ABSTRACT Tissue regeneration using bioactive biomaterials has made great progress in the field of wound healing. Biopolymers play a cardinal role in regenerative medicine by providing safe, biocompatible and bioresorbable support. The electrospinning fabrication technique has been used in creating suitable wound care materials. PHBV and PLLA are FDA approved polymers having important applications in biomedical field. In this study, to increase the wound healing potential, PHBV was functionalized with –COOH group and electrospun nano-fibrous mat was produced using PHBV-COOH and PLLA blended solution. Antibiofilm peptide (IDR-1018) with immunomodulatory activity was incorporated into the blended solution to improve infected wound treatment by actively fighting against bacterial infections. Furthermore, in-vitro experiments including cell cytotoxicity assay and scratch wound healing assay were done to evaluate the potential of the synthesized bioactive nanofibrous mat as a potential wound management aid.

Breast cancer is the primary cause of cancer-related deaths in the female population across the globe. Polycaprolactone (PCL)-polyethylene glycol (PEG) copolymer micelles have been described for different drug delivery applications for breast cancer. Herein, to deliver paclitaxel (PTX), a stable nanomicelle was developed by using a maleic anhydride bridged PCL-PEG copolymer (PCGM) synthesized by a polycondensation reaction. PTX entrapped (PTX-PCGM) nanomicelles were prepared by a thin film hydration method. The spherical PTX-PCGM nanomicelles had a diameter of 235 nm with a negative surface charge, which facilitated their long-term circulation in the bloodstream. Additionally, the PTX-PCGM nanomicelles showed excellent stability in PBS over a period of 30 days. In vitro characterization and cellular experiments showed that the nanomicelles entered MDA-MB-231 cells via passive targeting, and the cytotoxicity of PTX was significantly increased by an enhanced stabilization of tubulin. A steady and sustained release was observed in NOD-SCID mice bearing MDA-MB-231 breast cancer. Moreover, the administration of PTX-PCGM exhibited superior anticancer activity in vivo with a tumor growth inhibition rate of 90.6% with no side effects in major organs. In conclusion, the PTX-PCGM nanomicelle could be a potential breast cancer therapy tool.

Severe burns pose significant threats to patient well-being, characterized by pain, inflammation, bacterial infection, and extended recovery periods. While exosome-loaded hydrogels have demonstrated considerable promise in wound healing, current formulations often fall short of achieving optimal therapeutic efficacy for burn wounds due to challenges related to their adaptability to wound shape and limited anti-bacterial capabilities. In this study a novel exosome laden sprayable thermosensitive polysaccharide-based hydrogel (ADA-aPF127@LL18/Exo) comprising alginate dialdehyde (ADA) and aminated Pluronic F127 (aPF127) was fabricated via Schiff base reaction. ADA-aPF127@LL18/Exo exhibited sustained release of exosome and enhanced antibacterial efficacy. Furthermore, the biological assessments displayed excellent biocompatibility and enhanced in vitro cell proliferation and migration. In a deep partial thickness burn model, ADA-aPF127@LL18/Exo significantly augmented wound healing processes by accelerating epithelialization, promoting granulation tissue formation and collagen deposition, inducing hair follicle regeneration, effectively mitigating inflammatory responses, and facilitating enhanced neovascularization. In conclusion, ADA-aPF127@LL18/Exo represents a highly promising therapeutic dressing for the treatment of deep burns, exhibiting multifaceted properties conducive to efficient wound management.

Chronic wound management using biomaterial-based dressings has significantly impacted the standard and efficiency of wound healing. However, various available wound healing aids are ineffective in treating deep open injuries and chronic wounds such as diabetic wounds. Herein, we developed a 3D bilayered multifunctional sponge, which addresses the structural and functional issues faced by biomaterial dressings in treating deep and chronic wounds. The 3D bilayered sponge consists of a hydrogel base functionalized with wound healing peptide (Tylotoin)-carrying nanoparticles and topped with a nanofiber layer functionalized with an antimicrobial peptide (LLKKK18). The 3D bilayered sponge, with its highly porous, elastic, and enhanced fluid absorption ability, makes it a suitable wound treatment aid. The developed multifunctional 3D sponge shows antibacterial action and promotes a microenvironment similar to the extracellular matrix (ECM) in regulating dermal cell survival and migration. Study in a full-thickness skin defect diabetic mouse model has shown that the developed 3D bilayered sponge accelerated wound closure and promoted functional skin regeneration through reduced inflammation, faster granulation tissue formation, re-epithelialization, neovascularization, and skin appendage restoration, which make the developed 3D bilayered multifunctional sponge an efficient and advanced chronic wound management aid with potential for future clinical application.

