CD44 Receptor-mediated Endocytosis Research Articles

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.

Preparation, characterization and in vitro antitumor activity evaluation of hyaluronic acid-alendronate-methotrexate nanoparticles

As an anti-metabolic drug, methotrexate (MTX) plays an important role in the treatment of various malignant tumors. However, several side effects such as low selectivity and high toxic of MTX limited its further applications. With aims to increase its accumulation in the tumor sites and reduce the toxicity of normal tissue nonspecific uptake, a self-assembled hyaluronic acid-alendronate-methotrexate nanoparticle (HA-ALN-MTX NPs) with a dual-tumor-targeted drug loaded system was designed and synthesized with an average particle size of 265.6 ± 13.3 nm. The advantage of this nanosystem is that the anticancer drug MTX can be used as a tumor-targeted ligand for folate acid receptors (FA), and hyaluronic acid (HA) can be used as another tumor targeted ligand for CD44 receptors. In vitro experiments confirmed that HA-ALN-MTX NPs has lower toxic effect on normal tissue cells HUVECs and has relatively high proliferation inhibition effect on tumor cells A549. Moreover, the inhibition effect could be adjusted by altering the dose of given drugs. All these results revealed that the prepared HA-ALN-MTX NPs could be selectively taken up by tumor cells by FA and CD44 receptor-mediated endocytosis. Therefore, self-assembled HA-ALN-MTX NPs targeted by these FA/CD44 receptors for anticancer drugs could act as effective antitumor drugs.

Dual-stimuli responsive mesoporous copper (II) sulfide nanocomposite for chemo-photothermal synergistic therapy

A combination of chemo-photothermal therapy has recently emerged as a great potential cancer treatment due to enhanced therapeutic efficacy. Herein, we present a novel nanocomposite for chemo-photothermal synergistic therapy. The glutathione (GSH)-responsive mesoporous silica-coated copper sulfide (mesoporous CuS) nanocomposite was synthesized by co-condensation using tetraethyl orthosilicate (TEOS) and bis[3-(triethoxysilyl)propyl]tetrasulfide (BTES). Hyaluronic acid (HA) was functionalized on nanocarrier for drug leakage prevention, enzyme-triggered drug release and targeting moiety toward CD44 overexpressing cancer cells. The mesoporous CuS nanocomposite generated the heat for photothermal therapy in response to near-infrared (NIR) irradiation. The release of doxorubicin (Dox) from mesoporous CuS nanocomposite was controlled by dual-stimuli of response. We confirmed that mesoporous CuS nanocomposite was internalized to HeLa cells by CD44 receptor-mediated endocytosis and significantly enhanced anticancer effects due to the combination treatment. Therefore, we developed a tumor targeted dual-stimuli responsive drug delivery system for chemo-photothermal synergistic therapy. • GSH-responsive mesoporous silica coated CuS nanocomposites was prepared by in-situ co-condensation method using TEOS and BTES. • HA was functionalized on nanocarrier as a gate keeper and CD44 receptor targeting moiety. • Mesoporous CuS nanocomposite exhibited good photothermal effect and dual stimuli-responsive durg release property by GSH and HAase. • Mesoporous CuS nanocomposite enhanced therapeutic efficacy against cancer cell by chemo-photothermal combination treatment.

On-Chip Synthesis of Hyaluronic Acid-Based Nanoparticles for Selective Inhibition of CD44+ Human Mesenchymal Stem Cell Proliferation.

