Hyaluronic Acid Derivatives for Translational Medicines

Perspective pubs.acs.org/Biomac

Cite This: Biomacromolecules XXXX, XXX, XXX−XXX

Hyaluronic Acid Derivatives for Translational Medicines Hyemin Kim,† Myeonghwan Shin,‡ Seulgi Han,‡ Woosung Kwon,⊥ and Sei Kwang Hahn*,†,‡ †

PHI Biomed Co., 175 Yeoksam-ro, Gangnam-gu, Seoul 06247, South Korea Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, South Korea ⊥ Department of Chemical and Biological Engineering, Sookmyung Women’s University, 100 Cheongpa-ro-47-gil, Seoul 04310, South Korea Downloaded via NOTTINGHAM TRENT UNIV on July 17, 2019 at 07:04:05 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

ABSTRACT: The recent progress in various biomaterials with unique physiological and pharmacological properties has expedited the development of translational medicines for the diagnosis, prognosis, and therapy of intractable diseases. Hyaluronic acid (HA) is one of such biomaterials that has attracted great attention due to its unique characteristics for biomedical applications. In this Perspective, we provide an overview of HA-based medicines in a variety of forms such as chemical and biological conjugates, nanoparticles, nanoparticle hybrid systems, hydrogels, and nanogels. We highlight the current-state-of-the-art strategies to design and optimize innovative HA-based medicines for their clinical translations. Finally, we discuss the challenges for technical hurdles and the future directions to expand the feasibility of HA-based translational medicines.

1. INTRODUCTION Biomaterials for translational medicines cover a broad range of research fields, industry, and other disciplines, featuring the use of materials to address medical issues and concerns for the prevention and treatment of diseases. A variety of natural and synthetic materials with different biological functions have been designed for diagnostic and therapeutic applications.1−3 The typical examples of biomaterials include natural biological compounds such as proteins,4 nucleic acids,5 polysaccharides,6 and viruses,7 in addition to non-natural synthetic polymers and nanomaterials such as polyethylene glycol (PEG),8 quantum dots,9 liposomes,10 magnetic nanoparticles,11 and gold/carbon nanomaterials.12 These materials have been developed to realize the translational potential from the bench to the bedside. Furthermore, there have been great efforts to understand the biological processes mediated by the diverse functions of biomaterials in the body. Among various biomaterials, polymeric biomacromolecules have been widely investigated for multidisciplinary biomedical applications in the past three decades. Especially, controlled drug delivery is one of the most successful applications using polymer−drug conjugates,13 several kinds of drug depots,14−16 hydrogels,17 and nanoparticles18 to improve pharmacokinetics, bioavailability, and target specificity of therapeutics. Here, we have focused on unique biological functions of hyaluronic acid (HA) by the interaction with its receptors.19−21 HA, a naturally occurring polysaccharide, has been known for its superior biocompatibility and biodegradability. HA can not only improve the bioavailability of drugs but also mediate the targeted drug delivery for specific tissues such as liver and cancer via the active interaction of HA with its receptors.22,23 © XXXX American Chemical Society

HA is the major constituent in the vitreous of the eye or synovial joint fluid and has been used for ophthalmic viscosurgery and articular cartilage.24,25 In addition, as the essential component of extracellular matrix (ECM), HA has been extensively explored for the development of regenerative medicines ranging from dermal fillers to cell therapeutics.26,27 In this Perspective, we provide an overview of HA-based medicines in various forms such as chemical and biological conjugates, nanoparticles, nanoparticle hybrids, hydrogels, and nanogels. We categorize HA-based medicines by their conformations as shown in Figure 1, and describe their preparation methods, functions, and medical applications with exemplary cases. Then, we discuss future directions for the development of innovative HA-based medicines showcasing several successfully settled translational products.

2. HYALURONIC ACID DERIVATIVES Recently, HA and its derivatives have been widely investigated for drug delivery applications showing the significant clinical feasibility. One of the main benefits of HA is its facile chemical modification for the interaction with nanomaterials. HA has multiple sites available for the chemical modification. Figure 2 shows HA derivatives with their diverse functional groups for further applications. HA is commonly modified at the repeating carboxyl groups or the reducing end of HA by the conjugation with amine groups of coupling agents. The modification of carboxyl groups can provide multiple potential Received: April 24, 2019 Revised: June 15, 2019 Published: June 18, 2019 A

DOI: 10.1021/acs.biomac.9b00564 Biomacromolecules XXXX, XXX, XXX−XXX

Perspective

Biomacromolecules

Figure 1. Schematic illustration for various therapeutic applications of HA-based medicines in the forms of chemical and biological conjugates, nanoparticles, nanoparticle hybrid systems, hydrogels, and nanogels.

interaction sites per HA chain.28 In addition, HA with thiolreactive functional groups can be prepared by the conjugation with cystamine.29 HA was also modified with tyramine or dopamine for various biomedical applications.30,31 These HA derivatives might be further utilized for drug conjugation, structuring nanohybrid systems, and preparing hydrogels. In order for the chemical modification of HA in organic solvents, a tetrabutylammonium (TBA) salt of HA was prepared using ion-exchange resins.32,33 HA-TBA can be used for the modification of both the hydroxyl group and the carboxyl group of HA. For example, ethylenediamine (EDA) was introduced to the primary hydroxyl groups activated by bis(4-nitrophenyl)carbonate via the nucleophilic substitution.34 HA-EDA could be further conjugated with octadecylamine (C18) by a salt leaching technique without chemical cross-linking.35 The octadecyl HA has been utilized as the nanohybrid system like micrometric fiber for cell differentiation,36 and the hydrophobic octadecyl chain has been harnessed to load a chemotherapeutic agent.37 Although HA is one of the outstanding biomaterials for clinical applications, it is technically challenging to define the

exact chemical structure of HA derivatives, particularly in terms of the molecular weight distribution and the modification site. The clear molecular specification of HA derivatives is the prerequisite for their clinical applications. In addition, the recent study showed that the biological function of HA is affected by its molecular weight.38 The low molecular weight HA under 20 kDa induces the pro-inflammatory effect by stimulating Toll-like receptors for secretion of proinflammatory cytokines.39 The intermediate molecular weight HA (100−300 kDa) showed the tissue regeneration by promoting keratinocytes and the self-defense of skin epithelium by inducing β-defensin 2 known as skinantimicrobial peptide.40,41 In contrast, high molecular weight HA over 1000 kDa showed anti-inflammatory responses and immunosuppressive properties.42 The appropriate molecular weight of HA should be selected for each specific application. Nowadays, it is strongly required to select an adequate target disease and optimize the delivery system in terms of therapeutic efficacy and safety.20 Thus, HA should be produced to have a diverse MW and a narrow MW distribution with well-defined characterization. It would be beneficial to B


Perspective

Biomacromolecules

Figure 2. Hyaluronic acid (HA) derivatives with various functional groups for drug delivery applications via physical and chemical interactions. The polyanionic HA can be used in its native form for the electrostatic modification of drugs or nanoparticles. Reprinted from ref 21, Copyright 2019, with permission from Elsevier.

design a simple and fully defined system with reproducibility for scale-up.

these advantages, HA−anticancer drug conjugates have been investigated extensively and applied to clinical trials.20 In addition, the disease modifying antirheumatic drugs (DMARDs) such as methotrexate have also been conjugated with HA via ester linkage to enhance the residence time, antiinflammatory response and pain relief.47 Anti-inflammatory drugs such as ibuprofen (nonsteroidal-anti-inflammatorydrugs) and hydrocortisone (steroid drugs) have been conjugated to HA−adipic dihydrazide using carbodiimide and NHS.48 To maximize the therapeutic effect of chemical drugs, one of the main issues for the effective drug delivery is to increase the cellular uptake of the drugs. The previous studies clearly confirmed the target-specific therapeutic effect and the safety of HA−drug conjugates. Furthermore, the next generation of HA−chemical drug conjugate has been developed by taking advantages of the biological function of HA according to its molecular weight. The therapeutic effect of HA−chemical drug conjugate might be further improved by the immunogenic effect of low molecular weight HA and the

3. HA-BASED MEDICINES 3.1. HA−Chemical Drug Conjugates. HA has been used for the conjugation of diverse chemical drugs such as anticancer drugs, antirheumatic drugs, and anti-inflammatory drugs for target-specific and prolonged drug delivery. The typical anticancer drugs of paclitaxel,43,44 doxorubicin,45 and irinotecan46 have some problems including low aqueous solubility, low target specificity, and high cytotoxicity, causing severe side effects.20 In accordance, HA is chemically conjugated with the drugs to improve the delivery efficiency and the cancer therapeutic effect. HA−anticancer drug conjugates enhance the drug permeability into tumor tissues overexpressing cluster determinant 44 (CD44) and other HA receptors, and the drug accumulation by the enhanced permeability and retention (EPR) effect. On the basis of C


Perspective

Biomacromolecules

Figure 3. (a) Schematic illustration for hyaluronic acid (HA)−interferon alpha (IFNα) conjugate labeled with zwitterionic imaging agent of ZW800-1. (b) In vivo biodistribution of ZW800-1, IFNα-ZW800-1, and HA-IFNα-ZW800-1 conjugate in SD rats at 4 and 24 h after intravenous injection. Pharmacokinetic analysis of poly(ethylene glycol) (PEG)-IFNα and HA-IFNα conjugates by ELISA in (c) the liver and (d) blood serum after intravenous injection. Statistical analysis was carried out for the control (PBS) vs PEG-IFNα and HA-IFNα conjugates (*P < 0.05, **P < 0.01, and ***P < 0.001). (1) represents PEG-IFNα vs HA−IFNα conjugate. Reproduced with permission from ref 57. Copyright 2015 American Chemical Society.

