Chitosan hydrogels containing nanoencapsulated phenytoin for cutaneous use: Skin permeation/penetration and efficacy in wound healing.

Although phenytoin is an antiepileptic drug used in the oral treatment of epilepsy, its off-label use as a cutaneous healing agent has been studied in recent years due to the frequent reports of gingival hyperplasia after oral administration. However, the cutaneous topical application of phenytoin should prevent percutaneous skin permeation. Therefore, the aim of this study was to evaluate the in vitro skin permeation/retention and in vivo effects of nanocapsules and nanoemulsions loaded with phenytoin and formulated as chitosan hydrogels on the healing process of cutaneous wounds in rats. The hydrogels had adequate pH values (4.9-5.6) for skin application, drug content of 0.025% (w/w), and non-Newtonian pseudoplastic rheological behaviour. Hydrogels containing nanocapsules and nanoemulsions enabled improved controlled release of phenytoin and adhesion to skin, compared with hydrogels containing non-encapsulated phenytoin. In vitro skin permeation studies showed that phenytoin permeation to the receptor compartment, and consequently the risk of systemic absorption, may be reduced by nanoencapsulation without any change in the in vivo performance of phenytoin in the wound healing process in rats.

Covalently crosslinked organophosphorous derivatives-chitosan hydrogel as a drug delivery system for oral administration of camptothecin.

Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity.

Hydrogel Contact Lens Water Content is Dependent on Tearfilm pH.

Introduction: Based on clinical inferences, investigators theorized in situ soft lens hydration was linked to the precorneal tearfilm pH. Methods: Forty-one myopic subjects at Fort Rucker, AL, USA were fitted with one of two types of extended-wear soft contact lenses, and were followed quarterly for a period of 33 mo. The anterior soft contact lens surface pH was measured in situ, while the in vitro lens water content was measured immediately after lens removal, using a hand-held refractometer on one lens, and a gravimetric means of hydration measurement on the other lens. Results: The in situ pH increased logarithmically across extended wearing time, reaching an asymptote at approximately 5 d' wearing time at a pH of 7.45 ± 0.03. Lens water content was shown to similarly decrease at an inversely logarithmic rate, leveling off at 4-5 d' extended wearing time. Both means of hydration assessment correlated well with each other across days' extended wearing time (R = 0.98; p < 0.0001). Discussion: A log-log dual conversion yielded significantly different linear slopes (p < 0.001), based on a multifactorial analysis of both lens types, by the pH, and by their water content. The differing ionic status of each material accentuated their varied polar attraction characteristics. Two soft lenses, identical in all patient-based parameters, could provide differing oxygen availability, as well as differing physical fits in patients of identical physical characteristics, as a result of their unique tearfilm pH differences. Conclusion: The in situ hydrogel lens water content is directly dependent on the precorneal tearfilm pH.

Sustained-release of FGF-2 from a hybrid hydrogel of heparin-poloxamer and decellular matrix promotes the neuroprotective effects of proteins after spinal injury.

INTRODUCTION: The short lifetime of protein-based therapies has largely limited their therapeutic efficacy in injured nervous post-spinal cord injury (post-SCI). METHODS: In this study, an affinity-based hydrogel delivery system provided sustained-release of proteins, thereby extending the efficacy of such therapies. The affinity-based hydrogel was constructed using a novel polymer, heparin-poloxamer (HP), as a temperature-sensitive bulk matrix and decellular spinal cord extracellular matrix (dscECM) as an affinity depot of drug. By tuning the concentration of HP in formulation, the cold ternary fibroblast growth factor-2 (FGF2)-dscECM-HP solution could rapidly gelatinize into a hydrogel at body temperature. Due to the strong affinity for FGF2, hybrid FGF2-dscECM-HP hydrogel enabled sustained-release of encapsulated FGF2 over an extended period in vitro. RESULTS: Compared to free FGF2, it was observed that both neuron functions and tissue morphology after SCI were clearly recovered in rats treated with FGF2-dscECM-HP hydrogel. Moreover, the expression of neurofilament protein and the density of axons were increased after treatment with hybrid FGF2-dscECM-HP. In addition, the neuroprotective effects of FGF2-dscECM-HP were related to inhibition of chronic endoplasmic reticulum stress-induced apoptosis. CONCLUSION: The results revealed that a hybrid hydrogel system may be a potential carrier to deliver macromolecular proteins to the injured site and enhance the therapeutic effects of proteins.