In this study, an innovative microfluidics-based method was developed for one-step synthesis of hyaluronic acid (HA)-based nanoparticles (NPs), by exploiting polyelectrolytic interactions between HA and chitosan (CS), in order to improve reliability, reproducibility and possible scale-up of the NPs preparation. The on-chip synthesis, using a staggered herringbone micromixer, allowed to produce HA/CS NPs with tailored-made size and suitable for both parenteral (117.50 ± 4.51 nm) and loco-regional (349.15 ± 38.09 nm) administration, mainly composed by HA (more than 85% wt) with high negative surface charge (< −20 mV). HA/CS NPs were successfully loaded with a challenging water-insoluble molecule, Everolimus (EVE), an FDA- and EMA-approved anticancer drug able to lead to cell cycle arrest, reduced angiogenesis and promotion of apoptosis. HA/CS NPs resulted to be massively internalized in CD44+ human mesenchymal stem cells via CD44 receptor-mediated endocytosis. HA/CS NPs selectiveness towards CD44 was highlighted by blocking CD44 receptor by anti-CD44 primary antibody and by comparison to CS-based NPs cellular uptake. Eventually, high effectiveness in inhibiting cell proliferation was demonstrated on-chip synthetized EVE loaded HA/CS NPs by tracking in vitro DNA synthesis.

Enzyme/pH-triggered anticancer drug delivery of chondroitin sulfate modified doxorubicin nanocrystal

In this paper, we developed a novel strategy of preparing doxorubicin (DOX) nanocrystal (NC) exerting spherical particles with a diameter of 102 nm, which experienced following coating of chondroitin sulphate derivative (CSOA) shell via electrostatic and hydrophobic interactions. Such multifunctional outerwear resulted in drug nanocapsules with high drug loading content up to 70% and high colloidal stability under physiological conditions. It exhibited accelerated drug release behaviour when dispersing in hyaluronidase (HAase) containing medium or incubated with cancer cells. CSOA/NCs were effectively taken up by cancer cells via CD44 receptor-mediated endocytosis, but were rarely internalised into normal fibroblasts. With the comparison of typical drug-loaded micelles system (DOX/PEG-PCL), CSOA/NCs showed greater inhibition to cancer cells due to the targeted and sensitive drug delivery.

Acetylated Hyaluronic Acid-Poly(L-lactic acid) Conjugate Nanoparticles for Inhibition of Doxorubicinol Production from Doxorubicin

In this study, doxorubicin (DOX)-induced cardiotoxicity was overcome using cancer-recognizable DOX-loaded acetylated hyaluronic aicd-poly(L-lactic acid) (AcHA-PLLA) nanoparticles (DHPs). AcHA-PLLA was synthesized via ring opening polymerization of L-lactide with AcHA as a macroinitiator and characterized by 1H NMR and critical micelle concentration. DHPs were formed by self-assembly via dialysis, were estimated to be 160.7 ± 2.7 nm in average diameter, exhibited a slow rate release profile, and prevented DOX from being degraded in the circulation. In addition, DHPs demonstrated efficient cellular uptake into a colorectal cancer cell line (HCT-116) by CD44 receptor-mediated endocytosis, which was confirmed by in vitro cellular uptake, the competitive inhibition assay with free HA and flow cytometry. Furthermore, DHPs exhibited therapeutic efficacy against HCT-116 cells through receptor-mediated endocytosis: DHPs with free hyaluronic acid (HA) demonstrated 2-fold higher cell viability than DHPs without free HA. DHPs also inhibited doxorubicinol production, which induces cardiotoxicity, from DOX in vivo. The area-under-the-curve (AUC) of DOX administered as free DOX was 109.0 ± 25.0 µg min mL−1 and that from DHPs was 97.2 ± 10.2 µg min mL−1. Although these are comparable, the AUC of doxorubicinol was 1.36 ± 0.18 µg min mL−1 and 0.45 ± 0.12 µg min mL−1, with the treatment of free DOX-HCl and DHPs, respectively, demonstrating the reduction of the metabolic conversion of DOX to doxorubicinol in plasma. These results indicate the role of DHPs in preventing DOX transformation into doxorubicinol, which may contribute to the reduced toxicity. DHPs are promising cancer therapeutic nanoparticles, because they are highly biocompatible and tumor-recognizable, and prevent the DOX transformation..

