CD44 Receptor-mediated Endocytosis Research Articles

Chondroitin sulfate-based universal nanoparticle delivers angiogenic inhibitor and paclitaxel to exhibit a combination of chemotherapy and anti-angiogenic therapy

Blocking the tumor nutrient supply through angiogenic inhibitors is an effective treatment approach for malignant tumors. However, using angiogenic inhibitors alone may not be enough to achieve a significant tumor response. Therefore, we recently designed a universal drug delivery system combining chemotherapy and anti-angiogenic therapy to target tumor cells while minimizing drug-related side effects. This system (termed as PCCE) is composed of biomaterial chondroitin sulfate (CS), the anti-angiogenic peptide ES2, and paclitaxel (PTX), which collectively enhance antitumor properties. Interestingly, the PCCE system is conferred exceptional cell membrane permeability due to inherent characteristics of CS, including CD44 receptor-mediated endocytosis. The PCCE could respond to the acidic and high glutathione conditions, thereby releasing PTX and ES2. PCCE could effectively inhibit the proliferation, migration, and invasion of tumor cells and cause apoptosis, while PCCE can affect the endothelial cells tube formation and exert anti-angiogenic function. Consistently, more potent in vivo antitumor efficacy and non-toxic sides were demonstrated in B16F10 xenograft mouse models. PCCE can achieve excellent antitumor activity via modulating angiogenic and apoptosis-related factors. In summary, we have successfully developed an intelligent and responsive CS-based nanocarrier known as PCCE for delivering various antitumor drugs, offering a promising strategy for treating malignant tumors.

Unveiling the potential of ursolic acid modified hyaluronate nanoparticles for combination drug therapy in triple negative breast cancer

Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 μg/mL. The HA-UA conjugate exhibited ∼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (∼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. In vitro, HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. In vivo, HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t1/2, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.

CD44-Targeted Lipid Polymer Hybrid Nanoparticles Enhance Anti-Breast Cancer Effect of Cordyceps militaris Extracts.

This study aimed to improve the anticancer effect of Cordyceps militaris herbal extract (CME) on breast cancer cells with hyaluronic acid (HYA) surface-decorated lipid polymer hybrid nanoparticles (LPNPs) and evaluate the applicability of a synthesized poly(glycerol adipate) (PGA) polymer for LPNP preparation. Firstly, cholesterol- and vitamin E-grafted PGA polymers (PGA-CH and PGA-VE, respectively) were fabricated, with and without maleimide-ended polyethylene glycol. Subsequently, CME, which contained an active cordycepin equaling 9.89% of its weight, was encapsulated in the LPNPs. The results revealed that the synthesized polymers could be used to prepare CME-loaded LPNPs. The LPNP formulations containing Mal-PEG were decorated with cysteine-grafted HYA via thiol-maleimide reactions. The HYA-decorated PGA-based LPNPs substantially enhanced the anticancer effect of CME against MDA-MB-231 and MCF-7 breast cancer cells by enhancing cellular uptake through CD44 receptor-mediated endocytosis. This study demonstrated the successful targeted delivery of CME to the CD44 receptors of tumor cells by HYA-conjugated PGA-based LPNPs and the new application of synthesized PGA-CH- and PGA-VE-based polymers in LPNP preparation. The developed LPNPs showed promising potential for the targeted delivery of herbal extracts for cancer treatment and clear potential for translation in in vivo experiments.

Formulation and evaluation of a two-stage targeted liposome coated with hyaluronic acid for improving lung cancer chemotherapy and overcoming multidrug resistance

