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Doxycycline Loaded Collagen-Chitosan Composite Scaffold for the Accelerated Healing of Diabetic Wounds

One major complication of diabetes mellitus is diabetic wounds (DW). The prolonged phase of inflammation in diabetes obstructs the further stages of an ...

JSS Academy of Higher Education & Research

5-Aminosalicylic acid (5-ASA) is an aminosalicylate anti-inflammatory drug, which is also known as mesalazine or mesalamine. Currently employed in treating inflammatory bowel disease, ulcerative colitis, inflamed anus or rectum, and maintain remission in Crohn's disease. Evidence from the researchers highlighted its significant re-epithelization in allergic asthma, aphthous, and gastric ulcerative conditions. The objective of the study was to formulate the pluronic lecithin organogel (PLO) containing 5-ASA and evaluate its wound-healing ability in a full thickness excision wound rat model. The data obtained from in silico docking studies revealed 5-ASA is having an affinity towards the transforming growth factor-beta (TGF-β) specifically towards beta1. Among various formulations prepared (F1 to F8), F1, and F6 have shown a maximum in vitro drug release with optimum pH and viscosity. From MTT assay it was found that selected PLO formulations showed no toxicity and enhanced cell proliferation in HaCaT cell lines. In vivo wound-healing studies in albino Wistar rats has revealed that PLO accelerates wound closure and reepithelization to the statistically significant level on day 3 (p < .05) in comparison with untreated wounds. In conclusion, the overall results suggest that 5-ASA PLO gel is a potential therapeutic option for the treatments of wounds, however, further studies are highly warrened to determine the various mechanisms of 5-ASA in regulating the cell migration and reepithelization in wound healing to outspread its use in clinics.

Pluronic lecithin organogel of 5-aminosalicylic acid for wound healing.

Drug delivery to the brain is challenging because of the low permeability of blood-brain barrier, and therefore, optimum concentration of chemotherapeutics in the target area specifically for glioblastoma, an aggressive brain tumor, opens a new path of research. To achieve the goal, the oral alkylating agent temozolomide was incorporated into niosomes, and the surface was modified with chlorotoxin, a small 36 amino acid peptide discovered from the venom of scorpion . Active targeting using nanosized particles facilitates an increase in the accumulation of drugs in the cerebri by 3.04-folds. Temozolomide-loaded niosomes were prepared using conventional thin-film hydration method and characterized. Niosomes coated with chlorotoxin were produced with the size of 220 ± 1.45 nm with an entrapment efficiency of 79.09 ± 1.56%. Quantitative tissue distribution studies indicate enhanced permeation of the drug into the brain because of surface modification with less deposition in the highly perfused organs.

Smart niosomes of temozolomide for enhancement of brain targeting.

Diabetic wound is a major problem that often needs amputation of the concerned organ in patients suffering from diabetes. In diabetes, the prolonged phase of inflammation obstructs the further phases of healing which, in turn, lead to improper healing of the wounds in diabetes. Pioglitazone (Pio) hydrochloride is an antidiabetic drug with reported anti-inflammatory properties. The aim of this study was to develop a Pio-nanostructured lipid carrier (Pio-NLC)-loaded collagen/chitosan (COL-CS) scaffold and evaluate its healing ability in diabetic wounds. The results of characterization of composite scaffolds reveal that cross-linked scaffolds possess optimum porosity, low matrix degradation, and sustained drug release compared with noncross-linked scaffolds. The  studies reveal that the Pio-NLC-COL-CS scaffold was biocompatible and enhanced cell growth compared with control and NLC-COL-CS. Using the streptozotocin-induced diabetic wound model, significantly ( < 0.001) higher rates of wound contraction in Pio-NLC-COL-CS scaffold-treated group were observed in comparison with that in control and NLC-COL-CS-treated group. The enzyme-linked immunosorbent assay results indicate a significant ( < 0.001) decrease of matrix metalloproteinases-9 levels in the Pio-NLC-COL-CS-treated group compared with those in control group. Use of nanostructured lipid carrier (Pio-NLC-COL-CS) scaffold can prove to be a promising strategy for local treatment for diabetic wounds.

