Enhancing the transdermal penetration of nanoconstructs: could hyaluronic acid be the key?

Abstract

NanomedicineVol. 9, No. 6 EditorialFree AccessEnhancing the transdermal penetration of nanoconstructs: could hyaluronic acid be the key?Ho Sang Jung, Ki Su Kim, Seok Hyun Yun & Sei Kwang HahnHo Sang JungDepartment of Materials Science & Engineering, Pohang University of Science & Technology (POSTECH), San 31, Hyoja‐dong, Nam‐gu, Pohang, Kyungbuk 790‐784, KoreaSearch for more papers by this author, Ki Su KimWellman Center for Photomedicine, Department of Dermatology, Harvard Medical School & Massachusetts General Hospital, 65 Landsdowne St UP‐5, Cambridge, MA 02139, USASearch for more papers by this author, Seok Hyun YunWellman Center for Photomedicine, Department of Dermatology, Harvard Medical School & Massachusetts General Hospital, 65 Landsdowne St UP‐5, Cambridge, MA 02139, USASearch for more papers by this author & Sei Kwang Hahn*Author for correspondence: E-mail Address: skhanb@postech.ac.krDepartment of Materials Science & Engineering, Pohang University of Science & Technology (POSTECH), San 31, Hyoja‐dong, Nam‐gu, Pohang, Kyungbuk 790‐784, KoreaSearch for more papers by this authorPublished Online:1 Jul 2014https://doi.org/10.2217/nnm.14.47AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: hyaluronic acidnanoconstructsnanomedicinestransdermal deliveryNanoconstructs, such as liposomes, polymeric micelles, gold nanoparticles, carbon nanomaterials and nanocrystalline quantum dots, have been widely investigated for diagnostic, bioimaging and therapeutic applications [1]. Nanoconstructs have been also extensively explored in the field of dermatology. For example, liposomes and polymeric nanoparticles loaded with drugs were applied as topical administration agents for the treatment of skin diseases such as psoriasis, dermatitis and skin cancer [2,3]. Titanium dioxide and zinc oxide (ZnO) nanoparticles have been used as sun‐screen formulation for the protection of skin from UV by the scattering, absorption and reflection of UV [4]. Silver nanoparticles are commercially used as wound and burn dressing agents with antibacterial effects [5]. Quantum dots and ZnO nanoparticles were utilized as bioimaging agents for the diagnosis of skin diseases [6,7]. Moreover, gold nanoconstructs and carbon nanomaterials have been actively investigated as promising agents for the photothermal ablation therapy of skin cancers due to their high light‐to‐heat conversion capability [8,9].For further applications of nanoconstructs in dermatology, we need efficient transdermal delivery carriers of the nanoconstructs. The transdermal delivery has several advantages over other administration routes, such as oral delivery and needle based injection. The advantages include noninvasive treatment, self‐administration, improved patient compliance and avoidance of hepatic first‐pass metabolism or digestion system [10]. Despite these benefits, the low skin permeability of nanoconstructs such as polymers, proteins, hydrophilic drugs and nanoparticles limited their wide applications to the transdermal delivery. To facilitate the transdermal delivery of nanoconstructs, additional treatments have been adopted using penetration enhancers, iontophoresis, ultrasound and microneedles [11]. However, these methods require physical perturbations to the skin tissue, causing skin damage in some cases [12]. A noninvasive molecular carrier for transdermal delivery would have compelling advantages. The understanding for the characteristics of skin layers can be a good starting point for the development of transdermal delivery carriers of nanoconstructs.Stratum corneum (SC), the outermost skin layer, is the main barrier composed of densely packed dead cells forming hydrophobic surfaces. For the penetration of hydrophobic SC, hydrophobic molecules have clear benefits over hydrophilic molecules. The hydrophobic molecules can infiltrate into densely packed lipid layers in SC. However, nanoconstructs are usually formulated to have hydrophilic surfaces enhancing the physiological stability in the biological conditions. This contradicting requirement of hydrophobicity and hydrophilicity for transdermal delivery should be reconciled to enhance the physiological stability and the skin permeability by lipid disruption in SC.Recently, hyaluronic acid (HA) has been investigated as a promising transdermal delivery carrier. HA is a naturally occurring