because the reaction with amine groups of lysyl side chain can affect the tertiary structure derived from three-dimensional folding.51 To overcome this limitation, HA-aldehyde derivatives were proposed for preferable conjugation onto Nterminal amine groups.52−54 Due to the pKa difference between amine groups of N-terminal and lysine residues, aldehyde groups showed higher reactivity onto the N-terminal amine groups at the mildly acidic condition. Two representative aldehyde derivatives of HA have been used for the conjugation of proteins to HA. One was synthesized by ring-opening reaction mediated by sodium periodate52,53 and the other was done by coupling carboxylic groups of HA with 4-aminobutyraldehyde diethyl acetal.54 Thiol groups of cysteine residues have been used for the conjugation of peptide molecules which are not severely affected by the formation or dissociation of disulfide linkages

immunosuppressive effect of high molecular weight HA at the right condition. 3.2. HA−Peptide/Protein Drug Conjugates. Other types of drugs that have been frequently conjugated to HA are peptide and protein therapeutics. In this case, however, only selected functional groups have been used for the sitespecific conjugation of these molecules. Two representative functional groups are the primary amine group of N-terminal residues or lysine and the thiol group of cysteine. The conjugation site should be determined considering the active site of peptides and proteins. For the conjugation with amine groups of peptide and protein drugs, the typical strategy was the amide bond formation via the carboxyl groups of HA using the carbodiimide chemistry in early stages.49,50 This conjugation method is simple and time-saving, but it can reduce the biological activity of especially protein therapeutics, D


Perspective

Biomacromolecules

Figure 4. HA derivatives for the preparation of micelles. Anticancer drugs or siRNA can be loaded and delivered in HA micelles linked to different hydrophobic moieties. Reprinted from ref 59. Copyright 2015, with permission from Elsevier.

between cysteine residues.32,55 Functional groups such as vinyl, methacrylate, and maleimide groups have been introduced to carboxyl groups of HA using the carbodiimide chemistry, which could react with thiol groups of peptides by Michael addition. This kind of modification strategy has been preferred due to the high conjugation efficiency and the mild reaction condition. Although most exemplary cases have been focused on the conjugation of peptide or protein molecules with repeating side chains of HA, their conjugation to the reducing end of HA has been recently investigated to develop a clinically feasible drug candidate with a well-defined chemical structure. The conjugation of peptide and protein drugs to HA can elongate their short half-lives by providing the shielding effect from peptidases and proteinases.53,56 Moreover, target-specific delivery to several tissues such as cancer and liver can be achieved via the interaction of HA with its receptors in the body. We previously synthesized HA−interferon alpha (IFNα) conjugate labeled with zwitterionic imaging agent ZW800-1 (Figure 3a), which showed that IFNα could be delivered target-specifically to the liver tissues after conjugation to HA with improved pharmacokinetic and antiviral behaviors as shown in Figure 3b−d.52,57 In addition, HA-assisted transdermal delivery of proteins such as human growth hormone (hGH),53 ovalbumin (OVA),39 and epidermal growth factor (EGF)56 has been demonstrated and applied for the facile transdermal immunization and the skin wound healing, respectively. 3.3. HA Nanoparticles. Chemical drugs generally suffer from physiological instability, resulting in the low drug-loading efficiency, the premature burst release, and the low target site

accumulation. To alleviate this limitation, HA micellar delivery systems are highly required for targeting, controlled micellar dissociation and triggered drug release after intracellular delivery. HA nanoparticles have been synthesized by coupling hydrophobic molecules to the hydrophilic HA. Due to many functional groups (−COOH) in the structural backbone of HA, a considerable amount of hydrophobic molecules can be readily grafted onto the polymer, forming a hydrophobic inner core and a hydrophilic HA shell layer encapsulating the hydrophobic drug.58 Figure 4 shows various types of HA− hydrophobic molecule conjugate micelles to encapsulate the hydrophobic drug.59 Polymeric micelle systems can facilitate the hydrophobic drug delivery, especially enhancing the anticancer therapeutic effect. These HA-based micelles can be effectively delivered to the tumor tissue via the passive targeting by EPR effect and the HA receptor-mediated active targeting.60 HA block copolymers that can self-assemble into nanoparticles have also been investigated due to enhanced therapeutic efficacy of encapsulated drugs.61 Amphiphilic HA block copolymers were synthesized by introducing hydrophobic polymers such as poly(ε-caprolactone),62 poly(γ-benzyl glutamate),63 poly(trimethylene carbonate-co-dithiolanetrimethylene carbonate),64 and so on. Many kinds of antineoplastic drugs have been conjugated to HA, forming a new compound with the promising antitumor effect. Paclitaxel is a well-known anticancer drug. The free drug has shown a tremendous potential as an anticancer compound, but its clinical use has been limited due to its poor physiological stability.65 In many studies, paclitaxel has been loaded to the HA micelles prepared with poly[lactic-coE


Perspective

Biomacromolecules

Figure 5. Schematic illustration of (a) HA-MoS2 conjugates for multimodal cancer theranosis, and (b) HA receptor-mediated delivery of HA-MoS2 conjugates into tumor cells and the following intracellular disulfide cleavage in the reducing environment. Reproduced with permission from ref 75. Copyright 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

their biocompatibility and prolong the residence time with HA receptor-mediated target-specific delivery. HA-NP hybrid systems can be prepared by the surface coating of NPs with short HA, the conjugation of NPs to the repeating units of long HA backbone, and layer-by-layer assembly of HA on NPs via electrostatic interactions.21 The HA-NP hybrid systems have been used for biomedical applications to bioimaging,74 phototherapy,75 photomedicine,76 and drug delivery.77 For example, Lee et al. developed gold nanoparticles (AuNPs) modified with thiolated low molecular weight HA (12 kDa) by chemical conjugation and with IFNα by physical binding.77 The target-specific HAAuNP/IFNα complex was successfully delivered to the liver for the treatment of hepatitis C virus infection with the long-term pro-inflammatory effect. The multifunctional NPs can be used for both diagnosis and therapy simultaneously. As shown in Figure 5, Shin et al. reported the multimodal cancer theranosis

(glycolic acid)], dendritic oligoglycerol, deoxycholic acidhistidine, and so on.66−68 Beyond the paclitaxel, other hydrophobic anticancer drugs have been successfully conjugated to HA, forming a micelle to overcome the toxicity and the physiological instability.69−71 They showed a synergistic targeting effect on tumor cells by both passive and active targeting. HA nanoparticles with a less negative surface charge appeared to be beneficial for high drug loading, leading to the reduced cost of final formulation and the increased drug accumulation.72 In order for the chemical conjugation of HA with hydrophobic polymers or lipids in a single organic phase, various chemical and physical solubilization methods of HA have been developed to produce a homogeneous mixture of hydrophilic HA and hydrophobic molecules for conjugation.66 3.4. HA−Nanoparticle Hybrid System. HA has also been used for the conjugation with nanoparticles (NPs) such as metallic NPs,73 silica NPs,74 and polymer NPs to enhance F


Perspective

Biomacromolecules

Figure 6. (a) Hydrogels were prepared by the hydrazine bond formation between complementary aldehyde (ALD)−hyaluronic acid (HA) and hydrazide (HYD)−dextran sulfate (DS). ① Matrixmetalloproteinase (MMP) degrades the hydrogel cross-linkers of MMP-cleavable peptide, ② liberating polysaccharide-bound recombinant tissue inhibitor of MMPs (rTIMP-3) to inhibit the local MMP activity, and ③ attenuate further hydrogel degradation. (b) Representative short-axis views (top) and m-mode targeted images (bottom) for each treatment group 14 days postmyocardiac infarction (MI) (scale bars, 1 cm). The posterior wall (PW) at the site of the infarct induction is shown by the arrows. Significant chamber dilation and wall thinning occurred following MI in consistent with the adverse remodelling process, which was unaffected by hydrogel injection alone. However, the degree of LV dilation and wall thinning was attenuated in the hydrogel/rTIMP-3 group. (c) Hydrogel/rTIMP-3 injections continued to show a therapeutic benefit 28 days following MI induction (EF: ejection fraction, LVEDV: left ventricle (LV) end diastolic volume, LVPWThd: LV posterior wall thickness at diastole, PCWP: pulmonary capillary wedge pressure). All values are mean ± s.e.m.; n = 3 for all groups; pairwise t-test with Bonferroni correction; *P < 0.05 versus sham, +P < 0.05 versus MI, #P < 0.05 versus MI/hydrogel. Reprinted by permission from Springer Nature, ref 87. Copyright 2014 Macmillan Publishers Limited, http://www.nature.com/nmat/.

using HA−molybdenum disulfide (MoS2) hybrid systems.75 HA-MoS2 conjugates synthesized by the disulfide bond formation between thiolated HA and MoS2 was intracellularly delivered into cancer cells via HA-receptor-mediated endocytosis, and the disulfide bond was cleaved in the reducing environment. They could be effectively used for the multimodal fluorescence imaging, photoacoustic imaging, and photothermal cancer therapy.75 Among diverse kinds of NPs, iron-oxide NPs have been approved by the Food and Drug Administration (FDA) for treating anemia and molecular imaging, and inorganic NPs such as silica NPs and gold NPs have been successfully applied in clinical studies.78 Nonetheless, the safety issues of various NPs should be intensively investigated in more detail. In addition, the reproducibility of HA-NP hybrid systems for scale-up should be fully investigated for further clinical

applications. With the great potentials, HA-NP hybrid systems might pave a new way to the theranostic applications of NPs. 3.5. HA Hydrogels for Drug Delivery. Hydrogels are cross-linked synthetic and natural polymer networks, and they have been developed as a localized drug delivery carrier for a long-term sustained release of drugs to the target site. The well-designed hydrogels can be employed for the controlled drug delivery of various therapeutics including macromolecular drugs of peptides and proteins as well as small molecular chemical drugs. Since HA is one of the main components in the ECM, it has low toxicity and great structural integrity with surrounding tissues.79 In addition, HA hydrogels can be well located in the target tissue area due to its mucoadhesive property and interaction with its receptors in the several tissues.80 G


