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19 pages, 6610 KiB

Open AccessArticle

Hydrodynamics of Intravitreal Injections into Liquid Vitreous Substitutes

by Christin Henein, Sahar Awwad, Nkiruka Ibeanu, Stavros Vlatakis, Steve Brocchini, Peng Tee Khaw and Yann Bouremel

Pharmaceutics 2019, 11(8), 371; https://doi.org/10.3390/pharmaceutics11080371 - 01 Aug 2019

Cited by 17 | Viewed by 5904

Abstract

Intravitreal injections have become the cornerstone of retinal care and one of the most commonly performed procedures across all medical specialties. The impact of hydrodynamic forces of intravitreal solutions when injected into vitreous or vitreous substitutes has not been well described. While computational [...] Read more.

Intravitreal injections have become the cornerstone of retinal care and one of the most commonly performed procedures across all medical specialties. The impact of hydrodynamic forces of intravitreal solutions when injected into vitreous or vitreous substitutes has not been well described. While computational models do exist, they tend to underestimate the starting surface area of an injected bolus of a drug. Here, we report the dispersion profile of a dye bolus (50 µL) injected into different vitreous substitutes of varying viscosities, surface tensions, and volumetric densities. A novel 3D printed in vitro model of the vitreous cavity of the eye was designed to visualize the dispersion profile of solutions when injected into the following vitreous substitutes—balanced salt solution (BSS), sodium hyaluronate (HA), and silicone oils (SO)—using a 30G needle with a Reynolds number (Re) for injection ranging from approximately 189 to 677. Larger bolus surface areas were associated with faster injection speeds, lower viscosity of vitreous substitutes, and smaller difference in interfacial surface tensions. Boluses exhibited buoyancy when injected into standard S1000. The hydrodynamic properties of liquid vitreous substitutes influence the initial injected bolus dispersion profile and should be taken into account when simulating drug dispersion following intravitreal injection at a preclinical stage of development, to better inform formulations and performance. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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10 pages, 2214 KiB

Open AccessArticle

pH-Responsive i-motif Conjugated Hyaluronic Acid/Polyethylenimine Complexes for Drug Delivery Systems

by Gyeong Jin Lee and Tae-il Kim

Pharmaceutics 2019, 11(5), 247; https://doi.org/10.3390/pharmaceutics11050247 - 27 May 2019

Cited by 10 | Viewed by 3565

Abstract

i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated [...] Read more.

i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated to each hyaluronic acid (HA) via amide bond linkages. Synthesis of HA-IBO conjugate (HB) was confirmed by FT-IR and agarose gel electrophoresis with Stains-All staining. After hybridization of HB with i-motif ODN (IMO), it was confirmed that doxorubicin (DOX) could be loaded in HB-IMO hybrid structure (HBIM) with 65.6% of drug loading efficiency (DLE) and 25.0% of drug loading content (DLC). At pH 5.5, prompt and significant DOX release from HBIM was observed due to the disruption of HBIM hybrid structure via i-motif formation of IMO, contrary to pH 7.4 condition. Then, HBIM was complexed with low molecular weight polyethylenimine (PEI1.8k), forming positively charged nanostructures (Z-average size: 126.0 ± 0.4 nm, zeta-potential: 16.1 ± 0.3 mV). DOX-loaded HBIM/PEI complexes displayed higher anticancer efficacy than free DOX in A549 cells, showing the potential for pH-responsive anticancer drug delivery systems. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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14 pages, 2297 KiB

Open AccessArticle

Hyaluronic Acid Nanocapsules as a Platform for Needle-Free Vaccination

by Juan I. Bussio, Carla Molina-Perea and José Vicente González-Aramundiz

Pharmaceutics 2019, 11(5), 246; https://doi.org/10.3390/pharmaceutics11050246 - 26 May 2019

Cited by 16 | Viewed by 4776

Abstract

Vaccination faces many challenges nowadays, and among them the use of adjuvant molecules and needle-free administration are some of the most demanding. The combination of transcutaneous vaccination and nanomedicine through a rationally designed new-formulation could be the solution to this problem. This study [...] Read more.

