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In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl 2 /4H 2 O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 10 2 (DOX@HA/Fe NPs, without DMA), ~8.1 × 10 2 (DOX@aHA-DMA 0.36 /Fe NPs), and ~9.3 × 10 2 (DOX@aHA-DMA 0.60 /Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe 2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.

We report here the use of near-infrared fluorescent dye-labelled hyaluronate (HA) dot named HDFc for tumor imaging. We took advantage of the unique auto-quenching characteristic that occurs when the fluorescent dye molecules are in close proximity to one another under ordinary conditions. However, when the HDFc is located in tumor cells, the tumor cell-specific enzyme (e.g., hyaluronidase: HAase) affects the structure of the HDFc, followed by the transition from auto-quenched dye molecules to dequenched dye molecules, resulting in the identification of the tumor cells. For this purpose, HDFcs were synthesized, characterized, and exogenously treated with HAase to demonstrate the enzyme-dependent HDFc photoactivity. Specifically, confocal microscopy and flow cytometry confirmed the efficient cellular internalization and fluorescence production of HDFc in CD44+ and HAase-abundant tumor cells. Collectively, this study opens the door for utilizing polymeric dots to visualize tumor cells by introducing biocompatible HA and tumor cell-on photoluminescent dye., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

pH-Responsive drug vehicles targeting the specific extracellular pH of tumors have served as potent tools to overcome the limitation (e.g., low tumor seletivity) in antitumor drug delivery system. Here, we describe the advantage of pH-responsive extracellular vesicles (HDEA@EVs) containing the hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA) and a model antitumor drug, doxorubicin (DOX). We demonstrated their physicochemical characteristics through in vitro cell endocytosis, in vitro tumor cell toxicity, in vivo biodistribution, and in vivo tumor regression efficacy experiments. Because the HDEA@EVs efficiently responded to extracellular tumor pH (pH 6.5) and actively bound to CD44 receptors on HCT-116 tumor cells, the EVs selectively inhibited CD44+ tumor cell growth in vitro, and CD44+ tumor development in vivo. From these results, we conclude that HDEA@EVs can help in designing effective strategies for pharmacologic intervention in tumor therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this study, we report pH-responsive liposomes consisting of hydrogenated soy phosphatidylcholine (HSPC) as a lipid, hyaluronic acid (HA) grafted with functional 3-diethylaminopropyl (DEAP) groups (hereafter denoted as HA-g-DEAP) as a pH-responsive polymer, and docetaxel (DTX) as an antitumor drug. DTX-loaded HSPC liposomes were prepared via a conventional liposome manufacturing procedure and then were decorated with HA-g-DEAP (HA-g-DEAP 0.15 , HA-g-DEAP 0.25 , and HA-g-DEAP 0.40 , according to the molar conjugate ratio of DEAP to HA) in an aqueous solution (pH 7.4), by sonication. The liposomes with HA-g-DEAP 0.40 allowed the efficient release of the encapsulated DTX content when the pH of the solution decreased to 6.5 (i.e., endosomal pH), owing to the acidic pH-induced protonation of the DEAP anchored to the vesicular lipid bilayers. These hyaluronated liposomes were effective at entering the human colon carcinoma HCT-116 cells with a CD44 receptor overexpression. In an in vitro tumor cell cytotoxicity test, the DTX-loaded liposomes caused a significant increase in HCT-116 tumor cell death, revealing their pharmaceutical potential in tumor therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nanoscale particles, such as quantum dots and carbon dots, are important materials for use in sensing and treating irregular biological events, but their versatility for biomedical applications are usually limited by their undesirable properties such toxicity and non-degradability. Here, we report biofunctional hyaluronic acid (HA) dots containing biodegradable/biocompatible HA. HA dots were prepared by conjugating multiple HA molecules to C 60 (used as a base dot) without any hydrothermal treatment. The hydroxyl groups of HA completely linked to all π-π carbon bonds in C 60 . The chemically synthesized HA dots (Mn=16.1kDa) were 2nm in diameter, soluble in aqueous solution, and possessed multiple functional (carboxyl) groups. The HA dots were biofunctional, enabling highly efficient binding to CD44 receptors overexpressed on in vitro/in vivo