Wound infection remains a significant challenge in wound management, leading to inflammation and tissue damage that can impair the healing process. Antimicrobial peptides (AMPs) have emerged as a promising therapeutic strategy to combat this issue. However, the degradation of AMPs limits their efficacy, thus requiring a controlled release approach to overcome this limitation. In this study, we report the development of a chitosan-based wound dressing for the controlled release of AMPs in response to the Matrix metalloproteinase (MMP-8) enzyme at the wound site. The prepared scaffold demonstrated excellent physical properties and displayed potent antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. In vitro experiments with keratinocytes confirmed the biocompatibility of the dressing and its ability to promote cell proliferation and migration. In vivo studies using a full-thickness cutaneous wound model showed that the developed dressing facilitated neovascularization, increased collagen deposition, and re-epithelialization, thereby enhancing tissue regeneration and skin function restoration. The results of this study suggest that the developed chitosan-based wound dressing could serve as an effective therapeutic strategy for wound management.

We have investigated the wound healing efficiency of calcium alginate wafer embedded with growth factor entrapped PLGA nanoparticle. Herein, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) entrapped PLGA nanoparticles were synthesized and embedded in a sodium alginate gel by freeze-drying technique. The synthesized dressing exhibited a high degree of swelling and appropriate porosity. The scaffold was characterized by Scanning Electron Microscopy (SEM) showing a highly porous morphology. Also, incorporation of growth factor loaded nanoparticles in a wafer-based delivery system resulted in localized growth factor delivery at the site of the wound in a sustained manner. The biocompatibility of the scaffold was evaluated by MTT assay, which showed a higher cell proliferation in the proposed scaffold as compared to the control. In vivo wound healing efficiency of the scaffold was evaluated using a full thickness murine wound model, which showed improved re-epithelialization, collagen deposition, and angiogenesis. These results suggest the use of the scaffold as a promising wound dressing material.

Hard to heal wounds such as diabetic wounds is one of the major problems in the healthcare sector. Delayed healing and shortfall of functional restoration at the wound site require upgraded wound management aids. In this study, we report that a nanofibrous mat enriched with bioactive peptides laden nano and microparticles achieve the requirements as an effective diabetic wound dressing. By means of electrospinning method, we fabricated Poly (lactic-co-glycolic acid)/Collagen nano-scale mat and surface functionalised with wound healing peptides, laden Chitosan nano and micro-sized particles, creating an Extracellular Matrix (ECM) -like structure with biomimetic features. The developed dressing displayed good cytocompatibility with Keratinocyte and fibroblast cells and enhanced their in-vitro cell proliferation and migration. Experiments in the streptozotocin-induced diabetic mice model showed that bioactive peptides released from Chitosan particles shorten the inflammatory stage and promote neovascularisation. The supporting nanoscale matrix promotes increased collagen deposition in the wound beds, thereby hastening the complete healing process by substantial tissue re-generation and functional restoration. The results evince that the nano/microparticles enriched nano-scale mat show potential as an effective wound repair dressing for diabetic wounds.

Purpose: This study aimed to design a prototypic drug delivery system (DDS) made of an amphiphilic, pullulan (Pull)-derived biodegradable polymer for targeting the asialoglycoprotein receptor (ASGPR) overexpressed in HCC. Stearic acid (SA) was conjugated to increase the hydrophobicity of pullulan (Pull-SA). Methods: Pullulan (Pull) was linked to stearic acid (SA) after functional group modifications via EDC/NHS chemistry and characterized. Sorafenib tosylate (SRFT) was entrapped in pullulan-stearic acid nanoparticles (Pull-SA-SRFT) and its particle size, zeta potential, entrapment efficiency (EE), loading capacity (LC), and release efficiency was measured. The competence of Pull-SA-SRFT over SRFT in vitro was assessed using the ASGPR over-expressing PLC/PRF/5 hepatocellular carcinoma (HCC) cell line. This was done by studying cytotoxicity by MTT assay and chromosome condensation assay, early apoptosis by annexin-Pi staining, and late apoptosis by live-dead assay. The cellular uptake study was performed by incorporating coumarin-6 (C6) fluorophore in place of SRFT in Pull-SA conjugates. A biodistribution study was conducted in Swiss-albino mice to assess the biocompatibility and targeting properties of SRFT and Pull-SA-SRFT to the liver and other organs at 1, 6, 24, and 48 h. Results: The characterization studies of the copolymer confirmed the successful conjugation of Pull-SA. The self-assembled amphiphilic nanocarrier could proficiently entrap the hydrophobic drug SRFT to obtain an entrapment efficiency of 95.6% (Pull-SA-SRFT). Characterization of the synthesized nanoparticles exhibited highly desirable nanoparticle characteristics. In vitro, apoptotic studies urged that Pull-SA-SRFT nanoparticle was delivered more efficiently to HCC than SRFT. The cellular uptake study performed, gave propitious results in 4 hrs. The biodistribution study conducted in immunocompetent mice suggested that Pull-SA-SRFT was delivered more than SRFT to the liver when compared to other organs, and that the system was biocompatible. Conclusion: Pull-SA-SRFT is a promisingly safe, biodegradable, cell-specific nanocarrier and a potential candidate to target hydrophobic drugs to HCC.