MiRNA-204-5p and oxaliplatin-loaded silica nanoparticles for enhanced tumor suppression effect in CD44-overexpressed colon adenocarcinoma

Main purpose of present study was to enhance the therapeutic efficacy in the treatment of colon adenocarcinoma by combining the benefits of chemotherapy and gene therapy. In this study, we have successfully formulated oxaliplatin (OXL) and miRNA-204-5p loaded polyethyleneimine (PEI)/hyaluronic acid (HA)-assembled mesoporous silica nanoparticles (OXmi-HSMN). Our study, for the first time, proved that miRNA-204-5p can generate a synergistic anticancer effect with OXL with HMSN, and thus improve the effects of therapeutic efficacy in colon cancers. In vitro targeting studies showed that OXmi-HSMN exhibited higher uptake efficiency in CD44 receptor over-expressed HT-29 cells via CD44 receptor-mediated endocytosis. OXmi-HMSN exhibited a higher cell cytotoxicity compared to any other formulations indicating that internalization via CD44 receptor-mediated endocytosis increased the anticancer effect. The OXmi-HMSN showed significantly higher pre-apoptotic cells (43.9%) with significant apoptosis fractions (upper right quadrant − 20%) indicating the superior anticancer efficacy in terms of apoptosis inducing potentials. Importantly, OXmi-HMSN caused conspicuous inhibition of tumor growth and was significantly greater than that of either OXL or OXL-MSN (p < 0.0001). OXmi-HMSN showed 30% of TUNEL positive cells compared to 8% TUNEL positive cells for free OXL and 6% for free miRNA-204-5p treated group indicating the wide spread apoptosis of cells throughout the tissue section. Current study provides a delivery platform for dual therapeutics for enhanced therapeutic efficacy in the management of colon cancer.

Enzyme-responsive mesoporous silica nanoparticles for tumor cells and mitochondria multistage-targeted drug delivery.

Background: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties.Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH).Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells.Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.

Zwitterionic pH-responsive hyaluronic acid polymer micelles for delivery of doxorubicin.

As zwitterionic polymers show great promise in drug delivery, hyaluronic acid (HA) was deacetylated and grafted with dodecylamine to prepare a pH-sensitive zwitterionic polymer dHAD used as a carrier for antitumor drugs. The polymer was negatively charged at pH 7.4 and became positive at pH 6.2. In vitro delivery of DOX against MCF-7 cells showed that the blank micelle dHAD had low cytotoxicity and the dHAD-DOX micelles could greatly prohibit the growth of the MCF-7 cells. In addition, the dHAD-DOX micelles had higher cellular uptake, indicating that the micelles were rapidly internalized into the cells via CD44 receptor-mediated endocytosis. The in vivo delivery of DOX to tumor-bearing mice confirmed that the dHAD-DOX micelles greatly inhibited the tumor growth and significantly reduced systemic toxicity of DOX. These results demonstrated that biocompatible pH-responsive zwitterionic dHAD micelles are promising carriers for the delivery of DOX.

Hyaluronic acid and polydopamine functionalized phase change nanoparticles for ultrasound imaging-guided photothermal-chemotherapy.

In this study, we successfully prepared polydopamine (PD) and hyaluronic acid (HA) coated liquid perfluorocarbon nanoparticles, which integrated the good photothermal conversion effect of PD, the ultrasound imaging properties of the liquid fluorocarbon and active tumor-targeting of HA. Liquid perfluorocarbon nanodroplets significantly improved in terms of their physical stability after being coated with PD and HA as the shell. Photothermal and ultrasound imaging experiments showed that PD could effectively convert near-infrared (NIR) laser energy into heat for photothermal therapy, which could induce a phase change of the liquid perfluorocarbon, thereby generating microbubbles, enhancing ultrasound imaging signals and promoting drug release. In vitro cellular experiments showed that HA on the surface of the nanoparticles could actively target 4T1 breast cancer cells by CD44 receptor-mediated endocytosis. Furthermore, the novel nanosystem has shown effective inhibition of tumor growth by synergistic photothermal-chemotherapy in tumor-bearing mice. In conclusion, the novel nanosystem we prepared in this study is expected to provide a new strategy for the diagnosis and treatment of cancer.

Redox-responsive hyaluronic acid-functionalized graphene oxide nanosheets for targeted delivery of water-insoluble cancer drugs.