Nanostructured Lipid Carriers of Pioglitazone Loaded Collagen/Chitosan Composite Scaffold for Diabetic Wound Healing.

The present research reports the beneficial effects of surface modified chitosan and tumor-homing peptide conjugated liposomes of capecitabine (CAP) for treating breast cancer. Liposomal formulation of CAP was prepared by film hydration method using cholesterol-THP conjugate (CTHP-CAP-LPs) to achieve active targeting through HER2 receptors. CTHP-CAP-LPs significantly improved the specificity and efficacy of CAP by improving cell uptake, cytotoxicity and tumor regression in tumor bearing mice. CTHP-CAP-LPs, therefore, is a promising approach to improve the anticancer effects of CAP.

HER2 targeted biological macromolecule modified liposomes for improved efficacy of capecitabine in breast cancer.

Diabetic wound (DW) is a major complication of diabetes mellitus that often ends up with amputation of the concerned organ. The current therapies for DW include glucose regulation, wound debridement, pressure off-loading, surgeries, hyperbaric oxygen therapy, maggot therapy, and so on. However, the majority are not meeting all the prerequisites of DW because of extensive pathology and cost associated with the strategies. So, to overcome the problems related to the existing conventional therapies, we hypothesized to repurpose the current drugs, which can target a receptor having a considerable role in the progression of DW might be beneficial. One major challenge of DW is multifaceted pathophysiology includes prolonged inflammation, increased infections, decreased cell proliferation, and migration. Many shreds of evidence disclosed that inhibition of GSK-3β could result in reduced inflammation and infection, followed by increased cell proliferation and migration. Thus, we selected the GSK-3β receptor as a ubiquitous target for the treatment of multifactorial pathophysiology of DW. In the current hypothetical study, we investigated the use of rosiglitazone as a therapeutic modulator against the GSK-3β receptor. To validate our hypothesis, computational studies such as molecular docking and MMGBSA were performed. From the in silico methods, it is evident that rosiglitazone established a higher binding affinity against the selected receptor. Further, the Molecular Dynamic simulation study has revealed stable interaction of rosiglitazone against GSK-3β complex. Thus, rosiglitazone might be a drug of choice in the therapeutic management of DW.

Hypothesis validation of rosiglitazone a potential inhibitor against glycogen synthase kinase-3β, for the management of multifaceted pathophysiology of the diabetic wound: An insilico study.

Diabetes mellitus (DM) is an endocrine disorder that causes increased blood glucose than usual due to insulin impairment. In DM, several complications arise in which diabetic wound (DW) is the most devastating complication. About 25% of patients with DM expected to develop DWs in their lifetime and undergo limb amputations. Even though several treatments such as surgery, debridement, wound dressings, advanced therapies were available, the overall conclusion has been that with very few exceptions, patients still suffer from limitations like pain, frequent dress changing, high rates of failure, and cost involvement. Further, the treatments involving the delivery of therapeutic agents in treating DWs have limited success due to abnormal levels of proteases in the DW environment. In this backdrop, in situ gelling injectable hydrogels have gained special attention due to their easy encapsulation of therapeutic medications and prolonged release, filling the wound defect areas, ease of handling, and minimally invasive surgical procedures. Though the in situ gelling injectable hydrogels are developed a couple of decades ago, their use for treating DW has not yet been explored thoroughly. Thus, in this review, we have covered the sequential events of DW healing, pathophysiology, current treatments, and its limitations, along with a particular emphasis on the mechanism of action of these in situ gelling injectable hydrogels treating DWs.

Overview of in situ gelling injectable hydrogels for diabetic wounds.

