Thermosensitive hydrogels for drug delivery

INTRODUCTION: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels. AREAS COVERED: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration. EXPERT OPINION: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Characterization of Methacrylated Inulin Hydrogels Designed for Colon Targeting: In Vitro Release of BSA

Purpose. To characterize methacrylated inulin hydrogels with respect to their release properties. Methods. Proteins (bovine serum albumin or lysozyme) were used as model drugs and were loaded during or after hydrogel formation. Parameters such as the drug loading method, the molecular weight of the proteins, the initial drug loading concentration, the hydrogel feed composition, degree of substitution, and size of the hydrogel were investigated by determining the release of the model proteins from the hydrogels in a phosphate buffer solution. The biodegradable properties were investigated by studying the release of bovine serum albumin in a solution of inulinase. Results. In vitro protein release from methacrylated hydrogels was influenced by factors such as the drug loading procedure and the molecular weight and loading concentration of the proteins. The feed composition and degree of substitution of inulin seem to be crucial in controlling both the extent and the rate of release. Protein release was clearly enhanced in the presence of inulinase, indicating the biodegradable properties of methacrylated inulin hydrogels. Conclusions. Several hydrogels show interesting properties with respect to the development of a colon-specific drug delivery system.     

Novel thermosensitive hydrogels based on methoxy polyethylene glycol-co-poly(lactic acid-co-aromatic anhydride) for cefazolin delivery

Thermosensitive micelles composed of a copolymer of methoxy polyethylene glycol (mPEG), polylactic acid (PLA), and 1,6-bis (p-carboxyphenoxy) hexane (CPH), namely methoxy polyethylene glycol-co-polylactic acid-co-aromatic anhydride (mPEG-PLCPHA), were fabricated for application as a promising hydrophilic drug carrier. The copolymer can self-assemble into micelles in PBS by hydrophobic interaction. The diameters of these micelles increased as the environmental temperature increased. An increase in viscosity with sol-to-gel transition occurred as temperature increased from room temperature to body temperature. During the in vitro degradation process, hydrogels demonstrated a more stable degradation rate. Both in vitro and in vivo cytotoxicity results showed that the materials had excellent biocompatibility due to less acidic products formation. In vitro cefazolin release profiles showed a stable release for 30 days. The hydrogel encapsulated cefazolin exhibited a good antibacterial effect. Based on these results, mPEG-PLCPHA can serve as an injectable depot gel for drug delivery.From the Clinical EditorIn this study, thermosensitive hydrogel encapsulated cefazolin was found to exhibit good antibacterial effects with sustained levels for up to 30 days, enabling the development of an injectable depot gel for long-term drug delivery.     

Hydrogels: Swelling,Drug Loading,and Release

Hydrogels have been used by many investigators in controlled-release drug delivery systems because of their good tissue compatibility and easy manipulation of swelling level and, thereby, solute permeability. The desired kinetics, duration, and rate of solute release from hydrogels are limited to specific conditions, such as hydrogel properties, amount of incorporated drug, drug solubility, and drug–polymer interactions. This review summarizes the compositional and structural effects of polymers on swelling, loading, and release and approaches to characterize solute release behavior in a dynamic state. A new approach is introduced to compensate drug effects (solubility and loading) with the release kinetics by varying the structure of heterogeneous polymers. Modulated or pulsatile drug delivery using functional hydrogels is a recent trend in hydrogel drug delivery.     

Hydrogels in controlled release formulations: network design and mathematical modeling

Over the past few decades, advances in hydrogel technologies have spurred development in many biomedical applications including controlled drug delivery. Many novel hydrogel-based delivery matrices have been designed and fabricated to fulfill the ever-increasing needs of the pharmaceutical and medical fields. Mathematical modeling plays an important role in facilitating hydrogel network design by identifying key parameters and molecule release mechanisms. The objective of this article is to review the fundamentals and recent advances in hydrogel network design as well as mathematical modeling approaches related to controlled molecule release from hydrogels. In the first section, the niche roles of hydrogels in controlled release, molecule release mechanisms, and hydrogel design criteria for controlled release applications are discussed. Novel hydrogel systems for drug delivery including biodegradable, smart, and biomimetic hydrogels are reviewed in the second section. Several mechanisms have been elucidated to describe molecule release from polymer hydrogel systems including diffusion, swelling, and chemically-controlled release. The focus of the final part of this article is discussion of emerging hydrogel delivery systems and challenges associated with modeling the performance of these devices.     

Hydrogels for lentiviral gene delivery

Introduction: Gene delivery from hydrogel biomaterials provides a fundamental tool for a variety of clinical applications including regenerative medicine, gene therapy for inherited disorders and drug delivery. The high water content and mild gelation conditions of hydrogels support their use for gene delivery by preserving activity of lentiviral vectors and acting to shield vectors from any host immune response.

