Folic acid-decorated alginate nanoparticles loaded hydrogel for the oral delivery of diferourylmethane in colorectal cancer.

The disease-related suffering in colorectal cancer remains prevalent despite advancements in the field of drug delivery. Chemotherapy-related side effects and non-specificity remain a challenge in drug delivery. The great majority of hydrophobic drugs cannot be successfully delivered to the colon orally mainly due to poor solubility, low bioavailability, pH differences, and food interactions. Polymeric nanoparticles are potential drug delivery candidates but there are numerous limitations to their usefulness in colon cancer. The nanoparticles are removed from the body rapidly by p-glycoprotein efflux, inactivation, or breakdown by enzymes limiting their efficiency. Furthermore, there is a lack of selectivity in targeting cancer cells; nanoparticles may also target healthy cells, resulting in toxicity and adverse effects. The study aimed to use nanoparticles for specific targeting of the colorectal tumor cells via the oral route of administration without adverse effects. Folic acid (FA), a cancer-targeting ligand possessing a high affinity for folate receptors overexpressed in colorectal cancers was conjugated to sodium alginate- nanoparticles by NH2-linkage. The folic-acid conjugated nanoparticles (FNPs) were delivered to the colon by a pH-sensitive hydrogel synthesized by the free radical polymerization method to provide sustained drug release. The developed system referred to as the "Hydrogel-Nano (HN) drug delivery system," was specifically capable of delivering diferourylmethane to the colon. The HN system was characterized by DLS, FTIR, XRD, TGA, DSC, and SEM. The FNPs size, polydispersity index, and zeta potential were measured. The folic acid-conjugation to nanoparticles' surface was studied by UV-visible spectroscopy using Beer-Lambert's law. In-vitro studies, including sol-gel, porosity, drug loading, entrapment efficiency, etc., revealed promising results. The swelling and release studies showed pH-dependent release of the drug in colonic pH 7.4. Cellular uptake and cytotoxicity studies performed on FR-overexpressed Hela cell lines and FR-negative A-549 cell lines showed facilitated uptake of nanoparticles by folate receptors. A threefold increase in Cmax and prolongation of the mean residence time (MRT) to 14.52 +/- 0.217 h indicated sustained drug release by the HN system. The findings of the study can provide a sufficient ground that the synergistic approach of the HN system can deliver hydrophobic drugs to colorectal cancer cells via the oral route, but further in-vivo animal cancer model studies are required.

Chitosan and carboxymethyl cellulose-based 3D multifunctional bioactive hydrogels loaded with nano-curcumin for synergistic diabetic wound repair.

Biopolymer-based thermoresponsive injectable hydrogels with multifunctional tunable characteristics containing anti-oxidative, biocompatibility, anti-infection, tissue regeneration, and/or anti-bacterial are of abundant interest to proficiently stimulate diabetic wound regeneration and are considered as a potential candidate for diversified biomedical application but the development of such hydrogels remains a challenge. In this study, the Chitosan-CMC-g-PF127 injectable hydrogels are developed using solvent casting. The Curcumin (Cur) Chitosan-CMC-g-PF127 injectable hydrogels possess viscoelastic behavior, good swelling properties, and a controlled release profile. The degree of substitution (% DS), thermal stability, morphological behavior, and crystalline characteristics of the developed injectable hydrogels is confirmed using nuclear magnetic resonance (1H NMR), thermogravimetric analysis, scanning electron microscopy (SEM), and x-ray diffraction analysis (XRD), respectively. The controlled release of cur-micelles from the hydrogel is evaluated by drug release studies and pharmacokinetic profile (PK) using high-performance liquid chromatography (HPLC). Furthermore, compared to cur micelles the Cur-laden injectable hydrogel shows a significant increase in half-life (t1/2) up to 5.92 ± 0.7 h, mean residence time (MRT) was 15.75 ± 0.76 h, and area under the first moment curve (AUMC) is 3195.62 ± 547.99 µg/mL*(h)2 which reveals the controlled release behavior. Cytocompatibility analysis of Chitosan-CMC-g-PF127 hydrogels using 3T3-L1 fibroblasts cells and in vivo toxicity by subcutaneous injection followed by histological examination confirmed good biocompatibility of Cur-micelles loaded hydrogels. The histological results revealed the promising tissue regenerative ability and shows enhancement of fibroblasts, keratinocytes, and collagen deposition, which stimulates the epidermal junction. Interestingly, the Chitosan-CMC-g-PF127 injectable hydrogels ladened Cur exhibited a swift wound repair potential by up-surging the cell migration and proliferation at the site of injury and providing a sustained drug delivery platform for hydrophobic moieties.