Vaccination faces many challenges nowadays, and among them the use of adjuvant molecules and needle-free administration are some of the most demanding. The combination of transcutaneous vaccination and nanomedicine through a rationally designed new-formulation could be the solution to this problem. This study focuses on this rational design. For this purpose, new hyaluronic acid nanocapsules (HA-NCs) have been developed. This new formulation has an oily nucleus with immunoadjuvant properties (due to α tocopherol) and a shell made of hyaluronic acid (HA) and decorated with ovalbumin (OVA) as the model antigen. The resulting nanocapsules are smaller than 100 nm, have a negative superficial charge and have a population that is homogeneously distributed. The systems show high colloidal stability in storage and physiological conditions and high OVA association without losing their integrity. The elevated interaction of the novel formulation with the immune system was demonstrated through complement activation and macrophage viability studies. Ex vivo studies using a pig skin model show the ability of these novel nanocapsules to penetrate and retain OVA in higher quantities in skin when compared to this antigen in the control solution. Due to these findings, HA-NCs are an interesting platform for needle-free vaccination. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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20 pages, 3816 KiB

Open AccessArticle

Developing Body-Components-Based Theranostic Nanoparticles for Targeting Ovarian Cancer

by Ravit Edelman, Yehuda G. Assaraf, Anton Slavkin, Tamar Dolev, Tal Shahar and Yoav D. Livney

Pharmaceutics 2019, 11(5), 216; https://doi.org/10.3390/pharmaceutics11050216 - 05 May 2019

Cited by 17 | Viewed by 4056

Abstract

Ovarian cancer mortality is the highest among gynecologic malignancies. Hence, the major challenges are early diagnosis and efficient targeted therapy. Herein, we devised model theranostic nanoparticles (NPs) for combined diagnostics and delivery of chemotherapeutics, targeted to ovarian cancer cells. These NPs were made [...] Read more.

Ovarian cancer mortality is the highest among gynecologic malignancies. Hence, the major challenges are early diagnosis and efficient targeted therapy. Herein, we devised model theranostic nanoparticles (NPs) for combined diagnostics and delivery of chemotherapeutics, targeted to ovarian cancer cells. These NPs were made of natural biocompatible and biodegradable body components: hyaluronic acid (HA) and serum albumin (SA). The hydrophilic HA served as the targeting ligand for cancer cells overexpressing CD44, the HA receptor. SA, the natural carrier of various ligands through the blood, served as the hydrophobic block of the self-assembling block copolymeric Maillard-conjugates. We show the successful construction of fluorescently-labeled SA-HA conjugate-based theranostic NPs, their loading with paclitaxel (PTX) (association constant (8.6 ± 0.8) × 10³ M⁻¹, maximal loading capacity of 4:1 PTX:BSA, and 96% encapsulation efficiency), selective internalization and cytotoxicity to CD44-overexpressing ovarian cancer cells (IC₅₀: 26.4 ± 2.3 nM, compared to 115.0 ± 17.4 of free PTX, and to 58.6 ± 19.7 nM for CD44-lacking cognate ovarian cancer cells). Fluorescein isothiocyanate (FITC) was used for in vitro imaging, whereas long wavelength fluorophores or other suitable tracers would be used for future in vivo diagnostic imaging. Collectively, our findings demonstrate that fluorescent HA-SA NPs harboring a cytotoxic drug cargo can specifically target, label CD44-expressing ovarian cancer cells and efficiently eradicate them. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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15 pages, 3722 KiB

Open AccessArticle

Chitosan-Based Hydrogels Embedded with Hyaluronic Acid Complex Nanoparticles for Controlled Delivery of Bone Morphogenetic Protein-2

by Qing Min, Xiaofeng Yu, Jiaoyan Liu, Jiliang Wu and Ying Wan

Pharmaceutics 2019, 11(5), 214; https://doi.org/10.3390/pharmaceutics11050214 - 04 May 2019

Cited by 20 | Viewed by 3501

Abstract

Chitosan(CH)-poly(dioxanone) (CH-PDO) copolymers containing varied amounts of PDO and having free amino groups at their CH backbone were synthesized using a group protection method. The selected CH-PDO with soluble characteristics in aqueous media was used together with hyaluronic acid (HA) to prepare HA/CH-PDO [...] Read more.

Chitosan(CH)-poly(dioxanone) (CH-PDO) copolymers containing varied amounts of PDO and having free amino groups at their CH backbone were synthesized using a group protection method. The selected CH-PDO with soluble characteristics in aqueous media was used together with hyaluronic acid (HA) to prepare HA/CH-PDO polyelectrolyte complex nanoparticles (NPs) via an ionotropic gelation technique, and such a type of HA/CH-PDO NPs was employed as a carrier for delivering bone morphogenetic protein-2 (BMP-2). The optimal BMP-2-encapsulated HA/CH-PDO NPs with high encapsulation efficiency were embedded into CH/glycerophosphate composite solutions to form different hydrogels in order to achieve long-term BMP-2 release. The formulated gels were found to be injectable at room temperature and had its thermosensitive phase transition near physiological temperature and pH. They also showed abilities to administer the release of BMP-2 in approximately linear manners for a few weeks while effectively preserving the bioactivity of the encapsulated BMP-2. In view of their fully biocompatible and biodegradable components, the presently developed gel systems have promising potential for translation to the clinic use in bone repair and regeneration where the sustained and controlled stimuli from active signaling molecules and the stable biomechanical framework for housing the recruited cells are often concurrently needed. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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35 pages, 7801 KiB