Areas covered: Strategies to control lentiviral entrapment within and retention/release from hydrogels are reviewed. The authors discuss the ability of hydrogel design parameters to control the transgene expression profile and the capacity of hydrogels to protect vectors from (and even modulate) the host immune response.

Expert opinion: Delivery of genetic vectors from scaffolds provides a unique opportunity to capitalize on the potential synergy between the biomaterial design for cell processes and gene delivery. Hydrogel properties can be tuned to directly control the events that determine the tissue response to controlled gene delivery, which include the extent of cell infiltration, preservation of vector activity and vector retention. While some design parameters have been identified, numerous opportunities for investigation are available in order to develop a complete model relating the biomaterial properties and host response to gene delivery.     

The delivery of platinum drugs from thermosensitive hydrogels containing different ratios of chitosan

New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were prepared and evaluated for use in the delivery of the platinum drugs, cisplatin and carboplatin. The effects of polymers containing different ratios of chitosan on the physicochemical and drug release characteristics were examined. The sol-gel transition temperature of the hydrogels was determined by differential scanning calorimetry (DSC) and viscometry. Discrepancies in the transition temperature among the various polymer systems were more pronounced when determined by viscosity compared by DSC, with the CPN showing a higher transition temperature than PNIPAAm. The cross-sectional structure and surface topography of the hydrogels were examined by scanning electronic microscopy (SEM) and atomic force microscopy (AFM), respectively. The incorporation of chitosan further increased the entanglement of the hydrogel network. An increase in the chitosan ratio in the polymers (CPN-H) also increased the cross-linking structure. A smoother surface of hydrogel matrices was observed for CPN compared with PNIPAAm. All hydrogels tested significantly reduced drug release compared with an aqueous solution. The release rate of platinum drugs from PNIPAAm was retarded at the late stage. CPN matrices could continuously deliver platinum drugs during the experiment. The rate of release from CPN-H was generally slower than that from hydrogels and had a lower chitosan ratio (CPN-L), presumably due to the more-tortuous pathways in the hydrogels. Thermosensitive hydrogels like those prepared in this study may be a promising carrier for the delivery of platinum drugs, as the drug release can be controlled and sustained using CPN networks.     

Physical hydrogels with self-assembled nanostructures as drug delivery systems

Introduction: As an essential complement to chemically crosslinked hydrogels, drug delivery systems based on physical hydrogels with self-assembled nanostructures are gaining increasing attention, owing to potential advantages of reduced toxicity, convenience of in situ gel formation, stimuli-responsiveness, reversible sol-gel transition, and improved drug loading and delivery profiles.

Areas covered: In this review, drug delivery systems based on physical hydrogels are discussed according to their self-assembled nanostructures, such as micelles, layer-by-layer constructs, supramolecular inclusion complexes, polyelectrolyte complexes and crystalline structures. The driving forces of the self-assembly include hydrophobic interaction, hydrogen bonding, electrostatic interaction, π–π stacking and weak van der Waals forces. Stimuli-responsive properties of physical hydrogels, including thermo- and pH-sensitivity, are considered with particular focus on self-assembled nanostructures.

Expert opinion: Fabricating self-assembled nanostructures in drug delivery hydrogels, via physical interactions between polymer–polymer and polymer–drug, requires accurately controlled macro- or small molecular architecture and a comprehensive knowledge of the physicochemical properties of the therapeutics. A variety of nanostructures within hydrogels, with which payloads may interact, provide useful means to stabilize the drug form and control its release kinetics.     

Pharmacokinetic Evaluation of Thermosensitive Sustained Release Formulations Developed for Subcutaneous Delivery of Protein Therapeutics

Injectable, thermosensitive hydrogels, constructed from cross-linked polymers, can offset the limitations of other sustained release delivery systems, overcome constrains of available therapies, and improve patient compliance to chronic therapy. The goal of this project was to identify and evaluate such sustained release, in situ formulations that can help achieve prolonged exposure of protein therapeutics with a short systemic half-life. Natural polymers were used to develop injectable, thermosensitive in situ hydrogels and single-chain variable fragment (scFv) of trastuzumab was used as the model protein with a short half-life. The three polymer combinations tested were: (1) Chitosan and β-glycerophosphate, (2) Chitosan, β-glycerophosphate, and Hyaluronic Acid, and (3) Hyaluronic Acid and Dextran. In vitro drug release experiments were conducted, using different combinations of various polymer concentrations and different drug loading amounts, to identify optimal combinations with prolonged and controlled drug release while exhibiting minimal burst release effect. Select formulations were injected subcutaneously in normal mice to evaluate the pharmacokinetics of scFv for 14 days and identify drug release kinetics in vivo. A two-compartment PK model was also established to quantitatively characterize the release kinetics and disposition of scFv following in vivo administration of the hydrogels. The scFv was undetectable in plasma after 4 and 24 hours following intravenous and subcutaneous administration, respectively. However, all three hydrogel systems were found to provide controlled release of scFv in vivo and maintain detectable concentrations of scFv for at least 14 days. The results suggested that subcutaneous injection of thermosensitive in situ hydrogels may be used to achieve sustained exposure of protein therapeutics which have a very short half-life and thus require frequent administration.     