A self-deploying drug release device using polymeric films.

Herein, we report a sheet-type device capable of self-deployment and sustained release of protein type drugs. The device consisted of a thin photopolymerized polyethylene glycol dimethacrylate (PEGDM) sheet and collagen microparticles (COLs), which were embedded in the sheet as drug carriers and for increased drug permeation. When the density of the COLs in the sheet was increased to be sufficiently interconnected, the drug permeability was increased. In addition, since protein type drugs electrostatically interacted with the COLs, a prolonged sustained release was possible. The PEGDM/COLs device was flexible enough to be rolled up, and the device maintained its structure due to van der Waals attractive forces between the sheet surfaces. When the device was immersed in water, the attractive forces acting between the sheet surfaces were relieved by water. Subsequently, the device unfolded by bending-stress relaxation. Moreover, the rolled-up device could be injected through a conventional syringe needle into water to recover its original shape. The developed sheet-type device provides the possibility of minimally invasive transplantation into diseased tissues and organs, and could provide better therapeutic outcomes and reduce possible side effects. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 780-786, 2018.

An injectable and self-healing hydrogel for spatiotemporal protein release via fragmentation after passing through needles.

A dynamic hydrogel formulated by mixing a glycol chitosan (GC) and an oxidized dextran (Odex) were studied for protein-controlled release in conjunction with the hydrogel fragmentation. A series of injectable dynamic hydrogels were derived from GC and Odex upon simple mixing without the addition of chemical crosslinking agents. The gelation readily took place at physiological pH and temperature. The influence of the concentration of GC and Odex on the gelation time, mechanical properties, water content, in vitro degradation were investigated. The Odex/GC hydrogels showed good self-healing ability under physiological conditions and kept the dynamic Schiff-base linkage at over 2 wt %. The release kinetics of a model protein (bovine serum albumin) was found to be controlled by changing the needle size upon injection, attributed to modulation of apparent size and shape of the fragmented hydrogels even in the self-healed state. Therefore, the GC-based injectable and dynamic hydrogels are expected to be a promising platform for protein delivery system and various biomedical applications.

Thermosensitive Hydrogel Containing Doxycycline Exerts Inhibitory Effects on Abdominal Aortic Aneurysm Induced By Pancreatic Elastase in Mice.

Doxycycline (DOX) is reported to exert therapeutic effects against abdominal aortic aneurysm (AAA), a severe degenerative disease. In this study, a DOX hydrogel formulation of DOX/PECTgel is studied, and its phase transition behavior and in vitro release profiles are explored. In addition, the anti-AAA effects and bioavailability of DOX/PECTgel are evaluated in an elastase induced AAA mouse model. The results show that the phase transition temperature of 30% poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) solution is above 34 °C. In vitro release profiles of DOX/PECTgel indicate a fast release of DOX at the first two days, followed by a slow and sustained release for 14 d. In vivo single-dose single subcutaneous injection of DOX/PECTgel containing 8.4 or 4.2 mg mL-1 DOX presents comparatively preventive effects on AAA, compared to intraperitoneal injections of DOX alone at a dose of 15 mg kg-1 for seven injections, while DOX bioavailability of the DOX/PECTgel treated groups is 1.39 times or 1.19 times of the DOX alone treated group, respectively.

A Hydrogel-Microsphere Drug Delivery System That Supports Once-Monthly Administration of a GLP-1 Receptor Agonist.