Perspective

Biomacromolecules

Figure 7. (a) Schematic illustration for the sequential synthesis of monoamino cucurbit[6]uril (mCB[6])-hyaluronic acid (HA) and the preparation of mCB[6]/diaminohexane (DAH)-HA hydrogels (TCEP: tris(2-carboxyethyl)phosphine, EDC: 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, HOBt: hydroxybenzo-triazole, eMSCs: engineered mesenchymal stem cells).106 Adapted from ref 106 with permission from the Royal Society of Chemistry. (b) In situ formation of CB[6]/DAH-HA hydrogels by the sequential subcutaneous injections of CB[6]-HA and DAH-HA solutions with (a) carboxyfluorescein as a control and (b) FITC-CB[6] solution for FITC-CB[6]@CB[6]/DAH-HA hydrogel. Reproduced with permission from ref 103. Copyright 2012 American Chemical Society. (c) Long-term repeated eMSC cancer therapy using CB[6]/DAH-HA hydrogels. ** P < 0.01 and * P < 0.05 versus CB[6]/R-DAH-HA. Reproduced with permission from ref 105. Copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (d) Analysis of reperfusion after ischemic limb therapy using eMSC-encapsulated CB[6]/ DAH-HA hydrogels by laser Doppler imaging. Black arrow indicates the ligation point of hind limb surgery.106 Adapted from ref 106 with permission from the Royal Society of Chemistry.

lated HA and thiolated HA for the controlled delivery of hGH. In situ rapid formation of the HA hydrogel was confirmed after subcutaneous injection of the precursor solution and the single injection resulted in the long term release of hGH for up to 4 weeks.82 In recent years, photo-cross-linking reactions and supramolecular self-assembly not requiring chemical catalysts have been actively explored to prepare in situ forming HA hydrogels.84,85 In addition, smart hydrogels have been developed for stimuli-responsive drug delivery. For example, the temperature-responsive hydrogels by the combinatorial use of HA and temperature-responsive polymers such as poly(Nisopropylacrylamide) could trigger the release of the drug in response to the temperature change. Furthermore, some hydrogels have been designed to respond to the disease progression.86 Purcell et al. developed injectable HA hydrogels

The preparation method of HA hydrogels can be categorized into three types: direct cross-linking of functional groups of HA, cross-linking of HA derivatives, and cross-linking between two different HA derivatives. Traditionally, HA hydrogels have been prepared using the cross-linkers reacting with hydroxyl groups of HA such as divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), and 1,2,7,8-diepoxyoctane (DEO) or with carboxyl groups of HA such as hexamethylene diamine and p-phenylene bis(ethylcarbodimide) (BCDI).81 On the other hand, to reduce the denaturation of protein and drugs, HA hydrogels have been prepared by the specific cross-linking reactions without toxic catalysts in the mild condition such as Michael addition cross-linking between thiol groups and vinyl groups, and Diels−Alder reaction cross-linking between dienophile and diene.82,83 Yang et al. reported HA hydrogels prepared by Michael addition between aminoethyl methacryH


Perspective

Biomacromolecules Table 1. Clinically Available Commercialized Hyaluronic Acid (HA) Products Applications Intra-articular injection

Ophthalmic treatment

Dermal filler

Adhesion barrier

Actinic keratosis treatment

Products

Company

Components

Adant Arthrum Artz/Supartz Durolane Go-On Hyalart Synvisc Hyalgan Hyalubrix Healon Hylo-VisionHDeye drops XailinHA Hylaform Hylaform Plus Captique Restylane Perlane JuvedermUltra/Ultra Plus Elevess Puragen Hyalobarrier Seprafilm Medicurtain Solaraze

Meiji Seika Pharma LCA Pharmaceutical Seikagaku Bioventus Rottapharm Sanofi-Aventis Sanofi-Aventis Fidia Pharma Fidia Pharma Pfizer OmniVision Nicox Allergan Allergan Mentor Corporation Galderma Galderma Allergan Anika Therapeutics Mentor Corporation Anika Therapeutics Genzyme Shin Poong Pharm. Almirall

1% HA (0.6−1.2 MDa) 2% HA (0.27−0.45 MDa) 1% HA (0.9 MDa) 0.7% HA (>100 MDa) 1% HA (0.8−1.5 MDa) 1% HA (0.5−0.75 MDa) 0.8% HA (6 MDa) 1% HA (0.5−0.73 MDa) 1.5% HA (1.5−2 MDa) 1% HA 0.1% HA 0.2% HA 4.5−6 mg/mL (DVS cross-linker) 4.5−6 mg/mL (DVS cross-linker) 4.5−6 mg/mL (DVS cross-linker) 20 mg/mL (BDDE cross-linker) 20 mg/mL (BDDE cross-linker) 20 mg/mL (BDDE cross-linker) 20 mg/mL (BCDI cross-linker) 20 mg/mL (DEO cross-linker) HA ACP gel HA/carboxymethylcellulose HA/hydroxyethyl starch Diclofenac in HA gel

could also serve as a contrast agent for noninvasive theranostic applications via the HA receptor-mediated pathway. 3.7. HA Hydrogels for Bioengineered Cell Therapy. One of the new therapeutic approaches is the delivery of cells bioengineered to secrete therapeutic molecules such as cytokines and growth factors. While the direct injection of a cell suspension may end up with a low retention rate and a low viability, hydrogels can offer physical and immunological protection of therapeutic cells in the body and long retention at the target site.98,99 Because hydrogel systems for cell delivery need high cytocompatibility to maintain a high survival rate of encapsulated cells, novel strategies have been intensively investigated to prepare HA hydrogels without causing cytotoxicity. The conventional physical cross-linking has suffered from low stability and requires nonphysiological external stimuli such as pH, temperature, or ionic strength change, whereas the chemical cross-linking can expose cells to cytotoxic reagents during the hydrogel formation and degradation processes.99−101 To circumvent these issues, supramolecular HA hydrogels have been developed by the host−guest interaction of β-cyclodextrin (CD) to ferrocene and adamantane derivatives or cucurbit[n]uril (CB[n], n = 5−8, 10, 14) to aliphatic polyamine.101 In addition, dynamic covalent crosslinking and catechol cross-linking derived by the oxidative conversion of the catechol groups have been harnessed to construct 3-dimensional (3D) hydrogel for controlled spatiotemporal therapeutic cell delivery.100,102 Especially, supramolecular HA hydrogels prepared by mixing diaminohexane-conjugated HA (DAH-HA) and CB[6]-conjugated HA (CB[6]-HA) have been extensively investigated for the delivery of bioengineered stem cells (Figure 7a).103−106 The hydrogels have been first exploited as a platform scaffold to deliver fibroblasts and mesenchymal stem cells (MSCs) for tissue engineering applications (Figure 7b).103,104 After

using the cross-linker degraded by active matrixmetalloproteinase (MMP) and employed the hydrogels to attenuate post myocardial infarction (MI) remodeling by releasing a recombinant tissue inhibitor of MMPs (rTIMP-3) in response to the MMP activity of surrounding tissues (Figure 6).87 3.6. HA Nanogels for Drug Delivery. To take the advantages of both hydrogels and nanomaterials, nanogels have been greatly investigated as drug-delivery carriers. Nanogels have the beneficial characteristics of high water content, good biocompatibility, high drug-loading capacity, and biological stability in the body.88,89 Moreover, they can provide a large surface area for surface modification, facile circulation in the blood, and accumulation in specific tissues in the active or passive manner.88,89 As described above, many kinds of HA hydrogels have been developed and HA nanogels can be prepared using the similar cross-linking chemistries. HA nanogels can efficiently deliver drugs to cancer tissues overexpressing HA receptors like CD44.90,91 Recently, HA nanogels have been designed to respond to different physiological stimuli such as pH,92,93 temperature,94 redox environment,95 and enzyme concentration96 or external stimuli like light and ultrasound.94,97 For example, pHresponsive HA nanogels were prepared by cross-linking the pH-sensitively coiled peptide, which could be efficiently taken up to CD44-positive cancer cells and release drugs at the acidic endosomal environment.93 Furthermore, the tunable interior network of nanogels enables the incorporation of multiple imaging agents and/or drugs into nanogels, providing multiple theranostic effects. Khatun et al. developed HA nanogels delivering graphene and doxorubicin simultaneously for synergistic photochemotherapy of lung cancers.97 The nanogel was cross-linked by pH-responsive disulfide bonding and appeared to be effective for the laser-mediated photothermal therapy and doxorubicin-mediated chemotherapy. Moreover, it I


Perspective

Biomacromolecules demonstrating the feasibility of the hydrogel system as a 3D scaffold, MSCs genetically engineered to secrete therapeutic proteins were entrapped into the hydrogels and applied to treat target diseases. Bioengineered MSCs to produce mutant interleukin-12 (IL-12M) delivered by the CB[6]/DAH-HA hydrogels showed a significant therapeutic effect on treating cancer (Figure 7c).105 Furthermore, MSCs bioengineered to secrete vascular endothelial growth factor A (VEGF-A) and hepatocyte growth factor (HGF) delivered by the CB[6]/ DAH-HA hydrogels promoted vascular repair and enhanced blood perfusion in hind-limb ischemia model mice (Figure 7d).106

types of anticancer chemical drugs including paclitaxel, irinotecan, doxorubicin, and 5-fluorouracil have been conjugated to HA, and their therapeutic effects have been assessed to treat various kinds of cancers such as the bladder, ovarian, breast, prostate, and metastatic lung cancers in preclinical/ clinical trials.43,120 Fidia Pharma Group reported that 6 weekly intravesical administration of Oncofid-P-B, paclitaxel−HA conjugate solution, resulted in the therapeutic effect for 45% of the patients with nonmuscle-invasive bladder cancer in phase II clinical trials last year.121 All these efforts will greatly contribute to the translational development of HA-based medicines.