Antibacterial resistance (ABR) is a major life-threatening problem worldwide. Rampant dissemination of ABR always exemplified the need for the discovery of novel compounds. However, to circumvent the disease, a molecular target is required, which will lead to the death of the bacteria when acted upon by a compound. One group of enzymes that have proved to be an effective target for druggable candidates is bacterial DNA topoisomerases (DNA gyrase and ParE). In our present work, phenylacetamide and benzohydrazides derivatives were screened for their antibacterial activity against a selected panel of pathogens. The tested compounds displayed significant antibacterial activity with MIC values ranging from 0.64 to 5.65 μg/mL. Amongst 29 title compounds, compounds 5 and 21 exhibited more potent and selective inhibitory activity against  with MIC values at 0.64 and 0.67 μg/mL, respectively, and MBC at onefold MIC. Furthermore, compounds exhibited a post-antibiotic effect of 2 h at 1× MIC in comparison to ciprofloxacin and gentamicin. These compounds also demonstrated the concentration-dependent bactericidal activity against  and synergized with FDA-approved drugs. The compounds are screened for their enzyme inhibitory activity against  ParE, whose IC values range from 0.27 to 2.80 μg/mL. Gratifyingly, compounds, namely 8 and 25 belonging to the phenylacetamide series, were found to inhibit ParE enzyme with IC values of 0.27 and 0.28 μg/mL, respectively. In addition, compounds were benign to Vero cells and displayed a promising selectivity index (169.0629-951.7240). Moreover, compounds 1, 7, 8, 21, 24, and 25 (IC: <1 and Selectivity index: >200) exhibited potent activity in reducing the  biofilm in comparison with ciprofloxacin, erythromycin, and ampicillin. These astonishing results suggest the potential utilization of phenylacetamide and benzohydrazides derivatives as promising ParE inhibitors for treating bacterial infections.

Benzohydrazide and Phenylacetamide Scaffolds: New Putative ParE Inhibitors.

The treatment of diabetic wounds (DWs) is always challenging for the medical community because of its multifaceted pathophysiology. Due to practical and ethical considerations, direct studies of therapeutic interventions on human subjects are limited. Thus, it is ideal for performing studies on animals having less genetic and biological variability. An ideal DW model should progress toward reproducibility, quantifiable interpretation, therapeutic significance, and effective translation into clinical use. In the last couple of decades, various animal models were developed to examine the complex cellular and biochemical process of skin restoration in DW healing. Also, these models were used to assess the potency of developed active pharmaceutical ingredients and formulations. However, many animal models lack studying mechanisms that can appropriately restate human DW, stay a huge translational challenge. This review discusses the available animal models with their significance in DW experiments and their limitations, focusing on levels of proof of effectiveness in selecting appropriate models to restate the human DW to improve clinical outcomes. Although numerous newer entities and combinatory formulations are very well appreciated preclinically for DW management, they fail in clinical trials, which may be due to improper selection of the appropriate model. The major future challenge could be developing a model that resembles the human DW environment, can potentiate translational research in DW care.

Article	Year
Pluronic lecithin organogel of 5-aminosalicylic acid for wound healing. Drug development and industrial pharmacy\| PubMed ID: 29848103	2018
Smart niosomes of temozolomide for enhancement of brain targeting. Nanobiomedicine\| PubMed ID: 30344765	2018
Nanostructured Lipid Carriers of Pioglitazone Loaded Collagen/Chitosan Composite Scaffold for Diabetic Wound Healing. Advances in wound care\| PubMed ID: 31737408	2019
HER2 targeted biological macromolecule modified liposomes for improved efficacy of capecitabine in breast cancer. International journal of biological macromolecules\| PubMed ID: 32061845	2020
Hypothesis validation of rosiglitazone a potential inhibitor against glycogen synthase kinase-3β, for the management of multifaceted pathophysiology of the diabetic wound: An insilico study. Medical hypotheses\| PubMed ID: 32592921	2020
Overview of in situ gelling injectable hydrogels for diabetic wounds. Drug development research\| PubMed ID: 33432634	2021
Benzohydrazide and Phenylacetamide Scaffolds: New Putative ParE Inhibitors. Frontiers in bioengineering and biotechnology\| PubMed ID: 34222214	2021
Preclinical models of diabetic wound healing: A critical review. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie\| PubMed ID: 34339915	2021

Bharat Kumar Reddy Sanapalli

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