BackgroundGefitinib (Gef), an important epidermal growth factor receptor (EGFR), is used to treat lung cancer, but low water solubility and poor bioavailability severely limit its application in cancer therapy.MethodsIn this study, nanographene oxide (NGO) was decorated with hyaluronic acid (HA) by a linker cystamine dihydrochloride containing disulfide bonds (-SS-), followed by the incorporation of gefitinib, thus, constructing a HA-functionalized GO-based gefitinib delivery system (NGO-SS-HA-Gef). Subsequently, studies of biological experiments in vitro and in vivo were performed to investigate the therapeutic effect of the system in lung cancer.ResultsThe HA-grafted GO nanosheets possessed enhanced physiological stability, admirable biocompatibility, and no obvious side effects in mice and could act as a nanocarrier for the delivery of gefitinib to tumor. Cellular uptake and intracellular cargo release assays showed that the uptake of NGO-SS-HA by A549 cells was facilitated via CD44 receptor-mediated endocytosis, and that more drug was released from NGO-SS-HA in the presence of GSH than in the absence of GSH. The target-specific binding of NGO-SS-HA to cancer cells with redox-responsive cargo release significantly enhanced the abilities of gefitinib-loaded GO nanosheets to induce cell apoptosis, suppress cell proliferation, and inhibit tumor growth in lung cancer cell-bearing mice.ConclusionThe results demonstrated the potential utility of NGO-SS-HA-Gef for therapeutic applications in the treatment of lung cancer.

Vitamin E-based redox-sensitive salinomycin prodrug-nanosystem with paclitaxel loaded for cancer targeted and combined chemotherapy.

Cancer stem cells (CSCs) can resist conventional chemotherapy to lead to cancer recurrence. For complete eradication of cancers, an effective CSCs therapeutic strategy should be developed to combine with conventional chemotherapy. In this work, a novel vitamin E-based redox-sensitive salinomycin (SAL, an inhibitor for CSCs) prodrug nanoparticles (TS NPs) and hyaluronic acid (HA)-coated TS NPs (HTS NPs) were fabricated to deliver paclitaxel (PTX) for cancer-targeted and combined chemotherapy. Both TS and HTS prodrug NPs had mean diameter of about 200 nm with uniform size distribution, excellent drug loading capacity for PTX, and glutathione-triggered SAL and PTX release profiles. The HTS prodrug NPs had enhanced cellular uptake efficiency over TS NPs due to CD44 receptor-mediated endocytosis, hence exerting stronger potency of SAL upon CSCs-enriched mammospheres formation and G0/G1 cell phase arresting. Cytotoxicity and 3D tumor spheroids assays demonstrated that both TS and HTS prodrug NPs themself can synergize with loaded PTX to maximize the chemotherapeutic effect. Obviously, the latter demonstrated a more potent anticancer efficacy due to improved intracellular drug delivery efficiency. These results suggested that the designed TS prodrug NPs, especially the coated HTS NPs can serve as an effective anti-CSCs strategy for cancer targeted and combination treatments.

Reduction-sensitive CD44 receptor-targeted hyaluronic acid derivative micelles for doxorubicin delivery.