4. TRANSLATIONAL DEVELOPMENT OF HA-BASED MEDICINES On the basis of extensive research works for the clinical applications of HA, several types of biomedical products have been successfully commercialized (Table 1) and actively investigated in clinical trials. Early stage products employed a native form of HA dissolved in the physiological buffer without further modification. Two representative products are a joint lubricant for the treatment of osteoarthritis and an eye drop formulation to alleviate the symptom of dry eye syndrome. Intra-articularly injected HA can enhance the viscoelasticity of synovial fluid and provide wear protection in the joint.107 Many kinds of HA products for intra-articular injection have been commercialized using HA from different sources, molecular weights, and contents such as Synvisc, Hyalgan, and Hyalubrix.108−110 On the other hand, eye drops consisted with HA solution have been mainly used as artificial tear to form stable tear film.111 Ophthalmic viscosurgical fluids like Healon have been also used to substitute the vitreous fluid and protect delicate tissues in ocular surgeries including cataract extraction, intraocular lens implantation, corneal transplant, and glaucoma filtration.112 As the next stage products, HA hydrogels have been developed as dermal fillers and adhesion barriers. Because HA is a major component of ECM and naturally derived from the body, it has been regarded as one of the best materials to construct dermal fillers for tissue augmentation.113 HA dermal fillers can be prepared by cross-linking hydroxyl groups or carboxyl groups of HA using cross-linkers like DVS, BDDE, BCDE, and DEO as previously described in section 3.5. The particle size, concentration, and molecular weight of HA have been controlled to tune the degradation rate.20 A few companies launched drug-loaded HA fillers such as lidocaine to reduce pain, erythema and bruising.114,115 Furthermore, HA hydrogels have been used for the development of postsurgical adhesion barriers. HA membrane can not only act as a mechanical barrier, but also inhibit fibrin formation after coating the surgical area and saturating the CD44 receptor of the tissue.116 HA has advantages in view of the tissue repair and the regulation of inflammatory responses.117 There have been two types of HA hydrogels used for adhesion barriers: one is auto-cross-linked polysaccharide (ACP) hydrogel formed by intramolecular esterification of carboxyl groups and hydroxyl groups of HA, and the other is chemically crosslinked HA hydrogels.118 Adducts such as carboxymethyl cellulose and hydroxyethyl starch have been incorporated to retard the degradation and achieve the efficient prevention of tissue adhesion.116,119 In recent years, HA−chemical drug conjugates for anticancer therapy have been actively investigated in clinical trials. Several

5. CONCLUSION AND FUTURE PERSPECTIVES In this Perspective, we have described a variety of HA derivatives and their translational developments for clinical applications. HA derivatives can be prepared by the chemical modification of hydroxyl groups and carboxyl groups on the backbone of HA. They have been effectively harnessed to develop various medical products in the forms of HA−drug conjugates, HA nanoparticles, HA−nanoparticle hybrid systems, HA bulk and nanosized hydrogels for drug delivery and bioengineered cell therapy. HA-based products have been commercialized mainly as joint lubricants, ophthalmic viscosurgical fluids, dermal fillers, and adhesion barriers. To span its feasibility to the broad biomedical fields, a great effort has been made for the translational development to preclinical and clinical applications. One of the promising products with great feasibility for further commercialization is HA−drug conjugate. Since HA can enhance the solubility, blood circulation time, and tumor targeting efficiency of anticancer drugs, HA−anticancer drug conjugates are being eagerly investigated in preclinical and clinical trials. Although the translational research on HA−drug conjugates has been mainly focused on chemical drugs so far, HA−peptide/protein drug conjugates can be excellent potential targets for further clinical applications. Currently, PEGylated protein drugs have been successfully harnessed in the clinic after FDA approval with the improved pharmacokinetic and pharmacological effects.122 Accordingly, for further development of HA−peptide/protein drug conjugates, it would be crucial to demonstrate their clinical benefits over PEGylated protein drugs. Considering the biocompatibility and superior physiological characteristics of HA in the eye and the skin, the development of HA−drug conjugates for ocular and transdermal delivery would be also a good strategy for further clinical development. Ocular and transdermal delivery of HA−drug conjugates can offer a high accumulation rate and a long residence time at the target site while providing additional hydration effect to the surrounding tissue.56,123 In addition, because HA is highly accumulated in the liver after intravenous injection, the target-specific HA−drug conjugate would be a good clinical candidate for the treatment of liver diseases. As HA hydrogels have been used for clinical applications in the forms of dermal fillers and adhesion barriers, they can be easily applied to drug delivery. For example, lidocaine-loaded HA fillers and diclofenac-loaded HA hydrogels are already commercially available under the trade names of Perlane and of Solaraze, respectively. Another promising approach for the clinical use of HA hydrogels is their development as a carrier of genetically engineered therapeutic cells. The structural integrity of HA hydrogels with surrounding tissues and their J


Perspective

Biomacromolecules

phenylene bis(ethylcarbodimide); DVS, divinyl sulfone; BDDE, 1,4-butanediol diglycidyl ether; DEO, 1,2,7,8-diepoxyoctane; MMP, matrixmetalloproteinase; MI, myocardial infarction; rTIMP-3, recombinant tissue inhibitor of MMPs; CD, cyclodextrin; CB[n], cucurbit[n]uril; 3D, 3-dimensional; MSCs, mesenchymal stem cells; IL-12M, mutant interleukin12; VEGF-A, vascular endothelial growth factor A; HGF, hepatocyte growth factor; ACP, autocrosslinked polysaccharide

long-term safety have been confirmed through enormous studies using HA dermal fillers.81,113−115 Recent studies have also shown that supramolecular HA hydrogels formed by host−guest chemistry might not be cytotoxic enabling the spatiotemporal control of bioengineered cells for therapeutic applications.101−106 Thus, these supramolecular HA hydrogels would be successfully applied for various bioengineered cell therapeutics expressing the tailored proteins according to the intractable diseases such as cancer, neuronal diseases, and ischemic diseases.105,106 Despite a lot of extensive research efforts for the biomedical applications of HA and its derivatives, there are still several unmet issues which should be addressed to bridge the translational gap between the basic research and the clinical development. First, the production, chemical modification, and accurate characterization of HA and its derivatives should be carefully performed in consideration of clinical applications. Second, the effect of HA molecular weight on the biological and immunological functions should be more clearly explored in vitro and in vivo. Third, the safety and the clearance of HA derivatives should be fully understood after in vivo applications. Taken together, HA and its derivatives would greatly contribute to the development of innovative medicines for the treatment of various intractable diseases.

■

■

REFERENCES

(1) Sadtler, K.; Singh, A.; Wolf, M. T.; Wang, X.; Pardoll, D. M.; Elisseeff, J. H. Design, Clinical Translation and Immunological Response of Biomaterials in Regenerative Medicine. Nat. Rev. Mater. 2016, 1, 1−17. (2) Pelaz, B.; Alexiou, C.; Alvarez-Puebla, R. A.; Alves, F.; Andrews, A. M.; Ashraf, S.; Balogh, L. P.; Ballerini, L.; Bestetti, A.; Brendel, C.; Bosi, S.; Carril, M.; Chan, W. C. W.; Chen, C.; Chen, X.; Chen, X.; Cheng, Z.; Cui, D.; Du, J.; Dullin, C.; Escudero, A.; Feliu, N.; Gao, M.; George, M.; Gogotsi, Y.; Grünweller, A.; Gu, Z.; Halas, N. J.; Hampp, N.; Hartmann, R. K.; Hersam, M. C.; Hunziker, P.; Jian, J.; Jiang, X.; Jungebluth, P.; Kadhiresan, P.; Kataoka, K.; Khademhosseini, A.; Kopeček, J.; Kotov, N. A.; Krug, H. F.; Lee, D. S.; Lehr, C.-M.; Leong, K. W.; Liang, X.-J.; Lim, M. L.; Liz-Marzán, L. M.; Ma, X.; Macchiarini, P.; Meng, H.; Möhwald, H.; Mulvaney, P.; Nel, A. E.; Nie, S.; Nordlander, P.; Okano, T.; Oliveira, J.; Park, T. H.; Penner, R. M.; Prato, M.; Puntes, V.; Rotello, V. M.; Samarakoon, A.; Schaak, R. E.; Shen, Y.; Sjöqvist, S.; Skirtach, A. G.; Soliman, M. G.; Stevens, M. M.; Sung, H.-W.; Tang, B. Z.; Tietze, R.; Udugama, B. N.; VanEpps, J. S.; Weil, T.; Weiss, P. S.; Willner, I.; Wu, Y.; Yang, L.; Yue, Z.; Zhang, Q.; Zhang, Q.; Zhang, X.-E.; Zhao, Y.; Zhou, X.; Parak, W. J. Diverse Applications of Nanomedicine. ACS Nano 2017, 11, 2313−2381. (3) Swierczewska, M.; Han, H. S.; Kim, K.; Park, J. H.; Lee, S. Polysaccharide-Based Nanoparticles for Theranostic Nanomedicine. Adv. Drug Delivery Rev. 2016, 99, 70−84. (4) Zuris, J. A.; Thompson, D. B.; Shu, Y.; Guilinger, J. P.; Bessen, J. L.; Hu, J. H.; Maeder, M. L.; Joung, J. K.; Chen, Z.-Y.; Liu, D. R. Cationic Lipid-Mediated Delivery of Proteins Enables Efficient Protein-Based Genome Editing In Vitro and In Vivo. Nat. Biotechnol. 2015, 33, 73−80. (5) Wittrup, A.; Lieberman, J. Knocking Down Disease: A Progress Report on siRNA Therapeutics. Nat. Rev. Genet. 2015, 16, 543−552. (6) Yan, L.; Crayton, S. H.; Thawani, J. P.; Amirshaghaghi, A.; Tsourkas, A.; Cheng, Z. A pH-Responsive Drug-Delivery Platform Based on Glycol Chitosan-Coated Liposomes. Small 2015, 11, 4870− 4874. (7) Manchester, M.; Singh, P. Virus-Based Nanoparticles (VNPs): Platform Technologies for Diagnostic Imaging. Adv. Drug Delivery Rev. 2006, 58, 1505−1522. (8) Pelaz, B.; del Pino, P.; Maffre, P.; Hartmann, R.; Gallego, M.; Rivera-Fernández, S.; de la Fuente, J. M.; Nienhaus, G. U.; Parak, W. J. Surface Functionalization of Nanoparticles with Polyethylene Glycol: Effects on Protein Adsorption and Cellular Uptake. ACS Nano 2015, 9, 6996−7008. (9) Rengan, A. K.; Bukhari, A. B.; Pradhan, A.; Malhotra, R.; Banerjee, R.; Srivastava, R.; De, A. In Vivo Analysis of Biodegradable Liposome Gold Nanoparticles as Efficient Agents for Photothermal Therapy of Cancer. Nano Lett. 2015, 15, 842−848. (10) Shen, S.; Wang, S.; Zheng, R.; Zhu, X.; Jiang, X.; Fu, D.; Yang, W. Magnetic Nanoparticle Clusters for Photothermal Therapy with Near-Infrared Irradiation. Biomaterials 2015, 39, 67−74. (11) Ruan, S.; Hu, C.; Tang, X.; Cun, X.; Xiao, W.; Shi, K.; He, Q.; Gao, H. Increased Gold Nanoparticle Retention in Brain Tumors by in Situ Enzyme-induced Aggregation. ACS Nano 2016, 10, 10086− 10098. (12) Kim, H.; Park, Y.; Beack, S.; Han, S.; Jung, D.; Cha, H.; Kwon, W.; Hahn, S. K. Dual-Color-Emitting Carbon Nanodots for