Purpose:The brain, protected by the cranium externally and the blood-brain barrier (BBB) internally, poses challenges in chemotherapy of aggressive brain tumors. Maximal tumor resection followed by radiation and chemotherapy is the standard treatment protocol; however, a substantial number of patients suffer from recurrence. Systemic circulation of drugs causes myelodysplasia and other side effects. To address these caveats, we report facile synthesis of a polyester-based supramolecular hydrogel as a brain biocompatible implant for in situ delivery of hydrophobic drugs.Methods:Polycaprolactone-diol (PCL) was linked to polyethyleneglycol-diacid (PEG) via an ester bond. In silico modeling indicated micelle-based aggregation of PCL-PEG co-polymer to form a supramolecular hydrogel. Brain biocompatibility was checked in Sprague Dawley rat brain cortex with MRI, motor function test, and histology. Model hydrophobic drugs carmustine and curcumin entrapment propelled glioma cells into apoptosis-based death evaluated by in vitro cytotoxicity assays and Western blot. In vivo post-surgical xenograft glioma model was developed in NOD-SCID mice and evaluated for efficacy to restrict aggressive regrowth of tumors.Results:20% (w/v) PCL-PEG forms a soft hydrogel that can cover the uneven and large surface area of a tumor resection cavity and maintain brain density. The PCL-PEG hydrogel was biocompatible, and well-tolerated upon implantation in rat brain cortex, for a study period of 12 weeks. We report for the first time the combination of carmustine and curcumin entrapped as model hydrophobic drugs, increasing their bioavailability and yielding synergistic apoptotic effect on glioma cells. Further in vivo study indicated PCL-PEG hydrogel with a dual cargo of carmustine and curcumin restricted aggressive regrowth post-resection significantly compared with control and animals with intravenous drug treatment.Conclusion:PCL-PEG soft gel-based implant is malleable compared with rigid wafers used as implants, thus providing larger surface area contact. This stable, biocompatible, supramolecular gel without external crosslinking can find wide applications by interchanging formulation of various hydrophobic drugs to ensure and increase site-specific delivery, avoiding systemic circulation.

Purpose Peptide-based therapy is a promising strategy for cancer treatment because of its low drug resistance. However, the major challenge is their inability to target cancer cells specifically. So, a targeted nano-delivery system that could deliver therapeutic peptides selectively to cancer cells to stimulate their action is highly desirable. This study aims to deliver the antitumor peptide, Pep5, to breast tumor cells selectively using a targeting peptide functionalised multi-layered PLGA-PEI nanoparticles. Methods In this study, Pep5 entrapped PLGA-PEI (Pep5-PPN) dual layered nanoparticles were developed. These nanoparticles were decorated with TKD (Pep5-TPPN) on their surface for site-specific delivery of Pep5 to breast tumor cells. The particles were then characterized using various instrumental analyses. In vitro cytotoxicity of the particles was evaluated in estrogen receptor positive (ER+ve) and triple negative breast cancer (TNBC) cells. An ex vivo tumor spheroid model was used to analyze the antitumor activity of the particles. Results Uniformly round Pep5-TPPN particles were synthesized with an average diameter of 420.8 ± 14.72 nm. The conjugation of PEI over Pep5-PLGA nanoparticles shifted the zeta potential from −11.6 ± 2.16 mV to +20.01 ± 2.97 mV. In vitro cytotoxicity analysis proved that TKD conjugation to nanoparticles enhanced the antitumor activity of Pep5 in tested breast cancer cells. Pep5-TPPN induced cytoskeletal damage and apoptosis in the tested cells, which showed that the mechanism of action of Pep5 is conserved but potentiated. Active targeting of Pep5 suppressed the tumor growth in ex vivo spheroid models. Conclusion A multi-layered nanoparticle functionalized with dual peptide was fabricated for active tumor targeting, which stimulated Pep5 activity to reduce the tumor growth in vitro and ex vivo.