Multidrug resistance (MDR) has emerged as a prominent challenge contributing to the ineffectiveness of chemotherapy in treating non-small cell lung cancer (NSCLC) patients. Currently, mitochondria of cancer cells are identified as a promising target for overcoming MDR due to their crucial role in intrinsic apoptosis pathway and energy supply centers. Here, a two-stage targeted liposome (HA/TT LP/PTX) was successfully developed via a two-step process: PTX-loaded cationic liposome (TT LP/PTX) were formulated by lipid film hydration & ultrasound technique, followed by further coating with natural anionic polysaccharide hyaluronic acid (HA). TT, an amphipathic polymer conjugate of triphenylphosphine (TPP)-tocopheryl polyethylene glycol succinate (TPGS), was used to modify the liposomes for mitochondrial targeting. The average particle size, zeta potential and encapsulation efficiency (EE%) of HA/TT LP/PTX were found to be 153 nm, −30.3 mV and 92.1% based on the optimal prescription of HA/TT LP/PTX. Compared to cationic liposome, HA-coated liposomes showed improved stability and safety, including biological stability in serum, cytocompatibility, and lower hemolysis percentage. In drug-resistant A549/T cells, HA was shown to improve the cellular uptake of PTX through CD44 receptor-mediated endocytosis and subsequent degradation by hyaluronidase (HAase) in endosomes. Following this, the exposure of TT polymer facilitated the accumulation of PTX within the mitochondria. As a result, the function of mitochondria in A549/T cells was disturbed, leading to an increased ROS level, decreased ATP level, dissipated MMP, and increased G2/M phase arrest. This resulted in a higher apoptotic rate and stronger anticancer efficacy.

Hyaluronic acid modified oral drug delivery system with mucoadhesiveness and macrophage-targeting for colitis treatment

Based on the biocompatibility and macrophage targeting of natural polysaccharides, combined with the physiological and pathological characteristics of the gastrointestinal tract and colonic mucosa of ulcerative colitis (UC), we prepare dexamethasone (Dex)-loaded oral colon-targeted nano-in-micro drug delivery systems coated with multilayers of chitosan (CS), hyaluronic acid (HA), and finally Eudragit S100 (ECHCD MPs) using a layer-by-layer coating technique for UC treatment through regulating the M1/M2 polarization of intestinal macrophages. HA/CS/Dex nanoparticles (HCD NPs) are ingested by macrophages via CD44 receptor-mediated endocytosis to regulate M1-to-M2 macrophage polarization and exert anti-inflammatory effects. Moreover, ECHCD MPs show better colon-targeting properties than Dex-loaded chitosan nanoparticles (CD NPs) and HCD NPs which is demonstrated by stronger mucoadhesion to inflamed colon tissues. After oral administration, ECHCD MPs exert significant anti-UC effects. Therefore, ECHCD MPs are proven to be as promising oral colon-targeting drug delivery systems for Dex and have potential application in UC treatment.

Tumor-targeted glycogen nanoparticles loaded with hemin and glucose oxidase to promote tumor synergistic therapy

Strategies which are used to address the low levels of intracellular hydrogen peroxide and the development of biocompatible catalysts still need to be fulfilled in tumor chemodynamic therapy. Therefore, a novel tumor-targeted glycogen-based nanoparticle system (GN/He/GOx/HA) was developed to co-deliver hemin (He) and GOx, which can self-supply glucose formed upon degradation of glycogen by α-glycosidase in the lysosome environment, in order to achieve synergistic antitumor therapy. Hyaluronic acid (HA) was selected as the outer shell to protect the activity of GOx, and to increase the uptake by tumor cells via CD44 receptor-mediated endocytosis. GN/He/GOx/HA NPs had a good stability in the blood circulation, but fast release of the therapeutic cargos upon intracellular uptake. Hemin had a cascade catalytic reaction with GOx. Furthermore, GN/He/GOx/HA NPs had the strongest cytotoxicity in Hela cells in a glucose concentration dependent manner. The NPs could efficiently produce reactive oxygen species in tumor cells, resulting in a decrease in the mitochondrial membrane potential and apoptosis of tumor cells. The in vivo results showed that the drug-loaded nanoparticles had good safety, biocompatibility, and efficacious antitumor effect. Therefore, the glycogen-based nanoparticle delivery system provides potential application for self-enhancing CDT, which can be used for effective antitumor therapy.