tumors. With light illumination, we demonstrated that the HA dots bearing a photosensitizing model drug (chlorin e6: Ce6) resulted in a significant enhancement in in vitro/in vivo tumor cell ablation. We believe that this approach offers a new strategy to create biopolymer dots., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this study, we developed facile synthesis method of multilayered polysaccharidic vesicles (hereafter termed 'mPSVs') using polysaccharides such as starch, hyaluronate (HA), and glycol chitosan (GC) via simple chemistry and using enzymatic reactions among polysaccharides. The enzymatic degradation of the HA shell by hyaluronidase (HYAL) enzyme contributed to accelerate the release of protein/peptide from the mPSVs. The mPSVs containing folate ligand and apoptotic cell death-inducing D-(KLAKLAK)2 peptide were effectively accumulated in in vivo KB tumor cells, primarily owing to passive tumor penetration via the enhanced permeability and retention (EPR) effect and active targeting via specific binding to folate receptors expressed on KB tumor cells. These mPSVs resulted in a significant increase in the in vivo tumor inhibition. This vesicle system is expected to exhibit great potential as an advanced platform technology for biomedical applications involving small molecular drugs with protein/gene targets., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study, we report the development of a novel pH-responsive nanoparticle composed of hyaluronic acid (HA) grafted with functional 3-diethylaminopropyl (DEAP) groups (HA-g-DEAP). The pH-responsive nanoparticles were fabricated by a self-assembled arrangement of a hydrophilic block (HA) and a hydrophobic block (non-protonated DEAP) of HA-g-DEAP at pH 7.4. HA-g-DEAP was prepared by a simple conjugation of the carboxylic acid groups of HA and the free amine groups of DEAP. The HA-g-DEAP nanoparticles displayed pH-dependent changes in their physicochemical properties. We observed nanoparticle destabilization because of the protonation of DEAP when the pH of the solution decreased to 5.0. This phenomenon resulted in the release of the encapsulated content (model drug, doxorubicin: DOX) from the nanoparticle core. In addition, the degradation of HA by hyaluronidase (Hyal) significantly accelerated the DOX release rate, which may allow for increased drug release in diseased cells with acidic endosomal pH (∼pH 5.0) in the presence of Hyal. Overall, a significant improvement in the drug release rate was evident when this nanoparticle system was stimulated by both an acidic pH and specific enzymes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Four-arm polyethylene glycol (PEG) cross-linked hyaluronic acid (HA) hydrogels containing PEGylated tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL) were fabricated, and their antitumor effects were evaluated in pancreatic cell (Mia Paca-2)-xenografted mice. HA was conjugated with 4-arm PEG(10k)-amine (a cross-linker) at ratios of 100:1 and 100:2 using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a cross-linker, and TRAIL or PEG-TRAIL was incorporated into these HA hydrogels. HA hydrogels at a 100:1 ratio were prepared in good yields (>88%), were moderately stiff, and gradually released PEG-TRAIL over ~14 days in vitro and over ~7 days in vivo (as determined by high-pressure liquid chromatography and infrared imaging). The released PEG-TRAIL was found to have obvious apoptotic activity in Mia Paca-2 cells. PEG-TRAIL HA hydrogels displayed remarkably more antitumor efficacy than TRAIL HA hydrogels in Mia Paca-2 cell-xenografted mice in terms of tumor volumes (size) and weights (453.2mm(3) and 1.03 g vs. 867.5mm(3) and 1.86 g). Furthermore, this improved antitumor efficacy was found to be due to the apoptotic activity of PEG-TRAIL in vivo (determined by a TUNEL assay) despite its substantially lower cytotoxicity than native TRAIL (IC50 values: 71.8 and 202.5 ng ml(-1), respectively). This overall enhanced antitumor effect of PEG-TRAIL HA hydrogels appeared to be due to the increased stability of PEGylated TRAIL in HA hydrogels. These findings indicate that this HA hydrogel system combined with PEG-TRAIL should be considered a potential candidate for the treatment of pancreatic cancer., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hyaluronated fullerene has strong near-infrared (NIR) fluorescence intensity without labelling with any fluorophores or isotopes. This fullerene allowed high-resolution fluorescent imaging of tumor sites in vivo and resulted in a significant regression of HCT-116 tumors.