Synthesis,physicochemical properties and ocular pharmacokinetics of thermosensitive in situ hydrogels for ganciclovir in cytomegalovirus retinitis treatment

Ganciclovir (GCV) is one of the most widely used antiviral drugs for the treatment of cytomegalovirus (CMV) retinitis. In this context, the aim of this study was to design in situ thermosensitive hydrogels for GCV ocular delivery by intravitreal injection to achieve sustained drug release behavior and improved ocular bioavailability in the treatment of CMV retinitis. A thermosensitive poly-(β-butyrolactone-co-lactic acid)-polyethylene glycol-poly (β-butyrolactone-co-lactic acid) (PBLA-PEG-PBLA) triblock copolymer was synthesized by ring-opening polymerization and characterization. The GCV-loaded PBLA-PEG-PBLA in situ hydrogels (15%, w/w) were then prepared with drug concentration at 2?mg·mL^?1 and the gelation temperatures, rheological properties, in vitro degradation and syringeability of in situ hydrogels for intravitreal injection were also investigated. Membraneless dissolution model was used to explore drug release behavior of PBLA-PEG-PBLA in situ hydrogel. The results indicated that more than 45 and 85% of GCV can be released within 24 and 96?h, respectively, which was verified by a non-Fickian diffusion mechanism. In vivo ocular pharmacokinetics study showed that area under drug-time curve (AUC) and half-life of PBLA-PEG-PBLA in situ hydrogel was higher (AUC was 61.80?μg·mL^?1·h (p?t_1/2 was 10.29?h in aqueous humor; AUC was 1008.66?μg·mL^?1·h (p?t_1/2 was 13.26?h (p?in situ hydrogel is a promising carrier of GCV for intravitreal injection.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Galactosylated chitosan-g-PEI/DNA complexes-loaded poly(organophosphazene) hydrogel as a hepatocyte targeting gene delivery system

Hydrogels are widely used in drug delivery systems because they can control the release and thereby enhance the efficiency of locally delivered bioactive molecules such as therapeutic drugs, proteins, or genes. For gene delivery, localized release of plasmid DNA or polymer/DNA complexes can transfect cells and produce sustained protein production. We tested the galactosylated chitosan-graft-polyethylenimine (GC-g-PEI)/DNA complexes-loaded poly(organophosphazene) thermosensitive biodegradable hydrogel as a hepatocyte targeting gene delivery system. The poly(organophosphazene) hydrogel loaded with GC-g-PEI/DNA complexes showed low cytotoxicity and higher transfection efficiency than PEI/DNA complexes, as well as good hepatocyte specificity in vitro and in vivo. Our results indicate that poly(organophosphazene) hydrogels loaded with GC-g-PEI/DNA complexes may be a safe and efficient hepatocyte targeting gene delivery system.     

Evaluation of micelles incorporated into thermosensitive hydrogels for intratumoral delivery and controlled release of docetaxel: A dual approach for in situ treatment of tumors

The in situ gelling hybrid hydrogel system has been reported to effectively concentrate chemotherapeutic drugs at the tumor site and sustain their release for a long period. DTX-micelles (docetaxel-loaded mixed micelles) are able to increase the solubility of DTX in water, and then a high drug loading rate of hydrogels can be achieved by encapsulating the docetaxel-loaded mixed micelles into the hydrogels. The thermosensitive nature of DTX-MM-hydrogels (thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles) can accelerate the formation of a depot of this drug-loaded system at the site of administration. Therefore, the hydrogels provide a much slower release compared with DTX-micelles and DTX-injection. An in vivo retention study has demonstrated that the DTX-MM-hydrogels can prolong the drug retention time and in vivo trials have shown that the DTX-MM-hydrogels have a higher antitumor efficacy and systemic safety. In conclusion, the DTX-MM-hydrogels prepared in this study have considerable potential as a drug delivery system, with higher tumor inhibition effects and are less toxic to normal tissues.     

Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment

Abstract

Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8?wt%) containing DTX exhibited a thermosensitive sol–gel–sol transition that was independent of the concentration of DTX (1–3?mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p?<?0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.     

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation,characterization and application in a vaginal drug delivery system

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH₂) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH₂-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH₂ is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH₂ and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.     