The rate of lung cancer incidence is alarmingly mounting, despite the decline of smoking and tobacco consumption. Recent reports indicate a very high correlation between the growing fast food culture and lung cancer incidence. Benzo[a]pyrene (B[a]P) is a potent carcinogen abundantly present in grilled and deep-fried food and in tobacco smoke. Our previous studies have proved the efficacy of curcumin in curbing B[a]P-induced lung carcinogenesis. However, the poor pharmacokinetic profile of the compound considerably hampers its potential as an effective chemopreventive. This study was intended to evaluate whether encapsulation of curcumin in chitosan nanoparticles can improve the cellular uptake and prolong the tissue retention of curcumin yielding better chemoprevention. The curcumin-loaded chitosan nanoparticles (chitosan nanocurcumin) exhibited a size of 170-200 nm in transmission electron microscopy. In vitro drug release studies showed sustained release of curcumin over a period of approximately 180 hours and excellent intracellular uptake and cytotoxicity in lung cancer cells. Bioavailability studies using healthy Swiss albino mice demonstrated drastic enhancement in lung localization of chitosan nanocurcumin compared with free curcumin. Toxicologic evaluation using chronic toxicity model in Swiss albino mice confirmed the pharmacologic safety of the formulation. Moreover, the formulation, even at a dose equivalent to one fourth that of free curcumin, exhibits better efficacy in reducing tumor incidence and multiplicity than free curcumin, thereby hampering development of B[a]P-induced lung adenocarcinomas in Swiss albino mice. Hence, our study underscores the supremacy of the formulation over free curcumin and establishes it as a potential chemopreventive and oral supplement against environmental carcinogenesis.

Application of growth factors at wound site has improved the efficiency and quality of healing. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) induce proliferation of various cells in wound healing. Delivery of growth factor from controlled release systems protect it from degradation and also result in sustained delivery of it at the site of injury. The goal of the study was to develop a Polyethylene glycol (PEG) cross-linked cotton-like chitosan scaffold (CS-PEG-H) by freeze-drying method and chemically conjugate heparin to the scaffold to which the growth factors can be electrostatically bound and evaluate its wound healing properties in vitro and in vivo. The growth factor containing scaffolds induced increased proliferation of HaCaT cells, increased neovascularization and collagen formation seen by H and E and Masson's trichrome staining. Immunohistochemistry was performed using the Ki67 marker which increased proliferation of cells in growth factor containing scaffold treated group. Frequent dressing changes are a major deterrent to proper wound healing. Our system was found to release both VEGF and bFGF in a continuous manner and attained stability after 7 days. Thus our system can maintain therapeutic levels of growth factor at the wound bed thereby avoiding the need for daily applications and frequent dressing changes. Thus, it can be a promising candidate for wound healing.

This interdisciplinary research highlights the engineering of glycolipid nanomicelles with surface modification using a BBB crossing peptide for in vivo drug delivery especially for glioma therapy. We demonstrated an eco-friendly, green synthesis of a nanomicelle followed by felicitous characterization which substantiates the merits of the drug delivery system.

Background Treatment of wounds with the help of nanoparticles (NPs) is more effective and superior in comparison to traditional wound healing methods as it protects and sustains active drug release at the wound site thus enhancing the safety of the drug and reducing the possibility of side effects. The advantages of this method are the possibility of allowing a reduction in administered dose, limiting toxicity levels to the minimum, and increasing safety of topical delivery of the drug. Materials and methods We report the synthesis of a novel poly (lactic-co-glycolic acid) (PLGA) NP-based multicargo delivery system for growth factors and antimicrobial peptide. Growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were entrapped in PLGA NPs by solvent diffusion method and an antimicrobial peptide (K4) was conjugated to the NP by carbodiimide chemistry. The developed multiple cargo delivery systems with growth factors (VEGF and bFGF) and an antimicrobial peptide (K4) were investigated and optimized for potential wound healing. Results The system showed a sustained release of growth factors and was evaluated for cytotoxicity by MTT and live/dead assay, which revealed that the bioactivity of the growth factor-entrapped NPs was higher than that of free growth factors, and it also induced enhanced cell proliferation in vitro. Conclusion The development of a system for the codelivery of growth factors (VEGF and bFGF) and an antimicrobial peptide (K4) was investigated for potential wound healing application. The entrapment of growth factors with very high efficiency is an advantage in this method along with its sustained release from the nanoparticulate system, which will enhance the angiogenesis. Our system also displayed broad-spectrum antimicrobial activity against both gram-positive and gram-negative bacteria.