We have developed a chemically controlled very long-acting delivery system to support once-monthly administration of a peptidic GLP-1R agonist. Initially, the prototypical GLP-1R agonist exenatide was covalently attached to hydrogel microspheres by a self-cleaving ß-eliminative linker; after subcutaneous injection in rats, the peptide was slowly released into the systemic circulation. However, the short serum exenatide half-life suggested its degradation in the subcutaneous depot. We found that exenatide undergoes deamidation at Asn28 with an in vitro and in vivo half-life of approximately 2 weeks. The [Gln28]exenatide variant and exenatide showed indistinguishable GLP-1R agonist activities as well as pharmacokinetic and pharmacodynamic effects in rodents; however, unlike exenatide, [Gln28]exenatide is stable for long periods. Two different hydrogel-[Gln28]exenatide conjugates were prepared using ß-eliminative linkers with different cleavage rates. After subcutaneous injection in rodents, the serum half-lives for the released [Gln28]exenatide from the two conjugates were about 2 weeks and one month. Two monthly injections of the latter in the Zucker diabetic fatty rat showed pharmacodynamic effects indistinguishable from two months of continuously infused exenatide. Pharmacokinetic simulations indicate that the delivery system should serve well as a once-monthly GLP-1R agonist for treatment of type 2 diabetes in humans.

131I-labeled chitosan hydrogels for radioembolization: A preclinical study in small animals.

INTRODUCTION: The purpose of the study was to examine potential of 131I-labeled chitosan hydrogels (Chi) for treatment of liver cancer. METHODS: Orthotopic hepatoma was induced by McA-RH7777-fLuc cells (1×107) that were injected into the left hepatic lobe of rats. Ten days later, tumor-bearing rats evidenced by bioluminescence received 125I-labeled Chi with left hepatic artery access. Pharmacokinetics and excretion (n=8) and biodistribution (n=6/time point) were studied after injection. To examine therapeutic potential, animals (n=8/group) were also treated with Chi labeled with or without 131I. Changes in tumor volume by magnetic resonance (MR) imaging were studied. RESULTS: The rate of tumor induction assessed by bioluminescence imaging was 72% (68/95). Gamma counter and scintigraphy imaging analyses showed accumulation of 125I-labeled Chi dominantly in the liver. A small fraction of 125I-labeled Chi was detected in the stomach (2.02±3.07%ID) and muscle (1.37±1.48%ID) at 2 d post-treatment. Blood sample analysis showed the maximum blood concentration of 0.09±0.03%ID/mL, which peaked at 0.60±0.45 d. Over a 4-week period, 31.22±8.16%ID were excreted in the urine and 3.5±1.3% in the feces. Treatment of Chi (median, 876mm3; IQR, 496mm3-1413mm3) markedly reduced the extent of tumor growth, compared to controls (median, 12,085mm3; IQR, 7786mm3-25,832mm3; P<0.05 vs control). 131I Chi (median, 80mm3; IQR, 35mm3-172mm3; P<0.05 vs control) induced a greater tumor-suppressing effect, compared to Chi alone. CONCLUSIONS: In this study, we have characterized a new radioembolization device, 131I Chi, in vivo and provided evidence for its therapeutic potential. ADVANCES IN KNOWLEDGE: Transarterial embolization is a conceivable treatment option for patients with inoperable liver cancer to mitigate the disease progression. Recently, we have developed chitosan-based hydrogel microparticles. In the present study, the hydrogel microparticles were radiolabeled with 131I for treatment of liver cancer. Our results demonstrated that a hepatic arterial injection of 125I-labeled Chi resulted in substantial liver accumulation, which was accompanied by virtually no extrahepatic deposition. The results of the present study also showed that administration of 131I Chi markedly suppressed tumor growth, compared to controls and to animals receiving unlabeled Chi. 131I-labeled chitosan hydrogel microparticles represent a new therapeutic approach for treatment of liver cancer.

Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations.