On the Release of Proteins from Degrading Dextran Methacrylate Hydrogels and the Correlation with the Rheologic Properties of the Hydrogels

Purpose. To study the release of macromolecules of different sizes (bovine serum albumin, immunoglobulin G) from degrading (addition of dextranase) dextran methacrylate (dex-MA) hydrogels and to correlate the release with the evolution of the rehologic properties of the hydrogels during degradation. Methods. The size of the macromolecules, the degree of substitution (i.e., number of methacrylates per 100 glycopyranose residues) of the dex-MA and the dextranase concentration in the hydrogels was varied. The rheologic properties were measured with a controlled stress rheometer. Results. The release from dex-MA hydrogels without dextranase was very small [7-20% (time frame up to 180 days)] showing that most of the molecules were entrapped within the hydrogel network. The release from degrading dex-MA hydrogels followed zero-order kinetics for all molecules during a substantial period of the release. This was explained by a liberation and an increasing diffusivity of the proteins in the course of the degradation. The total amount released and the release rates could be well correlated with the rheologically observed degradation rates. Conclusions. It was shown that rheology can be a useful tool to help explain the release from degrading hydrogels.     

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Introduction: Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure–function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release.

Areas covered: An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence–structure–function relationships, stimuli-responsive features and current and potential drug delivery applications.

Expert opinion: The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.     

Thermosensitive hydrogels a versatile concept adapted to vaginal drug delivery

Vaginal drug delivery represents an attractive strategy for local and systemic delivery of drugs otherwise poorly absorbed after oral administration. The rather dense vascular network, mucus permeability and the physiological phenomenon of the uterine first-pass effect can all be exploited for therapeutic benefit. However, several physiological factors such as an acidic pH, constant secretion, and turnover of mucus as well as varying thickness of the vaginal epithelium can impact sustained drug delivery. In recent years, polymers have been designed to tackle challenges mentioned above. In particular, thermosensitive hydrogels hold great promise due to their stability, biocompatibility, adhesion properties and adjustable drug release kinetics. Here, we discuss the physiological and anatomical uniqueness of the vaginal environment and how it impacts the safe and efficient vaginal delivery and also reviewed several thermosensitive hydrogels deemed suitable for vaginal drug delivery by addressing specific characteristics, which are essential to engage the vaginal environment successfully.     

Silk fibroin biomaterials for controlled release drug delivery

Introduction: Given the benefits of polymer drug delivery implants over traditional periodic systemic administration, the development of biomaterial systems with the necessary properties (biocompatibility, degradation, stabilization, controllability) is paramount. Silk fibroin represents a promising, naturally derived polymer for local, controlled, sustained drug release from fully degrading implants and the polymer can be processed into a broad array of material formats.

Areas covered: This review provides an overview of silk biomaterials for drug delivery, especially those that can function as long-term depots. Fundamentals of structure and assembly, processing options, control points and specific examples of implantable silk drug delivery systems (sponges, films) and injectable systems (microspheres, hydrogels) from the 1990s and onwards are reviewed.

Expert opinion: Owing to its unique material properties, stabilization effects and tight controllability, silk fibroin is a promising biomaterial for implantable and injectable drug delivery applications. Many promising control points have been identified, and characterization of the relationships between silk processing and/or material properties and the resulting drug loading and release kinetics will ultimately enhance the overall utility of this unique biomaterial. The ever-expanding biomaterial ‘tool kit’ that silk provides will eventually allow the simultaneous optimization of implant structure, material properties and drug release behavior that is needed to maximize the cost-efficiency, convenience, efficacy and safety of many new and existing therapeutics, especially those that cannot be delivered by means of traditional administration approaches.     

Preparation and Characterization of Freeze-dried Chitosan-Poly(Ethylene Oxide) Hydrogels for Site-Specific Antibiotic Delivery in the Stomach

Purpose. The purpose of this study was to develop novel drug delivery systems with pH-sensitive swelling and drug release properties for localized antibiotic delivery in the stomach. Methods. The drug delivery systems were synthesized by crosslinking chitosan and poly(ethylene oxide) (PEO) in a blend to form semi-interpenetrating polymer network (semi-IPN). Scanning electron microscopy was used to compare the surface and bulk morphology of the freeze-dried and air-dried chitosan-PEO semi-IPN. The hydrogels were allowed to swell and release the antibiotics—amoxicillin and metronidazole—in enzyme-free simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.2) at 37°C. Results. Freeze-dried chitosan-PEO semi-IPN with a porous matrix had swollen extensively as compared to the air-dried hydrogel. The swelling ratio of freeze-dried and air-dried chitosan-PEO semi-IPN after 1 h in SGF was 16.1 and 2.30, respectively. More than 65% of the entrapped amoxicillin and 59% of metronidazole were released from the freeze-dried chitosan-PEO semi-IPN after 2 h in SGF. Conclusions. The results of this study suggest that freeze-dried chitosan-PEO semi-IPN could be useful for localized delivery of antibiotics in the acidic environment of the gastric fluid.