Synthesis, characterization, and in vitro anti-tumor activity studies of the hyaluronic acid-mangiferin-methotrexate nanodrug targeted delivery system

In this study, to increase the accumulation of MTX in the tumor site and reduce the toxicity to normal tissues by MA, a novel nano-drug delivery system comprised of hyaluronic acid (HA)-mangiferin (MA)-methotrexate (MTX) (HA-MA-MTX) was developed by a self-assembly strategy. The advantage of the nano-drug delivery system is that MTX can be used as a tumor-targeting ligand of the folate receptor (FA), HA can be used as another tumor-targeting ligand of the CD44 receptor, and MA serves as an anti-inflammatory agent. 1HNMR and FT-IR results confirmed that HA, MA, and MTX were well coupled together by the ester bond. DLS and AFM images revealed that the size of HA-MA-MTX nanoparticles was about ~138 nm. In vitro cell experiments proved that HA-MA-MTX nanoparticles have a positive effect on inhibiting K7 cancer cells while having relatively lower toxicity to normal MC3T3-E1 cells than MTX does. All these results indicated that the prepared HA-MA-MTX nanoparticles can be selectively ingested by K7 tumor cells through FA and CD44 receptor-mediated endocytosis, thus inhibiting the growth of tumor tissues and reducing the nonspecific uptake toxicity caused by chemotherapy. Therefore, these self-assembled HA-MA-MTX NPs could be a potential anti-tumor drug delivery system.

Preparation of multifunctional mesoporous SiO2 nanoparticles and anti-tumor action

A targeted drug delivery system was developed to accumulate specific drugs around tumor cells based on the redox, temperature, and enzyme synergistic responses of mesoporous silica nanoparticles. Mesoporous silica nanoparticles (MSN-NH2) and Doxorubicin (DOX) for tumor therapy were prepared and loaded into the pores of MSN- NH2 to obtain DOX@MSN(DM NPs). Hyaluronic acid (HA) was used as the backbone and disulfide bond was used as the linker arm to graft carboxylated poly (N-isopropylacrylamide)(PNIPAAm-COOH) to synthesize the macromolecular copolymer (HA-SS-PNIPAAm), which was modified to DM NPs with capped ends to obtain the nano-delivery system DOX@MSN@HA-SS-PNIPAAm(DMHSP NPs), and a control formulation was prepared in a similar way. DMHSP NPs specifically entered tumor cells via CD44 receptor-mediated endocytosis; the high GSH concentration (10 mM) of cells severed the disulfide bonds, the hyaluronidase sheared the capped HA to open the pores, and increased tumor microenvironment temperature due to immune response can trigger the release of encapsulated drugs in thermosensitive materials. In vitro and in vivo antitumor and hemolysis assays showed that DMHSP NPs can accurately target hepatocellular carcinoma cells with a good safety profile and have synergistic effects, which meant DMHSP NPs had great potential for tumor therapy.

Antioxidant, Enzyme, and H2O2-Triggered Melanoma Targeted Mesoporous Organo-Silica Nanocomposites for Synergistic Cancer Therapy.

The multi-stimuli responsive drug delivery system has recently attracted attention in cancer treatments, since it can reduce several side effects and enhance cancer therapeutic efficacy. Herein, we present the intracellular antioxidant (glutathione, GSH), enzyme (hyaluronidase, HAase), and hydrogen peroxide (H2O2) triggered mesoporous organo-silica (MOS) nanocomposites for multi-modal treatments via chemo-, photothermal, and photodynamic cancer therapies. A MOS nanoparticle was synthesized by two-types of precursors, tetraethyl orthosilicate (TEOS) and bis[3-(triethoxysilyl)propyl] tetrasulfide (BTES), providing large-sized mesopores and disulfide bonds cleavable by GSH. Additionally, we introduced a new β-cyclodextrin-hyaluronic acid (CDHA) gatekeeper system, enabling nanocomposites to form the specific interaction with the ferrocene (Fc) molecule, control the drug release by the HAase and H2O2 environment, as well as provide the targeting ability against the CD44-overexpressing melanoma (B16F10) cells. Indocyanine green (ICG) and doxorubicin (Dox) were loaded in the MOS-Fc-CDHA (ID@MOS-Fc-CDHA) nanocomposites, allowing for hyperthermia and cytotoxic reactive oxygen species (ROS) under an 808 nm NIR laser irradiation. Therefore, we demonstrated that the ID@MOS-Fc-CDHA nanocomposites were internalized to the B16F10 cells via the CD44 receptor-mediated endocytosis, showing the controlled drug release by GSH, HAase, and H2O2 to enhance the cancer therapeutic efficacy via the synergistic chemo-, photothermal, and photodynamic therapy effect.