Porous microparticles (PMs) with a low density (<0.4 g/cm3) for pulmonary protein delivery were prepared by the water-in-oil-in-water (W1/O/W2) multi-emulsion method using a cyclodextrin derivative as a porogen. The complexation of positively charged lysozyme (Lys) and negative-charged hyaluronate (HA) was investigated for long-term protein release from PMs. The interaction of Lys and HA not only increased protein encapsulation efficiency but also stabilized Lys against a denaturing organic solvent (dichloromethane). Furthermore, PMs with Lys/HA complexes increased the Lys release period up to 7 days, as opposed to a 4h Lys release time from PMs without Lys/HA complexes. In particular, PMs containing 10mg of HA and 50mg of Lys showed almost zero-order Lys release kinetic for 7 days and preserved the bioactivity of Lys more than 98% during its entire release period. This result suggests that PMs with Lys/HA complexes may be applied in long-term pulmonary administration of protein or peptide drugs, including those that require particles to arrive at a deep lung epithelium with the help of low density (high porosity) of PMs.

In this study, we developed nanoclusters that respond to singlet oxygen and can be adjusted in size to enhance the efficacy of tumor therapy. Specifically, we engineered nanoclusters, denoted as dHAc‐PSDA‐Ce6, through the covalent conjugation of hyaluronate dots (dHA) with 3,3‐(propane‐2,2‐diylbis(sulfanediyl))dipropionic acid (PSDA) as a cleavable crosslinker mediated by singlet oxygen, and chlorin e6 (Ce6) as a representative model drug for photodynamic therapy. The hyaluronic acid (HA) component within dHAc‐PSDA‐Ce6 was harnessed for the specific targeting of CD44 receptors that are overexpressed on tumor cells. Upon subjecting the vicinity of tumor cells to light irradiation, the PSDA crosslinker within dHAc‐PSDA‐Ce6 undergoes cleavage, likely facilitated by the singlet oxygen generated by Ce6. This cleavage process leads to the formation of dHA‐Ce6 molecules. We hypothesized that a nanocluster, circulating safely within the bloodstream, would undergo a transformation into individual dHA‐Ce6 molecules upon light irradiation at the localized tumor site. This transformation, in turn, enhances the photodynamic antitumor effect. Our in vitro investigations have demonstrated the remarkable efficacy of dHAc‐PSDA‐Ce6 in inducing tumor cell death upon light irradiation. Furthermore, our in vivo biodistribution studies have revealed the substantial accumulation of these nanoclusters within the tumor site. We anticipate that this singlet oxygen‐responsive nanocluster harbors substantial promise for enhancing tumor accumulation and fortifying the effectiveness of tumor eradication. [ABSTRACT FROM AUTHOR]

In this study, we have developed pH‐dependent nanogels based on hyaluronic acid (HA) to specifically target acidic tumors. Our initial approach involved modifying HA through the grafting of 3‐(diethylamino)propylamine (DEAP), a molecule known for its responsiveness to changes in pH. This modified HA was termed as HDEA. Subsequently, we performed chemical crosslinking of HDEA using adipic acid dihydrazide (ADH), a crosslinking molecule, resulting in the formation of nanogels referred to as cHDEA. Importantly, the non‐ionized DEAP molecules (with a pKb value of ~pH 7.0) at pH 7.4 support the formation of deswellable cHDEA. This property enables the encapsulation of a photodynamic model drug, chlorin e6 (Ce6), into cHDEA. However, when the DEAP molecules become protonated at pH 6.8, they induce a change in the nanogel structure, causing it to swell due to electrostatic repulsion. As a result, Ce6 is rapidly released from the nanogels. By modulating the pH, we can continuously control the nanogel structure, alternating between swelling and deswelling states. We anticipate that this system offers the advantage of facilitating drug release specifically under acidic tumor conditions while inhibiting drug release under normal pH conditions (i.e., pH 7.4). This approach will serve as an effective strategy for mitigating side effects by efficiently controlling drug release in specific disease areas. [ABSTRACT FROM AUTHOR]