Silymarin nanocrystals-laden chondroitin sulphate-based thermoreversible hydrogels; A promising approach for bioavailability enhancement.

Hydrogels has gained tremendous interest as a controlled release drug delivery. However, currently it is a big challenge to attain high drug-loading as well as stable and sustained release of hydrophobic drugs. The poor aqueous solubility and low bioavailability of many drugs have driven the need for research in new formulations. This manuscript hypothesized that incorporation of nanocrystals of hydrophobic drug, such as silymarin into thermoreversible hydrogel could be a solution to these problems. Herein, we prepared nanocrystals of silymarin by antisolvent precipitation technique and characterized for morphology, particle size, polydispersity index (PDI) and zeta potential. Moreover, physical cross-linking of hydrogel formulations based on chondroitin sulphate (CS), kappa-Carrageenan (κ-Cr) and Pluronic® F127 was confirmed by Fourier transformed infrared spectroscopy (FT-IR). The hydrogel gelation time and temperature of optimized hydrogel was 14 ± 3.2 s and 34 ± 0.6 °C, respectively. The release data revealed controlled release of silymarin up to 48 h and in-vivo pharmacokinetic profiling was done in rabbits and further analyzed by high-performance liquid chromatography (HPLC). It is believed that the nanocrystals loaded thermoreversible injectable hydrogel system fabricated in this study provides high drug loading as well as controlled and stable release of hydrophobic drug for extended period.

Chitosan/guar gum-based thermoreversible hydrogels loaded with pullulan nanoparticles for enhanced nose-to-brain drug delivery.

The biopolymers-based two-fold system could provide a sustained release platform for drug delivery to the brain resisting the mucociliary clearance, enzymatic degradation, bypassing the first-pass hepatic metabolism, and BBB thus providing superior bioavailability through intranasal administration. In this study, poloxamers PF-127/PF-68 grafted chitosan HCl-co-guar gum-based thermoresponsive hydrogel loaded with eletriptan hydrobromide laden pullulan nanoparticles was synthesized and subjected to dynamic light scattering, Fourier transform infrared spectroscopy, thermal analysis, x-ray diffraction, scanning electron microscopy, stability studies, mucoadhesive strength and time, gel strength, cloud point assessment, rheological assessment, ex-vivo permeation, cell viability assay, histology studies, and in-vivo Pharmacokinetics studies, etc. It is quite evident that CSG-EH-NPs T-Hgel has an enhanced sustained release drug profile where approximately 86 % and 84 % of drug released in phosphate buffer saline and simulated nasal fluid respectively throughout 48 h compared to EH-NPs where 99.44 % and 97.53 % of the drug was released in PBS and SNF for 8 h. In-vivo PKa parameters i.e., mean residence time (MRT) of 11.9 ± 0.83 compared to EH-NPs MRT of 10.2 ± 0.92 and area under the curve (AUCtot) of 42,540.5 ± 5314.14 comparing to AUCtot of EH-NPs 38,026 ± 6343.1 also establish the superiority of CSG-EH-NPs T-Hgel.

Bioactive and multifunctional keratin-pullulan based hydrogel membranes facilitate re-epithelization in diabetic model.

Hydrogel membrane dressings with multifunctional tunable properties encompassing biocompatibility, anti-bacterial, oxygen permeability, and adequate mechanical strength are highly preferred for wound healing. The present study aimed to develop biopolymer-based hydrogel membranes for the controlled release of therapeutic agent at the wound site. Toward this end we developed Cefotaxime sodium (CTX) loaded keratin (KR)-pullulan (PL) based hydrogel membrane dressings. All membranes show optimized vapor transmission rate (≥1000 g/ m2/day), oxygen permeability >8.2 mg/mL, MTT confirmed good biocompatibility and sufficient tensile strength (17.53 ± 1.9) for being used as a wound dressing. Nonetheless, KR-PL-PVA membranes show controlled CTX release due to enriched hydrophilic moieties which protect the wound from getting infected. In vivo results depict that CTX-KR-PL-PVA membrane group shows a rapid wound closure rate (p < 0.05) with appreciable angiogenesis, accelerated re-epithelization, and excessive collagen deposition at the wound site. These results endorsed that CTX-KR-PL-PVA hydrogel membranes are potential candidates for being used as dressing material in the diabetic wound.