Octenyl-succinylated inulins for the delivery of hydrophobic drug

The efficacy of hydrophobic anticancer drugs is limited by their poor solubility in water, inefficient target delivery, and toxic side effects. In this work, doxorubicin (DOX) was solubilized using OSA-inulins which created micellar aggregates in aqueous solution above a critical concentration. In vitro delivery of OSA-inulin-DOX micelles resulted in strong inhibition of the growth of MCF-7 breast cancer cells as compared to free DOX. They also displayed a faster cellular uptake rate, indicating that the micelles were promptly internalized into the cells through CD44 receptor-mediated endocytosis. During in vivo tumor suppression experiments in tumor-bearing mice, the OSA-inulin-DOX micelles strongly hindered tumor growth and showed substantially lower systemic toxicity compared with free DOX. Our achievements demonstrate that OSA-inulin has great potential for the encapsulating, dissolving, and targeted delivery of hydrophobic drugs, especially antitumor drugs, for nutraceutical, medical, and pharmaceutical applications.

An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization

The signaling cascade between nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) can be activated by proinflammatory M1 macrophages in rheumatoid arthritis (RA), which produces reactive oxygen species (ROS) and enhances M1 macrophage polarization, thus aggravating the development of RA. Therefore, an ROS-responsive artesunate prodrug micellar nanosystem for co-delivery of dexamethasone (DEX/HA-TK-ART micelles, abbreviated as DEX/HTA) was developed for synergistic inhibition of the HIF-1α/NF-κB cascade to regulate ROS scavenging and macrophage repolarization in RA combination therapy. DEX/HTA micelles displayed prolonged circulation in blood and efficiently co-delivered ART&DEX in the inflamed joints of adjuvant-induced arthritis (AIA) rats; moreover, they were specifically recognized and internalized into M1 macrophages through CD44 receptor-mediated endocytosis. ROS-responsive co-released ART&DEX then exerted a synergistic action to efficiently perform ROS scavenging and repolarization of M1 to M2 macrophages by inhibition of the HIF-1α/NF-κB cascade. The intravenous administration of DEX/HTA micelles into AIA rat models significantly alleviated inflammatory cell infiltration and repaired cartilage injury in the joint. Collectively, our study highlights the therapeutic potential of DEX/HTA micelles for treating RA through synergistic inhibition of the HIF-1α/NF-κB signaling cascade to regulate ROS scavenging and macrophage repolarization. Statement of significanceAn ROS-responsive artesunate (ART) prodrug micellar nanosystem for co-delivering dexamethasone (DEX), abbreviated as DEX/HA-TK-ART micelle, was developed for synergistic cascade regulation of the HIF-1α/NF-κB pathway on ROS scavenging and macrophage repolarization in combination therapy for rheumatoid arthritis. The well-designed nanosystem showed prolonged circulation in blood and superior ART&DEX accumulation in the inflamed joints of AIA rats; moreover, the micelles were specifically internalized into M1 macrophages and co-released ART&DEX, subsequently leading to inhibition of the HIF-1α/NF-κB pathway for ROS scavenging and macrophage repolarization, thus generating synergistic anti-inflammatory effects in RAW 264.7 cells and AIA rats. The HIF-1α/NF-κB cascade regulation on ROS scavenging and macrophage repolarization based on ART&DEX combination with smart nanotechnology could serve as a promising approach for rheumatoid arthritis therapy.

Tumor-targeted hyaluronic acid-based oxidative stress nanoamplifier with ROS generation and GSH depletion for antitumor therapy