AUTHOR INFORMATION

Corresponding Author

*Tel.: +82 54 279 2159; Fax: +82 54 279 2399; E-mail: address:[email protected] (S. K. Hahn). ORCID

Seulgi Han: 0000-0002-3659-6622 Woosung Kwon: 0000-0001-9362-7686 Sei Kwang Hahn: 0000-0002-7718-6259 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This research was supported by the Nano·Material Technology Development Program (No. 2017M3A7B8065278), the Basic Science Research Program (2017R1E1A1A03070458) and the Center for Advanced Soft-Electronics (Global Frontier Project, CASE-2015M3A6A5072945) of the National Research Foundation (NRF) funded by the Ministry of Science and ICT, Korea. This research was supported by POSCO Green Science Program (2018Y060). This work was also supported by the TIPS Project (S2557811) and the World Class 300 Project (S2482887) of the Ministry of SMEs and Startups, Republic of Korea. H.K. acknowledges support from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1A6A3A03009147).

■

ABBREVIATIONS HA, hyaluronic acid; PEG, polyethylene glycol; ECM, extracellular matrix; TBA, tetrabutylammonium; EDA, ethylenediamine; CD44, cluster determinant 44; RHAMM, receptor for HA-mediated motility; EPR, enhanced permeability and retention; DMARDs, disease modifying antirheumatic drugs; IFNα, interferon alpha; hGH, human growth hormone; OVA, ovalbumin; EGF, epidermal growth factor; NP, nanoparticle; MoS2, molybdenum disulfide; AuNPs, gold nanoparticles; FDA, Food and Drug Administration; BCDI, pK


Perspective

Biomacromolecules

(31) Lee, Y.; Lee, H.; Kim, Y. B.; Kim, J.; Hyeon, T.; Park, H. W.; Messersmith, P. B.; Park, T. G. Bioinspired Surface Immobilization of Hyaluronic Acid on Monodisperse Magnetite Nanocrystals for Targeted Cancer Imaging. Adv. Mater. 2008, 20, 4154−4157. (32) Oh, E. J.; Kim, J. W.; Kong, J. H.; Ryu, S. H.; Hahn, S. K. Signal Transduction of Hyaluronic Acid−Peptide Conjugate for FPRL1 Receptor. Bioconjugate Chem. 2008, 19, 2401−2408. (33) Cho, H. J.; Yoon, H. Y.; Koo, H.; Ko, S. H.; Shim, J. S.; Lee, J. H.; Kim, K.; Kwon, I. C.; Kim, D. D. Self-Assembled Nanoparticles Based on Hyaluronic Acid-Ceramide (HA-CE) and Pluronic for Tumor-Targeted Delivery of Docetaxel. Biomaterials 2011, 32, 7181− 7190. (34) Fiorica, C.; Palumbo, F. S.; Pitarresi, G.; Bongiovì, F.; Giammona, G. Hyaluronic Acid and Beta Cyclodextrins Films for the Release of Corneal Epithelial Cells and Dexamethasone. Carbohydr. Polym. 2017, 166, 281−290. (35) Fiorica, C.; Mauro, N.; Pitarresi, G.; Scialabba, C.; Palumbo, F. S.; Giammona, G. Double-Network-Structured Graphene OxideContaining Nanogels as Photothermal Agents for the Treatment of Colorectal Cancer. Biomacromolecules 2017, 18, 1010−1018. (36) Palumbo, F. S.; Fiorica, C.; Pitarresi, G.; Zingales, M.; Bologna, E.; Giammona, G. Multifibrillar Bundles of a Self-Assembling Hyaluronic acid Derivative Obtained Through a Microfluidic Technique for Aortic Smooth Muscle Cell Orientation and Differentiation. Biomater. Sci. 2018, 6, 2518−2526. (37) Palumbo, F. S.; Puleio, R.; Fiorica, C.; Pitarresi, G.; Loria, G. R.; Cassata, G.; Giammona, G. Matrices of a Hydrophobically Functionalized Hyaluronic Acid Derivative for the Locoregional Tumour Treatment. Acta Biomater. 2015, 25, 205−215. (38) Lim, S. T.; Forbes, B.; Berry, D. J.; Martin, G. P.; Brown, M. B. In vivo Evaluation of Novel Hyaluronan/Chitosan Microparticulate Delivery Systems for the Nasal Delivery of Gentamicin in Rabbits. Int. J. Pharm. 2002, 231, 73−82. (39) Kim, K. S.; Kim, H.; Park, Y.; Kong, W. H.; Lee, S. W.; Kwok, S. J. J.; Hahn, S. K.; Yun, S. H. Noninvasive Transdermal Vaccination Using Hyaluronan Nanocarriers and Laser Adjuvant. Adv. Funct. Mater. 2016, 26, 2512−2522. (40) Tolg, C.; Telmer, P.; Turley, E. Specific Sizes of Hyaluronan Oligosaccharides Stimulate Fibroblast Migration and Excisional Wound Repair. PLoS One 2014, 9, No. e88479. (41) Gariboldi, S.; Palazzo, M.; Zanobbio, L.; Selleri, S.; Sommariva, M.; Sfondrini, L.; Cavicchini, S.; Balsari, A.; Rumio, C. Low Molecular Weight Hyaluronic Acid Increases the Self-Defense of Skin Epithelium by Induction of β-Defensin 2 via TLR2 and TLR4. J. Immunol. 2008, 181, 2103−2110. (42) Cyphert, J. M.; Trempus, C. S.; Garantziotis, S. Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology. Int. J. Cell Biol. 2015, 2015, 563818. (43) De Stefano, I.; Battaglia, A.; Zannoni, G. F.; Prisco, M. G.; Fattorossi, A.; Travaglia, D.; Baroni, S.; Renier, D.; Scambia, G.; Ferlini, C.; Gallo, D. Hyaluronic Acid-Paclitaxel: Effects of Intraperitoneal Administration Against CD44(+) Human Ovarian Cancer Xenografts. Cancer Chemother. Pharmacol. 2011, 68, 107−116. (44) Lee, S. J.; Ghosh, S. C.; Han, H. D.; Stone, R. I.; BottsfordMiller, J.; Shen, D. Y.; Auzenne, E. J.; Lopez-Araujo, A.; Lu, C.; Nishimura, M.; Pecot, C. V.; Zand, B.; Thanapprapasr, D.; Jennings, N. B.; Kang, Y.; Huang, J.; Hu, W.; Klostergaard, J.; Sood, A. K. Metronomic Activity of CD44-Targeted Hyaluronic Acid-Paclitaxel in Ovarian Carcinoma. Clin. Cancer Res. 2012, 18, 4114−4121. (45) Cai, S.; Thati, S.; Bagby, T. R.; Diab, H. M.; Davies, N. M.; Cohen, M. S.; Forrest, M. L. Localized Doxorubicin Chemotherapy with a Biopolymeric Nanocarrier Improves Survival and Reduces Toxicity in Xenografts of Human Breast Cancer. J. Controlled Release 2010, 146, 212−218. (46) Gibbs, P.; Brown, T. J.; Ng, R.; Jennens, R.; Cinc, E.; Pho, M.; Michael, M.; Fox, R. M. A Pilot Human Evaluation of a Formulation of Irinotecan and Hyaluronic Acid in 5-Fluorouracil Refractory Metastatic Colorectal Cancer Patients. Chemotherapy 2009, 55, 49− 59.