Improved drug delivery and accelerated diabetic wound healing by chondroitin sulfate grafted alginate-based thermoreversible hydrogels.

Injectable hydrogels with multifunctional tunable properties comprising biocompatibility, anti-oxidative, anti-bacterial, and/or anti-infection are highly preferred to efficiently promote diabetic wound repair and its development remains a challenge. In this study, we report chondroitin sulphate (CS) and sodium alginate (SA)-based injectable hydrogel using solvent casting method loaded with curcumin that could potentiate reepithelization, increase angiogenesis, and collagen deposition at wound microenvironment to endorse healing cascade. The physical interaction and self-assembly of chondroitin sulfate grafted alginate (CS-Alg-g-PF127) hydrogel were confirmed using nuclear magnetic resonance (1H NMR) and Fourier transformed infrared spectroscopy (FT-IR), and cytocompatibility was confirmed by fibroblast viability assay. The Masson's trichrome (MT) and hematoxylin and eosin (H&E) results revealed that blank chondroitin sulfate grafted alginate (CS-Alg-g-PF127) and CUR loaded CS-Alg-g-PF127 hydrogel had promising tissue regenerative ability, and showing enhanced wound healing compared to other treatment groups. The controlled release of CUR from injectable hydrogel was evaluated by drug release studies and pharmacokinetic profile (PK) using high-performance liquid chromatography (HPLC) that exhibited the mean residence time (MRT) and area under the curve (AUC) was increased up to 16.18 h and 203.64 ± 30.1 µg/mL*h, respectively. Cytotoxicity analysis of the injectable hydrogels using 3 T3-L1 fibroblasts cells and in vivo toxicity evaluated by subcutaneous injection for 24 h followed by histological examination, confirmed good biocompatibility of CUR loaded CS-Alg-g-PF127 hydrogel. Interestingly, the results of in vivo wound healing by injectable hydrogel showed the upregulation of fibroblasts-like cells, collagen deposition, and differentiated keratinocytes stimulating dermo-epidermal junction, which might endorse that they are potential candidates for excisional wound healing models.

Curcumin-laden hyaluronic acid-co-Pullulan-based biomaterials as a potential platform to synergistically enhance the diabetic wound repair.

Injectable hydrogel with multifunctional tunable properties comprising biocompatibility, anti-oxidative, anti-bacterial, and/or anti-infection are highly preferred to efficiently promote diabetic wound repair and its development remains a challenge. In this study, we report hyaluronic acid and Pullulan-based injectable hydrogel loaded with curcumin that could potentiate reepithelization, increase angiogenesis, and collagen deposition at wound microenvironment to endorse healing cascade compared to other treatment groups. The physical interaction and self-assembly of hyaluronic acid-Pullulan-grafted-pluronic F127 injectable hydrogel were confirmed using nuclear magnetic resonance (1H NMR) and Fourier transformed infrared spectroscopy (FT-IR), and cytocompatibility was confirmed by fibroblast viability assay. The CUR-laden hyaluronic acid-Pullulan-g-F127 injectable hydrogel promptly undergoes a sol-gel transition and has proved to potentiate wound healing in a streptozotocin-induced diabetic rat model by promoting 93% of wound closure compared to other groups having 35%, 38%, and 62%. The comparative in vivo study and histological examination was conducted which demonstrated an expeditious recovery rate by significantly reducing the wound healing days i.e. 35 days in a control group, 33 days in the CUR suspension group, 21 days in unloaded injectable, and 13 days was observed in CUR loaded hydrogel group. Furthermore, we suggest that the injectable hydrogel laden with CUR showed a prompt wound healing potential by increasing the cell proliferation and serves as a drug delivery platform for sustained and targeted delivery of hydrophobic moieties.

Bio-functional hydrogel membranes loaded with chitosan nanoparticles for accelerated wound healing.