Tumor cells with innate oxidative stress are more susceptible to exogenous ROS-mediated oxidative damage than normal cells. However, the generated ROS could be scavenged by the overexpressed GSH in cancer cells, thus causing greatly restricted efficiency of ROS-mediated antitumor therapy. Herein, using cinnamaldehyde (CA) as a ROS generator while β-phenethyl isothiocyanate (PEITC) as a GSH scavenger, we designed a tumor-targeted oxidative stress nanoamplifier to elevate intracellular ROS level and synchronously suppress antioxidant systems, for thorough redox imbalance and effective tumor cells killing. First, an amphiphilic acid-sensitive cinnamaldehyde-modified hyaluronic acid conjugates (HA-CA) were synthesized, which could self-assemble into nano-assembly in aqueous media via strong hydrophobic interaction and π-π stacking. Then, aromatic PEITC was appropriately encapsulated into HA-CA nano-assembly to obtain HA-CA/PEITC nanoparticles. Through enhanced permeability retention (EPR) effect and specific CD44 receptor-mediated endocytosis, HA-CA/PEITC nanoparticles could accumulate in tumor tissues and successfully release CA and PEITC under acidic lysosomal environment. Both in vitro and in vivo results showed that the nanoparticles could efficiently boost oxidative stress of tumor cells via generating ROS and depleting GSH, and finally achieve superior antitumor efficacy. This nanoamplifier with good biosafety provides a potential strategy to augment ROS generation and suppress GSH for enhanced oxidation therapy.

Hyaluronic acid-coated shikonin liposomes for the treatment of triple-negative breast cancer via targeting tumor cells and amplification of oxidative stress

Triple-negative breast cancer (TNBC) is an aggressive phenotype that lacks effective therapies. Amplification of oxidative stress is reportedly effective against tumors. Shikonin (SHK) is a potent natural antitumor product that regulates oxidative stress. In the current study, hyaluronic acid-coated SHK liposomes (HA-SHK-Lip) were prepared for the treatment of TNBC. The prepared HA-SHK-Lip displayed high drug encapsulation efficiency and slow drug release. The antitumor effects of HA-SHK-Lip were evaluated both in vitro and in vivo. Our in vitro cytotoxicity study indicated that HA-SHK-Lip effectively inhibited the proliferation of MDA-MB-231 cells. Cellular uptake of HA-SHK-Lip via the CD44 receptor-mediated endocytosis pathway was much higher than that of free SHK and SHK-Lip. Further research showed that HA-SHK- could significantly enhanced the production of intracellular reactive oxygen species (ROS) and reduced intracellular glutathione (GSH). HA-SHK-Lip exerted a much better antitumor effect than free SHK and SHK-Lip in BALB/C mice bearing MDA-MB-231 tumors. These results suggested that HA-SHK-Lip could be an effective therapeutic strategy for combating TNBC via targeting tumor cells and enhancing cellular oxidative stress.

Hyaluronidase and pH Dual-Responsive Nanoparticles for Targeted Breast Cancer Stem Cells.

pH-responsive and CD44 receptor-mediated targeted nanoparticles for eliminating cancer stem cells (CSCs) were developed based on complexes of PEG-poly(β-amino ester) (PEG-PBAE) micelles (PPM) coated with hyaluronic acid (HA) (HA-coated PPM complex, or HPPMc). Thioridazine (Thz) was loaded into HPPMc with a decent drug loading content. The release results of the drug in vitro showed that Thz was released from the HPPMc, which was stimulated by both the acidic pH and specific enzymes. Cytotoxicity studies on mammospheres (MS) revealed that the toxicity potential of Thz-loaded HPPMc (Thz–HPPMc) at pH 5.5 was better than drug solutions. Compared with that at pH 7.4, a higher cellular uptake of a coumarin-6 (C6)-labeled complex at pH 5.5 was observed, which demonstrated that complexes were efficiently taken up in MS. Meanwhile, free HA competitively inhibited the cellular uptake of HPPMc, which revealed that the uptake mechanism was CD44 receptor-mediated endocytosis. Within the acidic endolysosomal environment, the protonation of PBAE facilitated the escape of the complex from the lysosome and releases the drug. The results of in vivo distribution studies and tumor suppression experiments showed that HPMMc could stay in the tumor site of BALB/c nude mice for a longer period of time, and Thz–HPPMc could significantly improve the tumor-suppressing effect. All these results demonstrated the great potential of the multifunctional nanoparticle system for eliminating CSCs.

PH/H2O2 Dual-Responsive Chiral Mesoporous Silica Nanorods Coated with a Biocompatible Active Targeting Ligand for Cancer Therapy.