linear polysaccharide composed of repeating units of d‐glucuronic acid and N‐acetyl‐d‐glucosamine. HA is abundant in the epithelial, connective and neural tissues. HA is biocompatible, biodegradable, nonimmunogenic and nontoxic. HA has been regarded as one of the best biopolymers for biomedical applications including drug delivery and tissue engineering. HA is one of the major components in the skin and plays an important role in extracellular matrix. HA also participates in tissue hydrodynamics, cell movement and proliferation, and interactions with a variety of cells with HA receptors like CD44 and RHAMM. Furthermore, HA is viscoelastic and hygroscopic enabling cosmetic and cosmeceutical applications. Brown et al. reported that radiolabeled HA with a high molecular weight of 360–400 kDa could pass through SC, epidermis and dermis layers of mouse and human skins [13]. Interestingly, high-molecular-weight HA was reported to inhibit the malignant tumor progression [14]. The antitumor effect of HA can contribute to the treatment of skin cancers using HA conjugated with various anticancer drugs.Although the exact mechanism for the transdermal delivery of HA derivatives is not fully proven yet, there are possible reasons and evidences for the transdermal delivery of HA derivatives across the skin barrier. First, HA is a hygroscopic polyanion that keeps high water content within its structural backbone. The skin hydration is important for the enhancement of skin permeability. When SC is exposed to water, the tissue swells and forms paths for the molecular transport into the skin. HA derivatives can hydrate SC, opening penetration routes and facilitating transdermal delivery of tethered cargos. Along with biocompatibility, viscoelasticity and antiwrinkle effect, the ability to hydrate the skin has made HA as a unique molecule for various cosmetic and cosmeceutical applications.Second, HA is an amphiphilic liner polysaccharide at the molecular level. HA is well known as one of the hydrophilic polysaccharides, but structural analysis has revealed at the molecular level that there is a hydrophobic patch domain consisting of eight CH groups [15]. In addition, NMR and rotary‐shadowing electron microscopy showed that hydrophobic patch domain of HA could make a complex with phospholipids [16,17]. The structural hydrophobic patch domain of HA may interact with lipid components in SC during penetration and disrupt skin barriers, enhancing the skin permeability of HA derivatives. Similarly, gold nanoparticle was reported to disrupt SC by the interaction of lipid–gold nanoparticle [18]. We previously compared the transdermal delivery of HA conjugated nanographene oxide (NGO) and polyethylene glycol conjugated NGO in normal and cancer model mice [9]. While the nonfouling polyethylene glycol inhibited the skin penetration of NGO in both normal and cancer model mice, HA conjugated NGO with a dimension of 200 nm appeared to be transdermally delivered through the cancerous skin.Third, HA receptors on skin resident cells facilitate the transdermal delivery of HA derivatives. HA receptors are highly expressed in the keratinocytes in epidermis and fibroblasts in dermis. We previously visualized the transdermal delivery of HA–human growth hormone (hGH) conjugate in Balb/c mice [11]. After topical delivery of HA derivatives, the HA receptor mediated internalization into skin cells appeared to facilitate the transdermal delivery of HA derivatives, forming the concentration gradient from the top to the bottom of skin tissues. The bioavailability of hGH in the HA–hGH conjugate after transdermal delivery was as high as 15%, reflecting the feasibility of HA as a promising transdermal delivery carrier of protein drugs. The transdermal delivery of HA derivatives was more efficient in cancerous skin. On the surface of skin cancer cells, especially melanoma, highly expressed HA receptors can internalize HA derivatives via the HA receptor mediated endocytosis. The effective transdermal delivery of HA–NGO conjugates for the photothermal ablation therapy of skin cancer might be also related with HA receptors locally overexpressed around cancerous skin tissues. The transdermally delivered HA–NGO accumulated specifically in leaky and damaged skin cancer regions, and the near-infrared laser irradiation successfully ablated the tumor tissues [9].In summary, with the development of various nanoconstructs, their transdermal delivery