Purpose: This work is aimed at describing the utility of positron emission tomography/computed tomography (PET/CT) as a noninvasive tool for pharmacokinetic studies of biopermanence of topical ocular formulations. Methods: The corneal biopermanence of a topical ophthalmic formulation containing gellan gum and kappa carragenan (0.82% wt/vol) labeled with 18Fluorine (18F) radiotracers (18F-FDG and 18F-NaF) was evaluated by using a dedicated small-animal PET/CT, and compared with the biopermanence of an aqueous solution labeled with the same compounds. Regions of interest (ROIs) were manually drawn on the reconstructed PET images for quantifying the radioactivity concentration in the eye. The biopermanence of the formulations was determined by measuring the radioactivity concentration at different times after topical application. Additionally, cellular and ex vivo safety assays were performed to assess the safety of the performed procedures. Results: Differences were observed in the ocular pharmacokinetics of the two formulations. After 1.5 hours of contact, 90% of the hydrogel remained in the ocular surface, while only 69% of the control solution remained. Furthermore, it was observed that flickering had a very important role in the approach of the trial. The application of 18F-FDG in the eye was neither irritating nor cytotoxic for human corneal epithelial cells. Conclusions: The use of small-animal PET and 18F radiotracers in ocular pharmacokinetics of ophthalmic formulations is feasible and could be a safe method for future ocular pharmacokinetic studies in humans.

Evaluation of a two-stage antibacterial hydrogel dressing for healing in an infected diabetic wound.

Various types of wound dressings have been used to treat complex infections in diabetes mellitus. This study is the first to evaluate the healing effects using a two-stage dressing in infected diabetic wounds. A two-stage antibacterial hydrogel dressing (two-stage dressing) was established with two time phases, an antibacterial phase and a drug release phase. We established each phase by using a swelling and rate of drug release test. These results suggested that the antimicrobial phase is activated as soon as the two-stage dressing attaches to the skin. The drugs in the drug release layer of the dressing were released to a greater extent than expected 20-36 h after attachment to the skin, likely due to extensive water absorption. Histological analysis and measurement of vascular endothelial growth factor expression through in vivo testing suggested that the benefits of a two-stage dressing include rapid antibacterial properties, sustained drug release, and promotion of wound healing through cell proliferation as compared with the traditional composite antibacterial hydrogel dressing. Further in vivo tests confirmed that separation of the antibacterial and drug-releasing properties, along with biocompatibility and rapid wound closure rates made two-stage dressings suitable for healing of infected wounds. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1808-1817, 2017.

Preparation, pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride.

Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy.

Utilization of Near-Infrared Fluorescent Imaging for Pharmaceutically Relevant Applications.

Optical imaging can be utilized for several pharmaceutical applications involving near-infrared fluorescent (NIRF) dyes or NIRF moiety-containing products. Especially during the early phases of product development, NIRF dyes can be used as surrogates for drugs and optical imaging methods can be utilized to optimize the pharmaceutical product properties based on dye entrapment efficiency, in vitro dye release, cellular uptake, and in vivo biodistribution. Based on in vivo accumulation, product efficacy and toxicity can be evaluated in the early development stage. Compared to visible fluorescent dyes, NIRF offers advantages such as low background from formulation excipients as well as biological components.In this chapter, the utility of NIRF imaging methods for in vitro characterization (in vitro release and cellular uptake) and in vivo/ex vivo applicability of pharmaceutically relevant products is presented in detail. Specifically, the application of fluorescence imaging to characterize perfluorocarbon-based formulations for dye loading, in vitro release, cellular uptake, and in vivo imaging to assess target accumulation and biodistribution is discussed. These methods are widely applicable to other nanoparticle-based products involved in inflammation/cancer imaging and therapy. Overall, NIRF-based techniques are indispensible because they are relatively easy, fast, and cost effective to characterize and optimize pharmaceutical products at different stages of product development.

In vitro and in vivo evaluation of thermosensitive chitosan hydrogel for sustained release of insulin.

Injectable In situ gel-forming chitosan/ß-glycerol phosphate (CS/ß-Gp) solution can be introduced into the body in a minimally invasive manner prior to solidifying within the target tissue. This hydrogel is a good candidate for achieving a prolonged drug delivery system for insulin considering its high molecular weight. In addition to the physicochemical characterization of this hydrogel, in vitro and in vivo applications were studied as a sustained insulin delivery system. In the in vitro release studies, 19-63% of total insulin was released from the CS/ß-Gp hydrogel within 150 h at different ß-Gp and insulin concentrations. The best formulation was selected for in vivo experimentation to control the plasma glucose of diabetic mice models. The hypoglycemic effect of this formulation following subcutaneous injection in diabetic mice lasted 5 d, significantly longer than that of free insulin solution which lasted several hours.