Multicolor Bioimaging and Optogenetic Control of Ion Channels. Adv. Sci. 2017, 4, 1700325. (13) Pang, X.; Jiang, Y.; Xiao, Q.; Leung, a. W.; Hua, H.; Xu, C. pHResponsive Polymer-Drug Conjugates: Design and Progress. J. Controlled Release 2016, 222, 116−129. (14) Kim, K.; Park, J. H.; Park, S. H.; Lee, H. Y.; Kim, J. H.; Kim, M. S. An Injectable, Click-Cross-Linked Small Intestinal Submucosa Drug Depot for the Treatment of Rheumatoid Arthritis. Adv. Healthcare Mater. 2016, 5, 3105−3117. (15) Han, H. S.; Choi, K. Y.; Ko, H.; Jeon, J.; Saravanakumar, G.; Suh, Y. D.; Lee, D. S.; Park, J. H. Bioreducible Core-Crosslinked Hyaluronic Acid Micelle for Targeted Cancer Therapy. J. Controlled Release 2015, 200, 158−166. (16) Zhang, P.; Zhang, L.; Qin, Z.; Hua, S.; Guo, Z.; Chu, C.; Lin, H.; Zhang, Y.; Li, W.; Zhang, X.; Chen, X.; Liu, G. Genetically Engineered Liposome-Like Nanovesicles as Active Targeted Transport Platform. Adv. Mater. 2018, 30, 1705350. (17) Merino, S.; Martin, C.; Kostarelos, K.; Prato, M.; Vázquez, E. Nanocomposite Hydrogels: 3D Polymer−Nanoparticle Synergies for On-Demand Drug Delivery. ACS Nano 2015, 9, 4686−4697. (18) Kim, H.; Beack, S.; Han, S.; Shin, M.; Lee, T.; Park, Y.; Kim, K. S.; Yetisen, A. K.; Yun, S. H.; Kwon, W.; Hahn, S. K. Multifunctional Photonic Nanomaterials for Diagnostic, Therapeutic, and Theranostic Applications. Adv. Mater. 2018, 30, 1701460. (19) Oh, E. J.; Park, K.; Kim, K. S.; Kim, J.; Yang, J.-A.; Kong, J.-H.; Lee, M. Y.; Hoffman, A. S.; Hahn, S. K. Target Specific and LongActing Delivery of Protein, Peptide, and Nucleotide Therapeutics Using Hyaluronic Acid Derivatives. J. Controlled Release 2010, 141, 2−12. (20) Kim, H.; Jeong, H.; Han, S.; Beack, S.; Hwang, B. W.; Shin, M.; Oh, S. S.; Hahn, S. K. Hyaluronate and Its Derivatives for Customized Biomedical Applications. Biomaterials 2017, 123, 155−171. (21) Kim, H.; Park, Y.; Stevens, M. M.; Kwon, W.; Hahn, S. K. Multifunctional Hyaluronate − Nanoparticle Hybrid Systems for Diagnostic, Therapeutic, and Theranostic Applications. J. Controlled Release 2019, 303, 55−66. (22) Yang, J.-A.; Kong, W. H.; Sung, D. K.; Kim, H.; Kim, T. H.; Lee, K. C.; Hahn, S. K. Hyaluronic Acid − Tumor Necrosis FactorRelated Apoptosis-Inducing Ligand Conjugate for Targeted Treatment of Liver Fibrosis. Acta Biomater. 2015, 12, 174−182. (23) Choi, K. Y.; Yoon, H. Y.; Kim, J.-H.; Bae, S. M.; Park, R.-W.; Kang, Y. M.; Kim, I.-S.; Kwon, I. C.; Choi, K.; Jeong, S. Y.; Kim, K.; Park, J. H. Smart Nanocarrier Based on PEGylated Hyaluronic Acid for Cancer Therapy. ACS Nano 2011, 5, 8591−8599. (24) Kogan, G.; Š oltés, L.; Stern, R.; Gemeiner, P. Hyaluronic Acid: A Natural Biopolymer with a Broad Range of Biomedical and Industrial Applications. Biotechnol. Lett. 2006, 29, 17−25. (25) Tan, H.; Chu, C. R.; Payne, K. A.; Marra, K. G. Injectable In Situ Forming Biodegradable Chitosan-Hyaluronic Acid Based Hydrogels for Cartilage Tissue Engineering. Biomaterials 2009, 30, 2499− 2506. (26) Chun, C.; Lee, D. Y.; Kim, J.-T.; Kwon, M.-K.; Kim, Y.-Z.; Kim, S.-S. Effect of Molecular Weight of Hyaluronic Acid (HA) on Viscoelasticity and Particle Texturing Feel of HA Dermal Biphasic Fillers. Biomater. Res. 2016, 20, 24. (27) Collin, E. C.; Grad, S.; Zeugolis, D. I.; Vinatier, C. S.; Clouet, J. R.; Guicheux, J. J.; Weiss, P.; Alini, M.; Pandit, A. S. An Injectable Vehicle for Nucletus Pulposus Cell-Based Therapy. Biomaterials 2011, 32, 2862−2870. (28) Banerji, S.; Wright, A. J.; Noble, M.; Mahoney, D. J.; Campbell, I. D.; Day, A. J.; Jackson, D. G. Structures of the Cd44−Hyaluronan Complex Provide Insight into a Fundamental Carbohydrate−Protein Interaction. Nat. Struct. Mol. Biol. 2007, 14, 234−239. (29) Hahn, S. K.; Park, J. K.; Tomimatsu, T.; Shimoboji, T. Synthesis and Degradation Test of Hyaluronic Acid Hydrogels. Int. J. Biol. Macromol. 2007, 40, 374−380. (30) Lee, F.; Chung, J. E.; Kurisawa, M. An Injectable Hyaluronic Acid−Tyramine Hydrogel System for Protein Delivery. J. Controlled Release 2009, 134, 186−193. L


Perspective

Biomacromolecules (47) Shin, J. M.; Kim, S.; Thambi, T.; You, D. G.; Jeon, J.; Lee, J. O.; Chung, B. Y.; Jo, D.; Park, J. H. A Hyaluronic Acid-Methotrexate Conjugate for Targeted Therapy of Rheumatoid Arthritis. Chem. Commun. 2014, 50, 7632−7635. (48) Mero, A.; Campisi, M. Hyaluronic acid bioconjugates for the delivery of bioactive molecules. Polymers 2014, 6, 346−369. (49) Oh, E. J.; Park, K.; Choi, J.-S.; Joo, C.-K.; Hahn, S. K. Synthesis, Characterization, and Preliminary Assessment of Anti-Flt1 Peptide− Hyaluroante Conjugate for the Treatment of Corneal Neovascularization. Biomaterials 2009, 30, 6026−6034. (50) Friedrich, E. E.; Sun, L. T.; Natesan, S.; Zamora, D. O.; Christy, R. J.; Washburn, N. R. Effect of Hyaluronic Acid Conjugation on Anti-TNF-α Inhibition Inflammation in Burns. J. Biomed. Mater. Res., Part A 2014, 102, 1527−1536. (51) Ferguson, E. L.; Alshame, A. M. J.; Thomas, D. W. Evaluation of Hyaluronic Acid − Protein Conjugates for Polymer MaskedUnmasked Protein Therapy. Int. J. Pharm. 2010, 402, 95−102. (52) Yang, J.-A.; Park, K.; Jung, H.; Kim, H.; Hong, S. W.; Yoon, S. K.; Hahn, S. K. Target Specific Hyaluronic Acid − Interferon Alpha Conjugate for the Treatment of Hepatitis C Virus Infection. Biomaterials 2011, 32, 8722−8729. (53) Yang, J.-A.; Kim, E.-S.; Kwon, J. H.; Kim, H.; Shin, J. H.; Yun, S. H.; Choi, K. Y.; Hahn, S. K. Transdermal Delivery of Hyaluronic Acid − Human Growth Hormone Conjugate. Biomaterials 2012, 33, 5947−5954. (54) Montagner, I. M.; Merlo, A.; Carpanese, D.; Dalla Pietà, A.; Mero, A.; Grigoletto, A.; Loregian, A.; Renier, D.; Campisi, M.; Zanovello, P.; Pasut, G.; Rosato, A. A Site-Selective HyaluronanInterferonα2a Conjugate for the Treatment of Ovarian Cancer. J. Controlled Release 2016, 236, 79−89. (55) Kong, J.-H.; Oh, E. J.; Chae, S. Y.; Lee, K. C.; Hahn, S. K. Long Acting Hyaluronate − Exendin 4 Conjugate for the Treatment of Type 2 Diabetes. Biomaterials 2010, 31, 4121−4128. (56) Kim, H.; Kong, W. H.; Seong, K.-Y.; Sung, D. K.; Jeong, H.; Kim, J. K.; Yang, S. Y.; Hahn, S. K. Hyaluronate−Epidermal Growth Factor Conjugate for Skin Wound Healing and Regeneration. Biomacromolecules 2016, 17, 3694−3705. (57) Kim, K. S.; Hyun, H.; Yang, J.-A.; Lee, M. Y.; Kim, H.; Yun, S.H.; Choi, H. S.; Hahn, S. K. Bioimaging of Hyaluronate−Interferon α Conjugates Using a Non-Interfering Zwitterionic Fluorophore. Biomacromolecules 2015, 16, 3054−3061. (58) Li, G.; Liu, J.; Pang, Y.; Wang, R.; Mao, L.; Yan, D.; Zhu, X.; Sun, J. Polymeric Micelles with Water-Insoluble Drug as Hydrophobic Moiety for Drug Delivery. Biomacromolecules 2011, 12, 2016−2026. (59) Dosio, F.; Arpicco, S.; Stella, B.; Fattal, E. Hyaluronic Acid for Anticancer Drug and Nucleic Acid Delivery. Adv. Drug Delivery Rev. 2016, 97, 204−236. (60) Kim, K. S.; Hong, S. W.; Kim, H.; Cho, M.; Kim, S.; Hur, W.; Yun, S. H.; Yoon, S. K.; Hahn, S. K. RSC Adv. 2015, 5, 48615−48618. (61) Gu, Z.; Wang, X.; Cheng, R.; Cheng, L.; Zhong, Z. Hyaluronic Acid Shell and Disulfide-Crosslinked Core Micelles for In Vivo Targeted Delivery of Bortezomib for the Treatment of Multiple Myeloma. Acta Biomater. 2018, 80, 288−295. (62) Haas, S.; Hain, N.; Raoufi, M.; Handschuh-Wang, S.; Wang, T.; Jiang, X.; Schönherr, H. Enzyme Degradable Polymersomes from Hyaluronic Acid-block-poly(ε;-caprolactone) Copolymers for the Detection of Enzymes of Pathogenic Bacteria. Biomacromolecules 2015, 16, 832−841. (63) Upadhyay, K. K.; Le Meins, J.-F.; Misra, A.; Voisin, P.; Bouchaud, V.; Ibarboure, E.; Schatz, C.; Lecommandoux, S. Biomimetic Doxorubicin Loaded Polymersomes from Hyaluronanblock-Poly(γ-benzyl glutamate) Copolymers. Biomacromolecules 2009, 10, 2802−2808. (64) Zhang, Y.; Wu, K.; Sun, H.; Zhang, J.; Yuan, J.; Zhong, Z. Hyaluronic Acid-Shelled Disulfide-Crosslinked Nano-Polymersomes for Ultrahigh-Efficiency Reactive Encapsulation and CD44-Targeted Delivery of Mertansine Toxin. ACS Appl. Mater. Interfaces 2018, 10, 1597−1604.