has been actively investigated for facile biomedical applications. HA could be the key molecule to enhance the transdermal penetration of nanoconstructs by the synergetic effect of the following factors. The hygroscopic HA molecules hydrate skin tissues and open the transdermal pathway of conjugated cargos. The structural hydrophobic patch domains in HA molecule help the penetration of HA and its cargo disrupting lipid structure of SC. HA receptors expressed on skin cells and highly expressed HA receptors on cancerous skin cells can facilitate the continuous penetration of HA derivatives via the HA receptor mediated internalization into the cells. Taken together, HA can be used as a promising transdermal delivery carrier of nanoconstructs for diagnostic and therapeutic applications.Financial & competing interests disclosureThis work was financially supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009‐0081871). This study was also supported by Mid‐career Researcher Program through NRF grant funded by the MEST (No. 2012R1A2A2A06045773). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Kim BYS, Rutka JT, Chan WCW. Nanomedicine. N. Engl. J. Med. 363, 2434–2443 (2010).Crossref, Medline, CAS, Google Scholar2 Schafer‐Korting M, Mehnert W, Korting HC. Lipid nanoparticles for improved topical application of drugs for skin diseases. Adv. Drug Deliv. Rev. 59, 427–443 (2007).Crossref, Medline, Google Scholar3 Zhang Z, Tsai PC, Ramezanli T et al. Polymeric nanoparticles‐based topical delivery systems for the treatment of dermatological diseases. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 5, 205–218 (2013).Crossref, Medline, CAS, Google Scholar4 Nel A, Xia T, Madler L et al. Toxic potential of materials at the nanolevel. Science 311, 622–627 (2006).Crossref, Medline, CAS, Google Scholar5 Kumar A, vemula PK, Ajayan PM et al. Silver‐nanoparticle‐embedded antimicrobial paints based on vegetable oil. Nat. Mater. 7, 236–241 (2008).Crossref, Medline, CAS, Google Scholar6 Larson DR, Zipfel WR, Williams RM et al. Water‐soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 300, 1434–1436 (2003).Crossref, Medline, CAS, Google Scholar7 Kuo TR, Wu CL, Hsu CT et al. Chemical enhancer induced changes in the mechanisms of transdermal delivery of zinc oxide nanoparticles. Biomaterials 30, 3002–3008 (2009).Crossref, Medline, CAS, Google Scholar8 Lu W, Xiong C, Zhang G et al. Targeted photothermal ablation of murine melanomas with melanocyte‐stimulating hormon analog‐conjugated hollow gold nanospheres. Clin. Cancer Res. 15, 876–886 (2009).Crossref, Medline, CAS, Google Scholar9 Jung HS, Kong WH, Sung DK et al. Nanographene oxide‐hyaluronic acid conjugate for photothermal ablation therapy of skin cancer. ACS Nano 8, 260–268 (2014).Crossref, Medline, CAS, Google Scholar10 Prausnitz MR, Langer R. Transdermal drug delivery. Nat. Biotechnol. 26, 1261–1268 (2008).Crossref, Medline, CAS, Google Scholar11 Yang JA, Kim ES, Kwon JH et al. Transdermal delivery of hyaluronic acid – human growth hormone conjugate. Biomaterials 33, 5947–5954 (2012).Crossref, Medline, CAS, Google Scholar12 Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nat. Rev. Drug. Discov. 3, 115–124 (2004).Crossref, Medline, CAS, Google Scholar13 Brown TJ, Alcom D, Fraser JR. Absorption of hyaluronan applied to the surface of intact skin. J. Invest. Dermatol. 113, 740–746 (1999).Crossref, Medline, CAS, Google Scholar14 Tian X, Azpurua J, Hine C et al. High‐molecular‐mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346–349 (2013).Crossref, Medline, CAS, Google Scholar15 Brown MB, Jones SA. Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. J. Eur. Acad. Dermatol. Venerol. 19, 308–318 (2005).Crossref, Medline, CAS, Google Scholar16 Ghosh P, Hutadilok N, Adam N et al. Interactions of hyaluronan (hyaluronic acid) with phospholipids as determined by gel permeation chromatography, multi‐angle laser‐light‐scattering photometry and 1H‐NMR spectroscopy. Int. J. Biol. Macromol. 16, 237–244 (1994).Crossref, Medline, CAS, Google Scholar17 Pasquali‐Ronchetti I, Quaglino D, Mori G et al. Hyaluronan–phospholipid interactions. J. Struct. Biol. 120, 1–10 (1997).Crossref, Medline, CAS, Google Scholar18 Huang Y, Yu F, Park YS et al. Co‐administration of protein drugs with gold nanoparticles to enable percutaneous delivery. Biomaterials 31, 9086–9091 (2010).