Open AccessArticle

Co-Delivery of Eugenol and Dacarbazine by Hyaluronic Acid-Coated Liposomes for Targeted Inhibition of Survivin in Treatment of Resistant Metastatic Melanoma

by Harshita Mishra, Pawan Kumar Mishra, Zeenat Iqbal, Manu Jaggi, Alka Madaan, Kimi Bhuyan, Namita Gupta, Neha Gupta, Karnika Vats, Ritu Verma and Sushama Talegaonkar

Pharmaceutics 2019, 11(4), 163; https://doi.org/10.3390/pharmaceutics11040163 - 03 Apr 2019

Cited by 40 | Viewed by 4206

Abstract

While melanoma remains a challenge for oncologists, possibilities are being continuously explored to fight resistant metastatic melanoma more effectively. Eugenol is reported to inhibit survivin protein in breast cancer cells. Survivin is also overexpressed by melanoma cells, and is known to impart resistance [...] Read more.

While melanoma remains a challenge for oncologists, possibilities are being continuously explored to fight resistant metastatic melanoma more effectively. Eugenol is reported to inhibit survivin protein in breast cancer cells. Survivin is also overexpressed by melanoma cells, and is known to impart resistance to them against chemotherapy-induced apoptosis. To be able to fight resistant melanoma, we formulated hyaluronic acid (HA)-coated liposomes loaded with an effective combination of anti-melanoma agents (Dacarbazine and Eugenol), using a solvent injection method. Quality-by-Design (QbD) was applied to optimize and obtain a final formulation with the desired quality attributes, and within an acceptable size range. The optimized formulation was then subjected to performance analysis in cell lines. Coated-Dacarbazine Eugenol Liposomes were found to possess 95.08% cytotoxicity at a dacarbazine concentration of 0.5 µg/mL, while Dacarbazine Solution showed only 10.20% cytotoxicity at the same concentration. The number of late apoptotic cells was also found to be much higher (45.16% vs. 8.43%). Furthermore, migration assay and proliferation study also revealed significantly higher inhibition of cell migration and proliferation by Coated-Dacarbazine Eugenol Liposomes, signifying its potential against metastasis. Thus, surface-functionalized dacarbazine- and eugenol-loaded liposomes hold great promise against resistant and aggressive metastatic melanoma, with much less unwanted cytotoxicity and reduced doses of the chemotherapeutic agent. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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19 pages, 2554 KiB

Open AccessArticle

Combination of Zinc Hyaluronate and Metronidazole in a Lipid-Based Drug Delivery System for the Treatment of Periodontitis

by Attila Léber, Mária Budai-Szűcs, Edit Urbán, Péter Vályi, Attila Gácsi, Szilvia Berkó, Anita Kovács and Erzsébet Csányi

Pharmaceutics 2019, 11(3), 142; https://doi.org/10.3390/pharmaceutics11030142 - 25 Mar 2019

Cited by 6 | Viewed by 4354

Abstract

Background: Despite being a highly prevalent disease and a possible contributor to adult tooth loss, periodontitis possesses no well-established therapy. The aim of the recent study was the development and evaluation of a mucoadhesive monophase lipid formulation for the sustained local delivery of [...] Read more.

Background: Despite being a highly prevalent disease and a possible contributor to adult tooth loss, periodontitis possesses no well-established therapy. The aim of the recent study was the development and evaluation of a mucoadhesive monophase lipid formulation for the sustained local delivery of amoxicillin, metronidazole, and/or zinc hyaluronate or gluconate. Methods: To investigate our formulations, differential scanning calorimetry, X-ray diffraction, swelling, erosion, mucoadhesivity, drug release, and antimicrobial measurements were performed. Results: Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results show that the loaded drugs are in a suspended form, the softening of the formulations starts at body temperature, but a part remains solid, providing sustained release. Swelling of the lipid compositions is affected by the hydrophilic components, their concentration, and the strength of the coherent lipid structure, while their erosion is impacted by the emulsification of melted lipid components. Conclusions: Results of drug release and antimicrobial effectiveness measurements show that a sustained release may be obtained. Amoxicillin had higher effectiveness against oral pathogens than metronidazole or zinc hyaluronate alone, but the combination of the two latter could provide similar effectiveness to amoxicillin. The applied mucoadhesive polymer may affect adhesivity, drug release through the swelling mechanism, and antimicrobial effect as well. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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10 pages, 1254 KiB