Wounds are often recalcitrant to traditional wound dressings and a bioactive and biodegradable wound dressing using hydrogel membranes can be a promising approach for wound healing applications. The present research aimed to design hydrogel membranes based on hyaluronic acid, pullulan and polyvinyl alcohol and loaded with chitosan based cefepime nanoparticles for potential use in cutaneous wound healing. The developed membranes were evaluated using dynamic light scattering, proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the novel crosslinking and thermal stability of the fabricated hydrogel membrane. The in vitro analysis demonstrates that the developed membrane has water vapors transmission rate (WVTR) between 2000 and 2500 g/m2/day and oxygen permeability between 7 and 14 mg/L, which lies in the range of an ideal dressing. The swelling capacity and surface porosity to liberate encapsulated drug (cefepime) in a sustained manner and 88% of drug release was observed. The cefepime loaded hydrogel membrane demonstrated a higher zone of inhibition against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli and excisional rat model exhibit expeditious recovery rate. The developed hydrogel membrane loaded with cefepime nanoparticles is a promising approach for topical application and has greater potential for an accelerated wound healing process.

HEMA based pH-sensitive semi IPN microgels for oral delivery; a rationale approach for ketoprofen.

Objectives: The study aimed to develop safe, effective, and targeted drug delivery system for administration of nonsteroidal anti-inflammatory drugs (NSAIDs) in the form of microgels. We developed pH responsive microgels to overcome the mucosal damage caused by traditional immediate release dosage forms. Colon targeting and controlled release formulations have the potential to improve efficacy and reduce undesirable effects associated with NSAIDs.Methods: The pH sensitive oral hydrogel demonstrates the potential to target the colon. Cellulose acetate phthalate (CAP) and hydroxyethyl methacrylate (HEMA) based microgel particles were produced using a free radical polymerization technique using ammonium persulfate (APS) initiator and methylenebisacrylamide (MBA) as the crosslinking agent. Swelling and in-vitro drug release studies were performed at a range of pH conditions. The produced formulations were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy (SEM), and X-ray diffraction. Biocompatibility of the microgels was analyzed in cytotoxicity studies.Key findings: The swelling and release rate were negligible at pH 1.2, which confirmed the pH-responsiveness of CAP-co-poly(HEMA). The co-polymeric system prevents the release of ketoprofen sodium in the stomach owing to limited swelling at gastric pH, whilst promoting release at the basic pH observed in the colon. SEM images confirmed porous nature of the microgels that facilitate effective drug diffusion through the polymeric matrix. Cytotoxicity studies revealed biocompatibility of hydrogels.Conclusion: These investigations showed that that the controlled drug release and gastro-protective drug delivery of NSAIDS was achieved using CAP-co-poly(HEMA) microgel particles.

Biopolymer-based biomaterials for accelerated diabetic wound healing: A critical review.

Non-healing, chronic wounds place a huge burden on healthcare systems as well as individual patients. These chronic wounds especially diabetic wounds will ultimately lead to compromised mobility, amputation of limbs and even death. Currently, wounds and limb ulcers associated with diabetes remain significant health issues; the associated healthcare cost ultimately leads to the increased clinical burden. The presence of diabetes interrupts a highly coordinated cascade of events in the wound closure process. Advances in the understanding of pathophysiological conditions associated with diabetic wounds lead to the development of drug delivery systems which can enhance wound healing by targeting various phases of the impaired processes. Wound environments typically contain degradative enzymes, along with an elevated pH and demonstrate a physiological cascade involved in the regeneration of tissue, which requires the application of an effective delivery system. This article aims to review the pathophysiological conditions associated with chronic and diabetic wounds. The delivery systems, involved in their treatment are described, highlighting potential biomaterials and polymers for establishing drug delivery systems, specifically for the treatment of diabetic wounds and the promotion of the associated mechanisms involved in advanced wound healing. Emerging approaches and engineered devices for effective wound care are reported. The discussion will give insight into the mechanisms relevant to all stages of wound healing.

Novel biodegradable pH-sensitive hydrogels: An efficient controlled release system to manage ulcerative colitis.