Sustained co-delivery of BIO and IGF-1 by a novel hybrid hydrogel system to stimulate endogenous cardiac repair in myocardial infarcted rat hearts.

Dedifferentiation and proliferation of endogenous cardiomyocytes in situ can effectively improve cardiac repair following myocardial infarction (MI). 6-Bromoindirubin-3-oxime (BIO) and insulin-like growth factor 1 (IGF-1) are two potent factors that promote cardiomyocyte survival and proliferation. However, their delivery for sustained release in MI-affected areas has proved to be challenging. In the current research, we present a study on the sustained co-delivery of BIO and IGF-1 in a hybrid hydrogel system to simulate endogenous cardiac repair in an MI rat model. Both BIO and IGF-1 were efficiently encapsulated in gelatin nanoparticles, which were later cross-linked with the oxidized alginate to form a novel hybrid hydrogel system. The in vivo results indicated that the hybrid system could enhance the proliferation of cardiomyocytes in situ and could promote revascularization around the MI sites, allowing improved cardiac function. Taken together, we concluded that the hybrid hydrogel system can co-deliver BIO and IGF-1 to areas of MI and thus improve cardiac function by promoting the proliferation of cardiomyocytes and revascularization.

Biodistribution and Toxicity Studies of PRINT Hydrogel Nanoparticles in Mosquito Larvae and Cells.

Mosquito-borne diseases continue to remain major threats to human and animal health and impediments to socioeconomic development. Increasing mosquito resistance to chemical insecticides is a great public health concern, and new strategies/technologies are necessary to develop the next-generation of vector control tools. We propose to develop a novel method for mosquito control that employs nanoparticles (NPs) as a platform for delivery of mosquitocidal dsRNA molecules to silence mosquito genes and cause vector lethality. Identifying optimal NP chemistry and morphology is imperative for efficient mosquitocide delivery. Toward this end, fluorescently labeled polyethylene glycol NPs of specific sizes, shapes (80 nm x 320 nm, 80 nm x 5000 nm, 200 nm x 200 nm, and 1000 nm x 1000 nm) and charges (negative and positive) were fabricated by Particle Replication in Non-Wetting Templates (PRINT) technology. Biodistribution, persistence, and toxicity of PRINT NPs were evaluated in vitro in mosquito cell culture and in vivo in Anopheles gambiae larvae following parenteral and oral challenge. Following parenteral challenge, the biodistribution of the positively and negatively charged NPs of each size and shape was similar; intense fluorescence was observed in thoracic and abdominal regions of the larval body. Positively charged NPs were more associated with the gastric caeca in the gastrointestinal tract. Negatively charged NPs persisted through metamorphosis and were observed in head, body and ovaries of adults. Following oral challenge, NPs were detected in the larval mid- and hindgut. Positively charged NPs were more efficiently internalized in vitro than negatively charged NPs. Positively charged NPs trafficked to the cytosol, but negatively charged NPs co-localized with lysosomes. Following in vitro and in vivo challenge, none of the NPs tested induced any cytotoxic effects.

Biodistribution and trafficking of hydrogel nanoparticles in adult mosquitoes.

BACKGROUND: Nanotechnology offers great potential for molecular genetic investigations and potential control of medically important arthropods. Major advances have been made in mammalian systems to define nanoparticle (NP) characteristics that condition trafficking and biodistribution of NPs in the host. Such information is critical for effective delivery of therapeutics and molecules to cells and organs, but little is known about biodistribution of NPs in mosquitoes. METHODOLOGY/PRINCIPAL FINDINGS: PRINT technology was used to construct a library of fluorescently labeled hydrogel NPs of defined size, shape, and surface charge. The biodistribution (organ, tissue, and cell tropisms and trafficking kinetics) of positively and negatively charged 200 nm x 200 nm, 80 nm x 320 nm, and 80 nm x 5000 nm NPs was determined in adult Anopheles gambiae mosquitoes as a function of the route of challenge (ingestion, injection or contact) using whole body imaging and fluorescence microscopy. Mosquitoes readily ingested NPs in sugar solution. Whole body fluorescence imaging revealed substantial NP accumulation (load) in the alimentary tracts of the adult mosquitoes, with the greatest loads in the diverticula, cardia and foregut. Positively and negatively charged NPs differed in their biodistribution and trafficking. Following oral challenge, negatively charged NPs transited the alimentary tract more rapidly than positively charged NPs. Following contact challenge, negatively charged NPs trafficked more efficiently in alimentary tract tissues. Following parenteral challenge, positively and negatively charged NPs differed in tissue tropisms and trafficking in the hemocoel. Injected NPs were also detected in cardia/foregut, suggesting trafficking of NPs from the hemocoel into the alimentary tract. CONCLUSIONS/SIGNIFICANCE: Herein we have developed a tool box of NPs with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector lethal cargoes for mosquito control.

Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies.

BACKGROUND: Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats). PURPOSE: The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions. METHODS: Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies. RESULTS: The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil(®), 13.44% Cremophor(®) RH40, 6.72% Labrasol(®), and 5.04% Transcutol(®) HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro(®)). The microemulsion gel irritated the skin less than Neupro. CONCLUSION: A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability.

Antitumor activity of TNF-α after intratumoral injection using an in situ thermosensitive hydrogel.

Local drug delivery strategies based on nanoparticles, gels, polymeric films, rods and wafers are increasingly used in cancer chemotherapy in order to enhance therapeutic effect and reduce systemic toxicity. Herein, a biodegradable and biocompatible in situ thermosensitive hydrogel was designed and employed to deliver tumor necrosis factor-α (TNF-α) locally by intratumoral injection. The triblock copolymer was synthesized by ring-opening polymerization (ROP) of ß-butyrolactone (ß-BL) and lactide (LA) in bulk using polyethylene glycol (PEG) as an initiator and Sn(Oct)2 as the catalyst, the polymer was characterized by NMR, gel permeation chromatography and differential scanning calorimetry. Blood and tumor pharmacokinetics and in vivo antitumor activity of TNF-α after intratumoral administration in hydrogel or solution with the same dose were evaluated on S180 tumor-bearing mice. Compared with TNF-α solution, TNF-α hydrogel exhibited a longer T1/2 (4-fold) and higher AUCtumor (19-fold), but Cmax was lower (0.5-fold), which means that the hydrogel formulation improved the efficacy with a lower systhemic exposure than the solution formation. In addition, TNF-α hydrogel improved the antitumor activity and survival due to lower systemic exposure than the solution. These results demonstrate that the in situ thermosensitive hydrogel-based local delivery system by intratumoral injection is well suited for the administration of TNF-α.

Assessment of the safety, targeting, and distribution characteristics of a novel pH-sensitive hydrogel.

In our previous study, we synthesized a pH-sensitive hydrogel based on poly (ɛ-caprolactone) (PCL), Pluronic (Poloxamer) and methacrylic acid (MAA) using UV-initiated free-radical polymerization. In the present study, we evaluated the safety of the obtained GMA-PCFC-GMA copolymer and a P(CFC-MAA-MEG) hydrogel both in vitro and in vivo. The pharmacokinetics study and distribution characteristics of dexamethasone in rat blood and mouse colon were investigated in detail. The in vitro toxicity of the GMA-PCFC-GMA copolymer was evaluated using a cell viability assay with HEK293 cells. An acute oral toxicity test was conducted by orally administering mice with a total of 10,000 mg/kg body weight of the P(CFC-MAA-MEG) hydrogel. The mice were then observed continuously for 14 days. After which, they were sacrificed and their blood collected for routine blood and serum chemistry tests. Pharmacokinetic and colonic tissue distribution studies were conducted using high-performance liquid chromatography to detect the concentration of dexamethasone in rat blood and mouse colon tissue. All of the results indicated that both the GMA-PCFC-GMA copolymer and P(CFC-MAA-MEG) hydrogel were nontoxic. Moreover, the hydrogel significantly enhanced the colon-targeting behavior of dexamethasone. These results suggested that the novel hydrogel has great potential in colon-targeted drug delivery.