(65) Jordan, M. A.; Wilson, L. Microtubules as a Target for Anticancer Drugs. Nat. Rev. Cancer 2004, 4, 253−265. (66) Lee, H.; Ahn, C. H.; Park, T. G. Poly[lactic co (glycolic acid)] Grafted Hyaluronic Acid Copolymer Micelle Nanoparticles for Target Specific Delivery of Doxorubicin. Macromol. Biosci. 2009, 9, 336−342. (67) Zhong, Y. N.; Goltsche, K.; Cheng, L.; Xie, F.; Meng, F. H.; Deng, C.; Zhong, A. Y.; Haag, R. Hyaluronic Acid-Shelled AcidActivatable Paclitaxel Prodrug Micelles Effectively Target and Treat CD44-Overexpressing Human Breast Tumor Xenografts in vivo. Biomaterials 2016, 84, 250−261. (68) Zhang, L.; Zhou, J. P.; Yao, J. Improved Anti-Tumor Activity and Safety Profile of a Paclitaxel-Loaded Glycyrrhetinic Acid-GraftHyaluronic Acid Conjugate as a Synergistically Targeted Drug Delivery System. Chin. J. Nat. Med. 2015, 13, 915−924. (69) Zhang, L.; Petroll, W. M.; Greyner, H. J.; Mummert, M. E. Development of a Hyaluronan Bioconjugate for the Topical Treatment of Melanoma. J. Dermatol. Sci. 2009, 55, 56−59. (70) Manju, S.; Sreenivasan, K. Conjugation of Curcumin onto Hyaluronic Acid Enhances its Aqueous Solubility and Stability. J. Colloid Interface Sci. 2011, 359, 318−325. (71) Ossipov, D. A. Nanostructured Hyaluronic Acid-Based Materials for Active Delivery to Cancer. Expert Opin. Drug Delivery 2010, 7, 681−703. (72) Liu, Y.; Zhou, C.; Wang, W.; Yang, J.; Wang, H.; Hong, W.; Huang, Y. CD44 Receptor Targeting and Endosomal pH-Sensitive Dual Functional Hyaluronic Acid Micelles for Intracellular Paclitaxel Delivery. Mol. Pharmaceutics 2016, 13, 4209−4221. (73) Lee, H. W.; Lee, M. Y.; Bhang, S. H.; Kim, B. S.; Kim, Y. S.; Ju, J. H.; Kim, K. S.; Hahn, S. K. Hyaluronate-Gold Nanoparticle/ Tocilizumab Complex for the Treatment of Rheumatoid Arthritis. ACS Nano 2014, 8, 4790−4798. (74) Lee, D.; Beack, S.; Yoo, J.; Kim, S. K.; Lee, C.; Kwon, W.; Hahn, S. K.; Kim, C. In vivo Photoacoustic Imaging of Livers Using Hyaluronic Acid-Conjugated Silica Nanoparticles. Adv. Funct. Mater. 2018, 28, 1800941. (75) Shin, M. H.; Park, E. Y.; Han, S.; Jung, H. S.; Keum, D. H.; Lee, G. H.; Kim, T.; Kim, C.; Kim, K. S.; Yun, S. H.; Hahn, S. K. Multimodal Cancer Theranosis Using Hyaluronate-Conjugated Molybdenum Disulfide. Adv. Healthcare Mater. 2019, 8, 1801036. (76) Han, S.; Hwang, B. W.; Jeon, E. Y.; Jung, D.; Lee, G. H.; Keum, D. H.; Kim, K. S.; Yun, S. H.; Cha, H. J.; Hahn, S. K. Upconversion Nanoparticles/Hyaluronate-Rose Bengal Conjugate Complex for Noninvasive Photochemical Tissue Bonding. ACS Nano 2017, 11, 9979−9988. (77) Lee, M. Y.; Yang, J. A.; Jung, H. S.; Beack, S.; Choi, J. E.; Hur, W.; Koo, H.; Kim, K.; Yoon, S. K.; Hahn, S. K. Hyaluronic Acid-Gold Nanoparticle/Interferon α Complex for Targeted Treatment of Hepatitis C Virus Infection. ACS Nano 2012, 6, 9522−9531. (78) Anselmo, A. C.; Mitragotri, S. Nanoparticles in the Clinic. Bioengineering & Translational Medicine 2016, 1, 10−29. (79) Mariggiò, M. A.; Cassano, A.; Vinella, A.; Vincenti, A.; Fumarulo, R.; Lo Muzio, L.; Maiorano, E.; Ribatti, D.; Favia, G. Enhancement of Fibroblast Proliferation, Collagen Biosynthesis and Production of Growth Factors as a Result of Combining Sodium Hyaluronate and Aminoacids. Int. J. Immunopathol. Pharmacol. 2009, 22, 485−492. (80) Burdick, J. A.; Prestwich, G. D. Hyaluronic Acid Hydrogels for Biomedical Applications. Adv. Mater. 2011, 23, H41−H56. (81) Yeom, J.; Bhang, S. H.; Kim, B.-S.; Seo, M. S.; Hwang, E. J.; Cho, I. H.; Park, J. K.; Hahn, S. K. Effect of Cross-Linking Reagents for Hyaluronic Acid Hydrogel Dermal Fillers on Tissue Augmentation and Regeneration. Bioconjugate Chem. 2010, 21, 240−247. (82) Yang, J.-A.; Kim, H.; Park, K.; Hahn, S. K. Molecular Design of Hyaluronic Acid Hydrogel Networks for Long-Term Controlled Delivery of Human Growth Hormone. Soft Matter 2011, 7, 868−870. (83) Fan, M.; Ma, Y.; Zhang, Z.; Mao, J.; Tan, H.; Hu, X. Biodegradable Hyaluronic Acid Hydrogels to Control Release of Dexamethasone through Aqueous Diels-Alder Chemistry for Adipose Tissue Engineering. Mater. Sci. Eng., C 2015, 56, 311−317. M


Perspective

Biomacromolecules

Assembling Supramolecular Hydrogels. J. Controlled Release 2015, 220, 119−129. (102) Shin, J.; Lee, J. S.; Lee, C.; Park, H.-J.; Yang, K.; Jin, Y.; Ryu, J. H.; Hong, K. S.; Moon, S.-H.; Chung, H.-M.; Yang, H. S.; Um, S. H.; Oh, J.-W.; Kim, D.-I.; Lee, H.; Cho, S.-W. Tissue Adhesive CatecholModified Hyaluronic Acid Hydrogel for Effective, Minimally Invasive Cell Therapy. Adv. Funct. Mater. 2015, 25, 3814−3824. (103) Park, K. M.; Yang, J.-A.; Jung, H.; Yeom, J.; Park, J. S.; Park, K.-H.; Hoffman, A. S.; Hahn, S. K.; Kim, K. In Situ Supramolecular Assembly and Modular Modification of Hyaluronic Acid Hydrogels for 3D Cellular Engineering. ACS Nano 2012, 6, 2960−2968. (104) Jung, H.; Park, J. S.; Yeom, J.; Selvapalam, N.; Park, K. M.; Oh, K.; Yang, J.-A.; Park, K. H.; Hahn, S. K.; Kim, K. 3D Tissue Engineered Supramolecular Hydrogels for Controlled Chondrogenesis of Human Mesenchymal Stem Cells. Biomacromolecules 2014, 15, 707−714. (105) Yeom, J.; Kim, S. J.; Jung, H.; Namkoong, H.; Yang, J.; Hwang, B. W.; Oh, K.; Kim, K.; Sung, Y. C.; Hahn, S. K. Supramolecular Hydrogels for Long-Term Bioengineered Stem Cell Therapy. Adv. Healthcare Mater. 2015, 4, 237−244. (106) Hwang, B. W.; Kim, Y.-E.; Kim, M.; Han, S.; Bok, S.; Park, K. M.; Shrinidhi, A.; Kim, K. S.; Ahn, G.-O.; Hahn, S. K. Supramolecular Hydrogels Encapsulating Bioengineered Mesenchymal Stem Cells for Ischemic Therapy. RSC Adv. 2018, 8, 18771−18775. (107) Ogston, A. G.; Stanier, J. E. The Physiological Function of Hyaluronic Acid in Synovial Fluid; Viscous, Elastic and Lubricant Properties. J. Physiol. 1953, 119, 244−252. (108) Adams, M. E.; Atkinson, M. H.; Lussier, A. J.; Schulz, J. I.; Siminovitch, K. A.; Wade, J. P.; Zummer, M. The Role of Viscosupplementation with Hylan G-F 20 (Synvisc®) in the Treatment of Osteoarthritis of the Knee: A Canadian Multicenter Trial Comparing Hylan G-F 20 Alone, Hylan G-F 20 with NonSteroidal Anti-Inflammatory Drugs (NSAIDS) and NSAIDS Alone. Osteoarthritis Cartilage 1995, 3, 213−226. (109) Altman, R. D.; Moskowitz, R. Intra-Articular Sodium Hyaluronate (Hyalgan®) in the Treatment of Patients with Osteoarthritis of the Knee: A Randomized Clinical Trial. J. Rheumatol. 1998, 25, 2203−2212. (110) Migliore, A.; Massafra, U.; Bizzi, E.; Vacca, F.; Martin-Martin, S.; Granata, M.; Alimonti, A.; Tormenta, S. Comparative, DoubleBlind, Controlled Study of Intra-Articular Hyaluronic Acid (Hyalubrix®) Injections Versus Local Anesthetic in Osteoarthritis of the Hip. Arthritis Res. Ther. 2009, 11, R183. (111) Mencucci, R.; Boccalini, C.; Caputo, R.; Favuzza, E. Effect of a Hyaluronic Acid and Carboxymethylcellulose Ophthalmic solution on Ocular comfort and Tear-Film Instability after Cataract Surgery. J. Cataract Refractive Surg. 2015, 41, 1699−1704. (112) Pape, L. G.; Balazs, E. A. The Use of Sodium Hyaluronate (Healon®) in Human Anterior Segment Surgery. Ophthalmology 1980, 87, 699−705. (113) Tezel, A.; Fredrickson, G. H. The Science of Hyaluronic Acid Dermal Fillers. J. Cosmet. Laser Ther. 2008, 10, 35−42. (114) Wahl, G. European Evaluation of a New Hyaluronic Acid Filler Incorporating Lidocaine. J. Cosmet. Dermatol. 2008, 7, 298−303. (115) Smith, L.; Cockerham, K. Hyaluronic Acid Dermal Fillers: Can Adjunctive Lidocaine Improve Patient Satisfaction without Decreasing Efficacy or Duration? Patient Prefer. Adherence 2011, 5, 133−139. (116) Kim, J. H.; Lee, J.-H.; Yoon, J.-H.; Chang, J. H.; Bae, J. H.; Kim, K.-S. Antiadhesive Effect of the Mixed Solution of Sodium Hyaluronate and Sodium Carboxymethylcellulose after Endoscopic Sinus Surgery. Am. J. Rhinol. 2007, 21, 95−99. (117) Petrey, A. C.; de la Motte, C. A. Hyaluronan, a Crucial Regulator of Inflammation. Front. Immunol. 2014, 5, 101. (118) Acunzo, G.; Guida, M.; Pellicano, M.; Tommaselli, G. A.; Sardo, A. D. S.; Bifulco, G.; Cirillo, D.; Taylor, A.; Nappi, C. Effectiveness of Auto-Cross-Linked Hyaluronic Acid Gel in the Prevention of Intrauterine Adhesions after Hysteroscopic Adhesiol-