Open AccessArticle

Evaluation of a Methylcellulose and Hyaluronic Acid Hydrogel as a Vehicle for Rectal Delivery of Biologics

by Andreea Aprodu, Julia Mantaj, Bahijja Raimi-Abraham and Driton Vllasaliu

Pharmaceutics 2019, 11(3), 127; https://doi.org/10.3390/pharmaceutics11030127 - 19 Mar 2019

Cited by 27 | Viewed by 6209

Abstract

Biologics have changed the management of Inflammatory Bowel Disease (IBD), but there are concerns regarding unexpected systemic toxicity and loss of therapeutic response following administration by injection. Local delivery of biologics directly to the inflamed mucosa via rectal enema administration addresses the problems [...] Read more.

Biologics have changed the management of Inflammatory Bowel Disease (IBD), but there are concerns regarding unexpected systemic toxicity and loss of therapeutic response following administration by injection. Local delivery of biologics directly to the inflamed mucosa via rectal enema administration addresses the problems associated with systemic administration. Hydrogels are potentially useful delivery vehicles enabling rectal administration of biologics. Here, we prepared a hydrogel system based on methylcellulose (MC) and hyaluronic acid (HA), which possesses mucosal healing properties, incorporating a model macromolecular drug, namely (fluorescently-labeled) bovine serum albumin (BSA). The BSA-loaded MCHA hydrogel showed temperature-dependent gelation (liquid-like at 20 °C and gel-like at 37 °C) and shear thinning behavior, with these being important and desirable characteristics for rectal application (enabling easy application and retention). BSA release from the MCHA system at 37 °C was linear, with 50% of the loaded drug released within 2 h. The system demonstrated acceptable toxicity towards intestinal (colon) Caco-2 epithelial cells, even at high concentrations. Importantly, application of the BSA-loaded MCHA hydrogel to polarized Caco-2 monolayers, with or without an exemplar absorption enhancer, resulted in transintestinal permeability of BSA. The study therefore indicates that the MCHA hydrogel shows potential for topical (rectal) delivery of biologics in IBD. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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12 pages, 2215 KiB

Open AccessArticle

Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34)

by Chihiro Naito, Hidemasa Katsumi, Tomoko Suzuki, Ying-shu Quan, Fumio Kamiyama, Toshiyasu Sakane and Akira Yamamoto

Pharmaceutics 2018, 10(4), 215; https://doi.org/10.3390/pharmaceutics10040215 - 04 Nov 2018

Cited by 35 | Viewed by 4672

Abstract

Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) [...] Read more.

Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) for the treatment of osteoporosis. PTH-loaded MNs, with needle length 800 µm, were fabricated via a micro-molding method. The stability of PTH in MNs was found to be 6-fold higher than that of PTH solution when stored at room temperature (15–20 °C) for one month. Micron-scale pores were clearly visible in rat skin following application of PTH-loaded MNs. PTH-loaded MNs were completely dissolved by 60 min following application to rat skin. The bioavailability (BA) of PTH relative to subcutaneous injection was 100 ± 4% following application of PTH-loaded MNs in rats. In addition, PTH-loaded MNs were found to effectively suppress decreases in bone density in a rat model of osteoporosis. Furthermore, no skin irritation was observed at the site of application in rats. These findings indicate that our dissolving MNs have a potential use in formulations for the transdermal delivery of PTH and for the treatment of osteoporosis. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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Review

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25 pages, 9872 KiB

Open AccessReview

Design of Soft Nanocarriers Combining Hyaluronic Acid with Another Functional Polymer for Cancer Therapy and Other Biomedical Applications

by Marlène Rippe, Vanina Cosenza and Rachel Auzély-Velty

Pharmaceutics 2019, 11(7), 338; https://doi.org/10.3390/pharmaceutics11070338 - 15 Jul 2019

Cited by 17 | Viewed by 4472

Abstract

The rapid advancement in medicine requires the search for new drugs, but also for new carrier systems for more efficient and targeted delivery of the bioactive molecules. Among the latter, polymeric nanocarriers have an increasingly growing potential for clinical applications due to their [...] Read more.