IntroductionA reduction-sensitive CD44-positive tumor-targetable drug delivery system for doxorubicin (DOX) delivery was developed based on hyaluronic acid (HA)-grafted polymers.Materials and methodsHA was conjugated with folic acid (FA) via a reduction-sensitive disulfide linkage to form an amphiphilic polymer (HA-ss-FA). The chemical structure of HA-ss-FA was analyzed by ultraviolet spectroscopy, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance (NMR) spectroscopy. The molecular weight of HA-ss-FA was determined by high-performance gel permeation chromatography. Blank HA-ss-FA micelles and DOX-loaded micelles were prepared and characterized. The reduction responsibility, cellular uptake, and in vivo biodistribution of HA-ss-FA micelles were investigated.ResultsDOX-loaded micelles were of high encapsulation efficiency (88.09%), high drug-loading content (22.70%), appropriate mean diameter (100–120 nm), narrow size distribution, and negative zeta potential (−6.7 to −31.5 mV). The DOX release from the micelles was significantly enhanced in reduction environment compared to normal environment. The result of in vitro cytotoxicity assay indicated that the blank micelles were of low toxicity and good biocompatibility and the cell viabilities were >100% with the concentration of HA-ss-FA from 18.75 to 600.00 μg/mL. Cellular uptake and in vivo biodistribution studies showed that DOX-loaded micelles were tumor-targetable and could significantly enhance cellular uptake by CD44 receptor-mediated endocytosis, and the cellular uptake of DOX in CD44-positve A549 cells was 1.6-fold more than that in CD44-negative L02 cells. In vivo biodistribution of HA-ss-FA micelles showed that micelles were of good in vivo tumor targetability and the fluorescence of indocyanine green (ICG)-loaded micelles was 4- to 6.6-fold stronger than free ICG within 6 h in HCCLM3 tumor-bearing nude mice.ConclusionHA-ss-FA is a promising nanocarrier with excellent biocompatibility, tumor targetability, and controlled drug release capability for delivery of chemotherapy drugs in cancer therapy.

Paclitaxel delivered by CD44 receptor-targeting and endosomal pH sensitive dual functionalized hyaluronic acid micelles for multidrug resistance reversion

The drug efflux mediated by P-glycoprotein (P-gp) transporter is a major factor responsible for multidrug resistance (MDR) of paclitaxel (PTX). The efficient intracellular PTX delivery is a promising strategy for overcoming the MDR of tumor cells. A CD44 receptor targeting and endosome-pH sensitive dual functionalized hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar formulation was developed to overcome MDR, and a CD44 receptor targeting hyaluronic acid-deoxycholic acid (HA-DOCA) micelles was used as a comparison. Compared with Taxol solution and HA-DOCA micelles, the cytotoxicity of PTX loaded in HA-DOCA-His micelles against drug-resistant tumor cells was improved significantly and possessed superior MDR-overcoming performance; this phenomenon is due to the increased intracellular PTX delivery by CD44 receptor-mediated endocytosis pathway and endosome-pH sensitivity-mediated PTX triggering release. Upon pharmacokinetic study, PTX/HA-DOCA-His micelles demonstrated longer blood circulation time, larger AUC, decreased Vd and CL than the Taxol solution. More importantly, PTX/HA-DOCA-His micelles were more effective in tumor growth inhibition in MCF-7/Adr tumor-bearing mice compared with PTX/HA-DOCA micelles and Taxol solution. Dual targeting strategy-functionalized HA-DOCA-His micelles demonstrated excellent MDR-reversing ability for therapeutic efficacy and improvement on MDR tumors, thereby providing an effective targeting strategy for PTX delivery of nano-drug delivery system in MDR cancer chemotherapy.

Construction of Hyaluronic Tetrasaccharide Clusters Modified Polyamidoamine siRNA Delivery System.

The CD44 protein, as a predominant receptor for hyaluronan (HA), is highly expressed on the surface of multiple tumor cells. HA, as a targeting molecule for a CD44-contained delivery system, increases intracellular drug concentration in tumor tissue. However, due to the weak binding ability of hyaluronan oligosaccharide to CD44, targeting for tumor drug delivery has been restricted. In this study, we first use a HA tetrasaccharide cluster as the target ligand to enhance the binding ability to CD44. A polyamidoamine (PAMAM) dendrimer was modified by a HA tetrasaccharide cluster as a nonviral vector for small interfering RNA (siRNA) delivery. The dendrimer/siRNA nanocomplexes increased the cellular uptake capacity of siRNA through the CD44 receptor-mediated endocytosis pathway, allowing the siRNA to successfully escape the endosome/lysosome. Compared with the control group, nanocomplexes effectively reduced the expression of GFP protein and mRNA in MDA-MB-231-GFP cells. This delivery system provides a foundation to increase the clinical applications of PAMAM nanomaterials.

Hyaluronic Acid-Modified Micelles Encapsulating Gem-C12 and HNK for Glioblastoma Multiforme Chemotherapy.