(84) Mealy, J. E.; Rodell, C. B.; Burdick, J. A. Sustained Small Molecule Delivery from Injectable Hyaluronic Acid Hydrogels through Host-Guest Mediated Retention. J. Mater. Chem. B 2015, 3, 8010−8019. (85) Baier Leach, J.; Bivens, K. A.; Patrick, C. W., Jr.; Schmidt, C. E. Photocrosslinked Hyaluronic Acid Hydrogels: Natural, Biodegradable Tissue Engineering Scaffolds. Biotechnol. Bioeng. 2003, 82, 578−589. (86) Ha, D. I.; Lee, S. B.; Chong, M. S.; Lee, Y. M.; Kim, S. Y.; Park, Y. H. Preparation of Thermo-Responsive and Injectable Hydrogels Based on Hyaluronic Acid and Poly(N-isopropylacrylamide) and Their Drug Release Behaviors. Macromol. Res. 2006, 14, 87−93. (87) Purcell, B. P.; Lobb, D.; Charati, M. B.; Dorsey, S. M.; Wade, R. J.; Zellars, K. N.; Doviak, H.; Pettaway, S.; Logdon, C. B.; Shuman, J. A.; Freels, P. D.; Gorman, J. H., III; Gorman, R. C.; Spinale, F. G.; Burdick, J. A. Injectable and Bioresponsive Hydrogels for On-Demand Matrix Metalloproteinase Inhibition. Nat. Mater. 2014, 13, 653−661. (88) Molina, M.; Asadian-Birjand, M.; Balach, J.; Bergueiro, J.; Miceli, E.; Calderón, M. Stimuli-Responsive Nanogel Composites and their Application in Nanomedicine. Chem. Soc. Rev. 2015, 44, 6161− 6186. (89) Zhang, H.; Zhai, Y.; Wang, J.; Zhai, G. New Progress and Prospects: The Application of Nanogel in Drug Delivery. Mater. Sci. Eng., C 2016, 60, 560−568. (90) Chen, J.; Zou, Y.; Deng, C.; Meng, F.; Zhang, J.; Zhong, Z. Multifunctional Click Hyaluronic Acid Nanogels for Targeted Protein Delivery and Effective Cancer Treatment In Vivo. Chem. Mater. 2016, 28, 8792−8799. (91) Zhong, Y.; Zhang, J.; Cheng, R.; Deng, C.; Meng, F.; Xie, F.; Zhong, Z. Reversibly Crosslinked Hyaluronic Acid Nanoparticles for Active Targeting and Intelligent Delivery of Doxorubicin to Drug Resistant CD44+ Human Breast Tumor Xenografts. J. Controlled Release 2015, 205, 144−154. (92) Luan, S.; Zhu, Y.; Wu, X.; Wang, Y.; Liang, F.; Song, S. Hyaluronic-Acid-Based pH-Sensitive Nanogels for Tumor-Targeted Drug Delivery. ACS Biomater. Sci. Eng. 2017, 3, 2410−2419. (93) Ding, L.; Jiang, Y.; Zhang, J.; Klok, H.-A.; Zhong, Z. pHSensitive Coiled-Coil Peptide-Cross-Linked Hyaluronic Acid Nanogels: Synthesis and Targeted Intracellular Protein Delivery to CD44 Positive Cancer Cells. Biomacromolecules 2018, 19, 555−562. (94) Stefanello, T. F.; Couturaud, B.; Szarpak-Jankowska, A.; Fournier, D.; Louage, B.; Garcia, F. P.; Nakamura, C. V.; De Geest, B. G.; Woisel, P.; van der Sanden, B.; Auzély-Velty, R. CoumarinContaining Thermoresponsive Hyaluronic Acid-Based Nanogels as Delivery Systems for Anticancer Chemotherapy. Nanoscale 2017, 9, 12150−12162. (95) Pedrosa, S. S.; Gonçalves, C.; David, L.; Gama, M. A Novel Crosslinked Hyaluronic Acid Nanogel for Drug Delivery. Macromol. Biosci. 2014, 14, 1556−1568. (96) Yang, C.; Wang, X.; Yao, X.; Zhang, Y.; Wu, W.; Jiang, X. Hyaluronic Acid Nanogels with Enzyme-Sensitive Cross-Linking Group for Drug Delivery. J. Controlled Release 2015, 205, 206−217. (97) Khatun, Z.; Nurunnabi, M.; Nafiujjaman, M.; Reeck, G. R.; Khan, H. A.; Cho, K. J.; Lee, Y. A Hyaluronic Acid Nanogel for Photo-Chemo Theranostics of Lung Cancer with Simultaneous LightResponsive Controlled Release of Doxorubicin. Nanoscale 2015, 7, 10680−10689. (98) Highley, C. B.; Prestwich, G. D.; Burdick, J. A. Recent Advances in Hyaluronic Acid Hydrogels for Biomedical Applications. Curr. Opin. Biotechnol. 2016, 40, 35−40. (99) Li, J.; Mooney, D. J. Designing Hydrogels for Controlled Drug Delivery. Nat. Rev. Mater. 2016, 1, 1−17. (100) Wang, H.; Zhu, D.; Paul, A.; Cai, L.; Enejder, A.; Yang, F.; Heilshorn, S. C. Covalently Adaptable Elastin-Like Protein− Hyaluronic Acid (ELP−HA) Hybrid Hydrogels with Secondary Thermoresponsive Crosslinking for Injectable Stem Cell Delivery. Adv. Funct. Mater. 2017, 27, 1605609. (101) Hwang, B. W.; Kim, S. J.; Park, K. M.; Kim, H.; Yeom, J.; Yang, J.-A.; Jeong, H.; Jung, H.; Kim, K.; Sung, Y. C.; Hahn, S. K. Genetically Engineered Mesenchymal Stem Cell Therapy Using SelfN


Perspective

Biomacromolecules ysis: A Prospective, Randomized, Controlled Study. Hum. Reprod. 2003, 18, 1918−1921. (119) Park, J. K.; Yeom, J.; Hahn, S. K.; Hwang, E. J.; Shin, J. S.; Cho, I. H.; Bhang, S. H.; Kim, B.-S. Anti-Coagulating Hydroxyethyl Starch Blended with Hyaluronic Acid as a Novel Post-Surgical Adhesion Barrier. Macromol. Res. 2010, 18, 1076−1080. (120) Miao, T.; Wang, J.; Zeng, Y.; Liu, G.; Chen, X. PolysaccharideBased Controlled Release Systems for Therapeutics Delivery and Tissue Engineering: From Bench to Bedside. Adv. Sci. 2018, 5, 1700513. (121) Bassi, P. F.; Racioppi, M.; Palermo, G.; Selli, C.; Battaglia, M.; Gontero, P.; Simeone, C.; Eisendhardt, A.; Vom Dorp, F.; Neisius, A.; Arjona, M. F.; Castro Diaz, D.; Ramirez Backhaus, M.; Moreno Sierra, J.; Llorente, C.; NohalesTaurines, G.; Giordan, N.; Marinello, A. Oncofid-P-B (Paclitaxel-Hyaluronic Acid) in the Intravesical Therapy of Patients Affected by Primary or Recurrent Ta G1-G2 Papillary Cancer of the Bladder. A Phase II Marker Lesion Study. Eur. Urol., Suppl. 2018, 17, No. e1056. (122) Grigoletto, A.; Maso, K.; Mero, A.; Rosato, A.; Schiavon, O.; Pasut, G. Drug and Protein Delivery by Polymer Conjugation. J. Drug Delivery Sci. Technol. 2016, 32, 132−141. (123) Oh, E. J.; Choi, J.-S.; Kim, H.; Joo, C.-K.; Hahn, S. K. AntiFlt1 Peptide − Hyaluronate Conjugate for the Treatment of Retinal Neovascularization and Diabetic Retinopathy. Biomaterials 2011, 32, 3115−3123.

O


Hyaluronic Acid Derivatives for Translational Medicines

Recommend Documents