The rapid advancement in medicine requires the search for new drugs, but also for new carrier systems for more efficient and targeted delivery of the bioactive molecules. Among the latter, polymeric nanocarriers have an increasingly growing potential for clinical applications due to their unique physical and chemical characteristics. In this regard, nanosystems based on hyaluronic acid (HA), a polysaccharide which is ubiquitous in the body, have attracted particular interest because of the biocompatibility, biodegradability and nonimmunogenic property provided by HA. Furthermore, the fact that hyaluronic acid can be recognized by cell surface receptors in tumor cells, makes it an ideal candidate for the targeted delivery of anticancer drugs. In this review, we compile a comprehensive overview of the different types of soft nanocarriers based on HA conjugated or complexed with another polymer: micelles, nanoparticles, nanogels and polymersomes. Emphasis is made on the properties of the polymers used as well as the synthetic approaches for obtaining the different HA-polymer systems. Fabrication, characterization and potential biomedical applications of the nanocarriers will also be described. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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19 pages, 882 KiB

Open AccessReview

Biomedical Applications of Hyaluronic Acid-Based Nanomaterials in Hyperthermic Cancer Therapy

by Subin Kim, Myeong ju Moon, Suchithra Poilil Surendran and Yong Yeon Jeong

Pharmaceutics 2019, 11(7), 306; https://doi.org/10.3390/pharmaceutics11070306 - 01 Jul 2019

Cited by 28 | Viewed by 4828

Abstract

Hyaluronic acid (HA) is a non-sulfated polysaccharide polymer with the properties of biodegradability, biocompatibility, and non-toxicity. Additionally, HA specifically binds to certain receptors that are over-expressed in cancer cells. To maximize the effect of drug delivery and cancer treatment, diverse types of nanomaterials [...] Read more.

Hyaluronic acid (HA) is a non-sulfated polysaccharide polymer with the properties of biodegradability, biocompatibility, and non-toxicity. Additionally, HA specifically binds to certain receptors that are over-expressed in cancer cells. To maximize the effect of drug delivery and cancer treatment, diverse types of nanomaterials have been developed. HA-based nanomaterials, including micelles, polymersomes, hydrogels, and nanoparticles, play a critical role in efficient drug delivery and cancer treatment. Hyperthermic cancer treatment using HA-based nanomaterials has attracted attention as an efficient cancer treatment approach. In this paper, the biomedical applications of HA-based nanomaterials in hyperthermic cancer treatment and combined therapies are summarized. HA-based nanomaterials may become a representative platform in hyperthermic cancer treatment. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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22 pages, 6033 KiB

Open AccessReview

Hyaluronic Acid-Coated Nanomedicine for Targeted Cancer Therapy

by Kibeom Kim, Huyeon Choi, Eun Seong Choi, Myoung-Hwan Park and Ja-Hyoung Ryu

Pharmaceutics 2019, 11(7), 301; https://doi.org/10.3390/pharmaceutics11070301 - 30 Jun 2019

Cited by 108 | Viewed by 10098

Abstract

Hyaluronic acid (HA) has been widely investigated in cancer therapy due to its excellent characteristics. HA, which is a linear anionic polymer, has biocompatibility, biodegradability, non-immunogenicity, non-inflammatory, and non-toxicity properties. Various HA nanomedicines (i.e., micelles, nanogels, and nanoparticles) can be prepared easily using [...] Read more.

Hyaluronic acid (HA) has been widely investigated in cancer therapy due to its excellent characteristics. HA, which is a linear anionic polymer, has biocompatibility, biodegradability, non-immunogenicity, non-inflammatory, and non-toxicity properties. Various HA nanomedicines (i.e., micelles, nanogels, and nanoparticles) can be prepared easily using assembly and modification of its functional groups such as carboxy, hydroxy and N-acetyl groups. Nanometer-sized HA nanomedicines can selectively deliver drugs or other molecules into tumor sites via their enhanced permeability and retention (EPR) effect. In addition, HA can interact with overexpressed receptors in cancer cells such as cluster determinant 44 (CD44) and receptor for HA-mediated motility (RHAMM) and be degraded by a family of enzymes called hyaluronidase (HAdase) to release drugs or molecules. By interaction with receptors or degradation by enzymes inside cancer cells, HA nanomedicines allow enhanced targeting cancer therapy. In this article, recent studies about HA nanomedicines in drug delivery systems, photothermal therapy, photodynamic therapy, diagnostics (because of the high biocompatibility), colloidal stability, and cancer targeting are reviewed for strategies using micelles, nanogels, and inorganic nanoparticles. Full article

(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)

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