Nano-drug delivery systems (nano-DDSs) with an existing specific interaction to tumor cells and intelligent stimulus-triggered drug delivery performance in a tumor microenvironment (TME) remain hotspots for effective cancer therapy. Herein, multifunctional pH/H2O2 dual-responsive chiral mesoporous silica nanorods (HA-CD/DOX-PCMSRs) were creatively constructed by first grafting phenylboronic acid pinacol ester (PBAP) onto the amino-functioned nanorods, then incorporating doxorubicin (DOX) into the mesoporous structure, and finally coating with the cyclodextrin-modified hyaluronic acid conjugate (HA-CD) through a weak host-guest interaction. Under a physiological environment, the gatekeeper CD could avoid the premature leakage of DOX and minimize the side effects to normal cells. After the uptake by the tumor cells, the H2O2-sensitive moieties of PBAP were exposed and a small amount of DOX was leaked along with the shift of the supramolecular switch HA-CD under the acidic condition. Notably, the self-supplying H2O2 mediated by the released DOX in turn accelerated the PBAP disintegration, further promoted the rapid release of DOX, and increased the DOX accumulation in tumor regions. Innovatively, this nano-DDS could simultaneously achieve the tumor-targeting ability via CD44 receptor-mediated endocytosis and pH/H2O2 dual responsiveness activated by the TME and hence exhibited superior antitumor efficacy. Furthermore, HA acting as the hydrophilic shell could improve the biocompatibility of this nano-DDS.

TPGS and chondroitin sulfate dual-modified lipid-albumin nanosystem for targeted delivery of chemotherapeutic agent against multidrug-resistant cancer

Multidrug resistance (MDR) remains the primary issue leading to the failure of chemotherapy. In this study, a d-α-tocopherol polyethylene 1000 glycol succinate (TPGS) and chondroitin sulfate (CS) dual-modified lipid-albumin nanosystem was constructed for targeted delivery of paclitaxel (PTX) in treating MDR cancer. The obtained nanosystem (TLA/PTX@CS) had an average size of around 176 nm and a negative zeta potential of around −18 mV. TPGS was confirmed to improve the intracellular accumulation of PTX and facilitate the mitochondrial-targeting of lipid-albumin nanosystem. Functionalized with the outer CS shell, TLA/PTX@CS entered MDR breast cancer (MCF-7/MDR) cells via CD44 receptor-mediated endocytosis. CS shell was degraded by concentrated hyaluronidase in the lysosomes, thereby releasing PTX into cytoplasm and inhibiting cell proliferation. In vivo studies revealed that TLA/PTX@CS possessed prolonged blood circulation, resulting in elevated tumor accumulation, excellent antitumor efficacy with a tumor inhibition ratio of 75.3%, and significant survival benefit in MCF-7/MDR tumor-bearing mice. Hence, this TPGS and CS dual-modified lipid-albumin nanosystem provides a promising strategy for targeted delivery of chemotherapeutic drug and reversal of MDR in cancer treatment.

Hyaluronic Acid-Coated MTX-PEI Nanoparticles for Targeted Rheumatoid Arthritis Therapy

Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA); however, long-term and high-dose usage of MTX for patients can cause many side effects and toxic reactions. To address these difficulties, selectively delivering MTX to the inflammatory site of a joint is promising in the treatment of RA. In this study, we prepared MTX-PEI@HA nanoparticles (NPs), composed of hyaluronic acid (HA) as the hydrophilic negative electrical shell, and MTX-linked branched polyethyleneimine (MTX-PEI) NPs as the core. MTX-PEI@HA NPs were prepared in the water phase by a one-pot method. The polymeric NPs were selectively internalized via CD44 receptor-mediated endocytosis in the activated macrophages. In the in vivo mice mode study, treatment with MTX-PEI@HA NPs mitigated inflammatory arthritis with notable safety at a high dose of MTX. We highlight the distinct advantages of aqueous-synthesized NPs coated with HA for arthritis-selective targeted delivery, thus verifying MTX-PEI@HA NPs as a promising MTX-based nanoplatform for treatment of RA.