The aim of this study was to develop and characterize a pH sensitive, biodegradable, interpenetrating polymeric network (IPNs) for colon specific delivery of sulfasalazine in ulcerative colitis. It also entailed in-vitro and in-vivo evaluations to optimize colon targeting efficiency, improve drug accumulation at the target site, and ameliorate the off-target effects of chemotherapy. Pectin was grafted with polyethylene glycol (PEG) and methacrylic acid (MAA) by free radical polymerization. Fourier transformed infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), energy dispersion X-ray (EDX) and powder X-ray diffraction (XRD) results confirmed the development of stable pectin-g-(PEG-co-MAA) hydrogels. The swelling and release studies exhibited that the hydrogels were capable of releasing drug specifically at colonic pH (pH 7.4). The toxicological potential of polymers, monomers and hydrogel was investigated using the Balb/c animal model, that confirmed the safety of the hydrogels. In vitro degradation of the hydrogel was evaluated using pectinase enzyme in various simulated fluids and the results showed that the hydrogels were susceptible to biodegradation by the natural microflora of the colon. In-vivo study was performed using Dextran sulphate sodium (DSS) rat model proved the hydrogels to be effective in the management of UC.

Chitosan based thermosensitive injectable hydrogels for controlled delivery of loxoprofen: development, characterization and in-vivo evaluation.

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.

pH-responsive CAP-co-poly(methacrylic acid)-based hydrogel as an efficient platform for controlled gastrointestinal delivery: fabrication, characterization, in vitro and in vivo toxicity evaluation.

Cellulose acetate phthalate-based pH-responsive hydrogel was synthesized for fabrication of polymeric matrix tablets for gastro-protective delivery of loxoprofen sodium. Cellulose acetate phthalate (CAP) was cross-linked with methacrylic acid (MAA) using free radical polymerization technique. Fourier transform infrared (FTIR) spectra confirmed the formation of cross-linked structure of CAP-co-poly(methacrylic acid). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) confirmed the thermal stability of polymeric networks, and scanning electron microscopy (SEM) and energy-dispersive X-ray spectrum (EDS) images unveiled that the prepared formulations were porous in nature and thus the developed formulations had shown better diffusibility. Swelling and in vitro drug release was performed at various pHs and maximum swelling and release was obtained at pH 7.4, while swelling and release rate was very low at pH 1.2 which confirmed the pH-responsive behavior of CAP-co-poly(MAA). CAP-co-poly(MAA) copolymer prevents the release of loxoprofen sodium into the stomach due to reduced swelling at gastric pH while showing significant swelling and drug release in the colon. Cytotoxicity studies revealed higher biocompatibility of fabricated hydrogel. Acute oral toxicity studies were performed for the evaluation and preliminary screening of safety profile of the developed hydrogels. Matrix tablets were evaluated for release behavior at simulated body pH. The investigations performed for analysis of hydrogels and fabricated matrix tablets indicated the controlled drug release and gastro-protective drug delivery of CAP-co-poly(MAA) hydrogels and pH-sensitive matrix tablets for targeted delivery of gastro-sensitive/irritative agents. Graphical abstract.

Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects.

Ulcerative colitis (UC) is an inflammatory disease of the colon that severely affects the quality of life of patients and usually responds well to anti-inflammatory agents for symptomatic relief; however, many patients need colectomy, a surgical procedure to remove whole or part of the colon. Though various types of pharmacological agents have been employed for the management of UC, the lack of effectiveness is usually predisposed to various reasons including lack of target-specific delivery of drugs and insufficient drug accumulation at the target site. To overcome these glitches, many researchers have designed and characterized various types of versatile polymeric biomaterials to achieve target-specific delivery of drugs via oral route to optimize their targeting efficiency to the colon, to improve drug accumulation at the target site, as well as to ameliorate off-target effects of chemotherapy. Therefore, the aim of this review was to summarize and critically discuss the pharmaceutical significance and therapeutic feasibility of a wide range of natural and synthetic biomaterials for efficient drug targeting to colon and rationalized treatment of UC. Among various types of biomaterials, natural and synthetic polymer-based hydrogels have shown promising targeting potential due to their innate pH responsiveness, sustained and controlled release characteristics, and microbial degradation in the colon to release the encapsulated drug moieties. These characteristic features make natural and synthetic polymer-based hydrogels superior to conventional pharmacological strategies for the management of UC.