was confirmed through 1H NMR, FT-IR spectroscopy, UV-Vis spectrum, DLS, and TEM. Drug-loading content, efficacy, and drug release were measured using HPLC. Cell toxicity was examined using an MTT assay. CEN/DOX-loaded nanoparticles were found to have spherical shapes with diameters of around 229.7 nm. The NPs exhibited high biocompatibility and released 92% DOX and 71.8% CEN in response to low pH and high GSH of tumor microenvironments. As dual drug-loaded nanoparticles, the efficacy of mPEG-PαLA-CEN-DOX NPs against tumor cell lines in vitro was enhanced for both MCF-7 and MCF-7/ADR compared to free DOX. Compared to free DOX, the IC50 of mPEG-PαLA-CEN-DOX NPs reduced from 46.10 μM to 8.36 μM for the MCF-7/ADR cell line. In conclusion, this study demonstrated that PEGylated poly (α-lipoic acid)-CEN copolymers can be used not only as biocompatible, stimulation-responsive anticancer drug nanocarriers but also as chemosensitizers to overcome multidrug resistance, which provide a theoretical base for clinical application of CEN/DOX nanodrug.