In this study, we reported pH‐responsive microparticles consisting of poly(D,L‐lactide‐co‐glycolide) (PLGA), aminated hyaluronic acid (aHA) conjugated with 2,3‐dimethylmaleic anhydride (DMA, as a pH‐responsive cleavable molecule) (aHA‐DMA), and doxorubicin (DOX, as an antitumor drug) for local tumor treatment. The DOX‐loaded microparticles, denoted as PLGA(aHA‐DMA)/DOX MPs, were fabricated using the W1/O/W2 multi‐emulsification method. These PLGA(aHA‐DMA)/DOX MPs (~10 μm in diameter) accelerated the rate of DOX release at pH 6.8 due to the acidic pH‐responsive cleavage of the DMA moieties followed by electrostatic‐repulsion between aHA and DOX. This event caused the structural destabilization and collapse of the MPs, leading to the rapid release of DOX. Consequently, the PLGA(aHA‐DMA)/DOX MPs resulted in significant inhibition of tumor growth, demonstrating their ability for acidic tumor‐specific treatment. [ABSTRACT FROM AUTHOR]

In this study, we designed and synthesized polysaccharidic nanogels comprising starch cross-linked with hyaluronic acid. These hyaluronated starch nanogels were prepared by cross-linking primary hydroxyl groups in polysaccharides (starch and hyaluronic acid) and epoxide groups in 1,4-butanediol diglycidyl ether (used as a cross-linking agent). The nanogels take advantage of hyaluronic acid as a specific ligand for CD44 receptors overexpressed on tumors and the hyaluronic acid/starch core as a compartment for the encapsulation of docetaxel (as model antitumor drug). Here, hyaluronic acid can be enzymatically degraded by tumor cell–specific enzyme (e.g. hyaluronidase-1), which could significantly accelerate docetaxel release from the nanogels. Our experimental results demonstrate that the nanogels promote the release of docetaxel content in the presence of hyaluronidase-1 enzyme. As a result, the nanogels selectively inhibited MCF-7 (with CD44 receptor and hyaluronidase-1 enzyme) tumor cell growth in vitro, suggesting their therapeutic potential for efficient tumor ablation. [ABSTRACT FROM AUTHOR]

In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, as a model antitumor drug). Consequently, HDEA/DOX anchored EVs (HDEA@EVs) can interact with origin tumor cells owing to EVs' homing ability to origin cells. Therefore, EV blends of HDEA@BTEVs and HDEA@SKEVs demonstrate highly increased cellular uptake in both BT-474 and SK-N-MC cells: HDEA@BTEVs for BT-474 tumor cells and HDEA@SKEVs for SK-N-MC tumor cells. Furthermore, the hydrophobic HDEA present in HDEA@EVs at pH 7.4 can switch to hydrophilic HDEA at pH 6.5 as a result of acidic pH-induced protonation of 3-(diethylamino)propylamine (DEAP) moieties, resulting in an acidic pH-activated EVs' disruption, accelerated release of encapsulated DOX molecules, and highly increased cell cytotoxicity. However, EV blends containing pH-insensitive HA grafted with deoxycholic acid (HDOC) (HDOC@BTEVs and HDOC@SKEVs) showed less cell cytotoxicity for both BT-474 and SK-N-MC tumor cells, because they did not act on EVs' disruption and the resulting DOX release. Consequently, the use of these tumor-homing pH-sensitive EV blends may result in effective targeted therapies for various tumor cells. [ABSTRACT FROM AUTHOR]