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByNovel drug delivery systems based on silver nanoparticles, hyaluronic acid, lipid nanoparticles and liposomes for cancer treatment23 August 2021 | Applied Nanoscience, Vol. 12, No. 11An update on biomaterials as microneedle matrixes for biomedical applications1 January 2022 | Journal of Materials Chemistry B, Vol. 10, No. 32Pectin nanogel formation via thiol-norbornene photo-click chemistry for transcutaneous antigen deliveryJournal of Industrial and Engineering Chemistry, Vol. 108Rationalizing the Design of Hyaluronic Acid-Decorated Liposomes for Targeting Epidermal Layers: A Combination of Molecular Dynamics and Experimental Evidence27 September 2021 | Molecular Pharmaceutics, Vol. 18, No. 11Repurposing pentosan polysulfate sodium as hyaluronic acid linked polyion complex nanoparticles for the management of osteoarthritis: A potential approachMedical Hypotheses, Vol. 321Formulation‐based approaches for dermal delivery of vaccines and therapeutic nucleic acids: Recent advances and future perspectives4 May 2021 | Bioengineering & Translational Medicine, Vol. 6, No. 3Galactosylated chitosan-modified ethosomes combined with silk fibroin nanofibers is useful in transcutaneous immunizationJournal of Controlled Release, Vol. 327Co-hybridized composite nanovesicles for enhanced transdermal eugenol and cinnamaldehyde delivery and their potential efficacy in ulcerative colitisNanomedicine: Nanotechnology, Biology and Medicine, Vol. 28Applications and delivery mechanisms of hyaluronic acid used for topical/transdermal delivery – A reviewInternational Journal of Pharmaceutics, Vol. 578Proniosomes: the effective and efficient drug-carrier systemTherapeutic Delivery, Vol. 11, No. 2Elastic liposomes and other vesiclesTranscutol® P/Cremophor® EL/Ethyl Oleate–Formulated Microemulsion Loaded into Hyaluronic Acid–Based Hydrogel for Improved Transdermal Delivery and Biosafety of Ibuprofen10 December 2019 | AAPS PharmSciTech, Vol. 21, No. 1Nanotechnology advances towards development of targeted-treatment for obesity16 December 2019 | Journal of Nanobiotechnology, Vol. 17, No. 1Hyaluronic Acid Nanocapsules as a Platform for Needle-Free Vaccination26 May 2019 | Pharmaceutics, Vol. 11, No. 5Azelaic acid-loaded nanoemulsion with hyaluronic acid – a new strategy to treat hyperpigmentary skin disorders28 January 2019 | Drug Development and Industrial Pharmacy, Vol. 45, No. 4Hyaluronic acid-containing ethosomes as a potential carrier for transdermal drug deliveryColloids and Surfaces B: Biointerfaces, Vol. 172Hyaluronic acid modified nanostructured lipid carriers for transdermal bupivacaine delivery: In vitro and in vivo anesthesia evaluationBiomedicine & Pharmacotherapy, Vol. 98Upconversion Nanoparticles/Hyaluronate–Rose Bengal Conjugate Complex for Noninvasive Photochemical Tissue Bonding15 September 2017 | ACS Nano, Vol. 11, No. 10Getting Drugs Across Biological Barriers28 July 2017 | Advanced Materials, Vol. 29, No. 37Hyaluronate and its derivatives for customized biomedical applicationsBiomaterials, Vol. 123Considerations in the use of microneedles: pain, convenience, anxiety and safety30 June 2016 | Journal of Drug Targeting, Vol. 25, No. 1Hyaluronate modified upconversion nanoparticles for near infrared light-triggered on–off tattoo systems1 January 2017 | RSC Advances, Vol. 7, No. 24Nanoparticle Targeting CD44-Positive Cancer Cells for Site-Specific Drug Delivery in Prostate Cancer Therapy7 November 2016 | ACS Applied Materials & Interfaces, Vol. 8, No. 45Hyaluronate—Epidermal Growth Factor Conjugate for Skin Wound Healing and Regeneration3 November 2016 | Biomacromolecules, Vol. 17, No. 11Stimuli-sensitive thiolated hyaluronic acid based nanofibers: synthesis, preclinical safety and in vitro anti-HIV activityVivek Agrahari, Jianing Meng, Miezan JM Ezoulin, Ibrahima Youm, Daniel C Dim, Agostino Molteni, Wei-Ting Hung, Lane K Christenson & Bi-Botti C Youan27 October 2016 | Nanomedicine, Vol. 11, No. 22 Vol. 9, No. 6 Follow us on social media for the latest updates Metrics History Published online 1 July 2014 Published in print May 2014 Information© Future Medicine LtdKeywordshyaluronic acidnanoconstructsnanomedicinestransdermal deliveryFinancial & competing interests disclosureThis work was financially supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009‐0081871). This study was also supported by Mid‐career Researcher Program through NRF grant funded by the MEST (No. 2012R1A2A2A06045773). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download