Cancer cells targeted visible light and alkaline Phosphatase-Responsive TiO2/Cu2+ carbon Dots-Coated wireless electrochemical biosensor

The utilization of visible light and pyrophosphates (PPi) accompanied by alkaline phosphatase (ALP) activity-responsive cancer cells-targeting carbon dots using carbonized hyaluronic acid (CD(HA)) by means of electrochemical signals generated from CD(HA)/TiO2/Cu2+-coated surfaces was investigated. The stimuli-responsive surface provided an effective method for wireless sensors under intracellular conditions with an antifouling effect to visualize the cell adhesion interaction with the surface as well as the detection of cancer cells. The highly distinctive intracellular PPi and ALP levels of cancer cells compared to normal cells and CD44 receptor-mediated endocytosis by the CD(HA) chain into cancer cells induced an electrochemical signal change in cell-cultured biosensors detected by electrochemical methods including EIS and a wireless sensing system. The antifouling properties of CD(HA)/TiO2/Cu2+ verified by the time-dependent cell detachment occurring on the modified surfaces in the presence of visible light were employed for the detection of cancer. The resistance of cancer cell-cultured CD(HA)/TiO2/Cu2+ biosensors considerably increased (248 kΩ) as detachment time triggered by visible light irradiation increased compared to normal cells (152 kΩ), which was ascribed to the dissociation of Cu2+ in the system by PPi and ALP in cancer cells and the cellular internalization of CD(HA). With high sensitivity and accuracy for cancer detection by the visible light and enzyme-responsiveness with low LOD value (2.31 cells/mL) on basis of electrochemical approach and 70.05 cells/mL for optical approach, the CD(HA)/TiO2/Cu2+ wireless biosensor offers a promising approach that facilitates cancer diagnosis with antifouling effects to investigate the interaction between cells and modified surfaces.

In Situ Self-Assembly Nanomicelle Microneedles for Enhanced Photoimmunotherapy via Autophagy Regulation Strategy.

Although certain therapeutic agents with immunogenic properties may enhance antitumor immunity, cancer cells can eliminate harmful cytoplasmic entities and escape immunosurveillance by orchestrating autophagy. Here, an ingenious in situ self-assembled nanomicelle dissolving microneedle (DMN) patch was designed for intralesional delivery of immunogenic cell death-inducer (IR780) and autophagy inhibitor (chloroquine, CQ) coencapsulated micelles (C/I-Mil) for efficient antitumor therapy. Upon insertion into skin, the self-assembled C/I-Mil was generated, followed by electrostatic binding of hyaluronic acid, the matrix material of DMNs, accompanied by the dissolution of DMNs. Subsequently, photothermal-mediated size-tunable C/I-Mil could effectively penetrate into deep tumor tissue and be massively internalized via CD44 receptor-mediated endocytosis, precisely ablate tumors with the help of autophagy inhibition, and promote the release of damage-associated molecular patterns. Moreover, CQ could also act as an immune modulator to remodel tumor-associated macrophages toward the M1 phenotype via activating NF-κB. In vivo results showed that the localized photoimmunotherapy in synergy with autophagy inhibition could effectively eliminate primary and distant tumors, followed by a relapse-free survival of more than 40 days via remodeling the tumor immunosuppressive microenvironment. Our work provides a versatile, generalizable framework for employing self-assembled DMN-mediated autophagy inhibition integrated with photoimmunotherapy to sensitize superficial tumors and initiate optimal antitumor immunity.

Inhibition of growth and metastasis of breast cancer by targeted delivery of 17-hydroxy-jolkinolide B via hyaluronic acid-coated liposomes

Hyaluronic acid (HA)-coated liposomes were designed for the targeted delivery of 17-hydroxy-jolkinolide B (HA-Lip-HJB). HA-Lip-HJB had a particle size of 130.8 ± 1.9 nm, zeta potential of -52.36 ± 1.91 mV, and encapsulation efficiency of 89.2 ± 1.5 %. In vitro cell experiments indicated that modification of HA-Lip-HJB increased its cytotoxicity and cellular uptake via CD44 receptor-mediated endocytosis pathway. Of particular importance is that HA-Lip-HJB suppressed cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) process. Moreover, the HA-Lip-HJB displayed notable growth inhibition on tumor spheroids. Furthermore, in vivo tissue distribution and anti-tumor experiments carried on BALB/C mice bearing 4T1 tumor indicated that HA-Lip-HJB had strong tumor targeting and tumor suppression abilities. The results also demonstrated that HA-Lip-HJB inhibited tumor cells migration and colonization on the lung. Therefore, HA-Lip-HJB is a promising formulation for metastatic breast cancer therapy.