Glioblastoma multiforme (GBM), a prevalent brain cancer with high mortality, is resistant to the conventional single-agent chemotherapy. In this study, we employed a combination chemotherapy strategy to inhibit GBM growth and addressed its possible beneficial effects. The synergistic effect of lauroyl-gemcitabine (Gem-C12) and honokiol (HNK) was first tested and optimized using U87 cells in vitro. Then, the hyaluronic acid-grafted micelles (HA-M), encapsulating the optimal mole ratio (1:1) of Gem-C12 and HNK, were prepared and characterized. Cell-based studies demonstrated that HA-M could be transported into cells by a CD44 receptor-mediated endocytosis, which could penetrate deeper into tumor spheroids and enhance the cytotoxicity of payloads to glioma cells. In vivo, drug-loaded HA-M significantly increased the survival rate of mice bearing orthotopic xenograft GBM compared with the negative control (1.85-fold). Immunohistochemical analysis indicated that the enhanced efficacy of HA-M was attributed to the stronger inhibition of glioma proliferation and induction of apoptosis. Altogether, our findings showed advantages of combination chemotherapy of GBM using HA-grafted micelles.

PH-responsive nanoreservoirs based on hyaluronic acid end-capped mesoporous silica nanoparticles for targeted drug delivery

Mesoporous silica nanoparticles (MSNs) are greatly appealing for efficient drug delivery due to their excellent drug loading capacities. However, it remains as a major challenge to realize site-specific controlled release with MSNs. This work examines a smart pH-responsive drug release system using MSNs for CD44-targeting drug delivery. Specifically, hyaluronic acid (HA) was applied as an end-capping agent to seal drug loads inside the mesoporous of MSNs through the acid labile hydrazine bonds. HA exposed on the surface of the particles can also serve as a targeting agent at the same time, enable site specific targeting toward CD-44 overexpressing cells. The system showed a good stability at physiological pHs, yet drug release could be triggered in response to changes in pH. Further studies showed that the HA-fabricated particles could achieve much enhanced cellular uptake via CD44 receptor-mediated endocytosis by Hela cells (CD44 receptor-positive), and as a result, doxorubicin-loaded MSNs exhibited significantly enhanced drug efficacy toward cancer cells overexpressing CD44 receptor (IC50 = 0.56 μg/mL), whereas the normal cells showed weakly cytotoxicity (IC50 = 1.03 μg/mL). Such a fabrication strategy may provide a new platform for preparation of high performance drug delivery systems for cancer therapy.

Hyaluronic acid/doxorubicin nanoassembly-releasing microspheres for the transarterial chemoembolization of a liver tumor

Doxorubicin (DOX)-loaded, hyaluronic acid-ceramide (HACE) nanoassembly-releasing poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) were developed for transarterial chemoembolization (TACE) therapy of liver cancer. DOX/HACE MSs with a mean diameter of 27 μm and a spherical shape were prepared based on the modified emulsification method. Their in vitro biodegradability in artificial biological fluids was observed. A more sustained drug release pattern was observed from DOX/HACE MS than from DOX MS at pH 7.4. The cellular internalization efficiency of DOX of the DOX/HACE MS group was higher than that of the DOX MS group in liver cancer cells (HepG2 and McA-RH7777 cells), mainly due to CD44 receptor-mediated endocytosis of the released DOX/HACE nanoassembly. In both HepG2 and McA-RH7777 cells, the antiproliferation and apoptotic potentials of the DOX/HACE MS were significantly higher than those of the DOX MS (p < .05). Notably, in the McA-RH7777 tumor-implanted rat models, a better tumor growth suppression, a lower tumor viable portion, and a higher incidence of apoptosis were presented in the DOX/HACE MS group than in the DOX MS group after intra-arterial (IA) administration. DOX/HACE-based nanoassembly release from the DOX/HACE MS seems to elevate the cellular accumulation of DOX and its anticancer activities. The developed DOX/HACE MS can be used as a drug-loaded HA nanoassembly-releasing MS system for TACE therapy of liver cancer.