Methylotrophs present in the soil play an important role in the regulation of one carbon compounds in the environment, and thereby aid in mitigating global warming. The study envisages the isolation and characterization of methanol-degrading bacteria from Kuttanad wetland ecosystem, India. Three methylotrophs, viz. Achromobacter spanius KUT14, Acinetobacter sp. KUT26 and Methylobacterium radiotolerans KUT39 were isolated and their phylogenetic positions were determined by constructing a phylogenetic tree based on 16S rDNA sequences. In vitro activity of methanol dehydrogenase enzyme, responsible for methanol oxidation was evaluated and the genes involved in methanol metabolism, mxaF and xoxF were partially amplified and sequenced. The specific activity of methanol dehydrogenase (451.9 nmol min−1 mg−1) observed in KUT39 is the highest, reported ever to our knowledge from a soil bacterium. KUT14 recorded the least activity of 50.15 nmol min−1 mg−1 and is the first report on methylotrophy in A. spanius.

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs.Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively.Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time.Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies.Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death.In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo, in Swiss albino mice.Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe.We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice.Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts.The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials.

Introduction: Very few successful interventions have been possible in glioma therapy owing to its aggressive nature as well as its hindrance of targeted therapy together with the limited access afforded by the blood-brain barrier (BBB). With the advent of nanotechnology based delivery vehicles such as micelles, dendrimers, polymer-based nanoparticles and nanogels, the breach of the BBB has been facilitated. However, there remains the issue of targeted therapy for glioma cells. Peptide-mediated surface modification of nanocarriers serves this purpose, extending the ability to target glioma further than the enhanced permeability and retention effect.Areas covered: Here we have tried to re-establish the significance of peptides that could be used in various ways for treating glioma. Peptide-embellished nanocarriers used to deliver anticancer drugs; nucleic acids (siRNA, miRNA); micelles or dendrimers grafted with immunogenic glioma-derived peptides used for stimulating active immunity in vaccine therapy, glioma targets for cell penetrating peptides and homing to specific receptors are reviewed.Expert opinion: Peptides have multifunctional potential in targeting, BBB and cell penetration, and can serve as antagonists of various ligands and agonists of particular over-expressed receptors as discussed in this review. Using peptides in targeted personalized therapy would be one step forward and may offer new avenues for glioma therapeutics.

Dry powder inhalers (DPI) attracted the attention of pharmaceutical field due to its enlarging market share in inhalable formulations. These formulations also pose patient compliance and good shelf life. Earlier DPI formulations were intended for local effect in lung (asthma and chronic obstructive pulmonary diseases), whereas 21st century witnessed formulations intended for systemic effect too. A better understanding of physiology of lung and fluidics of air flow helped in targeting alveoli using DPI technology. Modern characterization tools also accelerated the research pace. In addition to the synthetic molecules, DPI also was proved to be a better system for delivering biological molecules including vaccines. This review includes the mechanisms of drug deposition, advancements in the fields of DPI devices, various characterization tools and particle engineering. In this review we have related the chronological advancement of inhalational technology starting from 1788 AD to the present.

Effective delivery of drugs to alveoli in a controlled manner using hydrophobic polymers as carriers has already been reported. Preclinical studies revealed that toxicity and hydrophobicity are related to each other in pulmonary delivery. Here, we are reporting a chemically modified dextran having amphiphilicity and cationicity achieved by controlled grafting of stearyl amine. Two proportions of lipopolymers were synthesized and physico-chemical characterization was carried out. In vivo evaluation of sub-acute toxicity of the synthesized lipopolymer in Sprague–Dawley rats was carried out for three months. This was followed by a histological evaluation of the sacrificed animal's lung. Further, the synthesized lipopolymer was formulated with drug (Rifampicin) loaded inhalable microparticles through spray drying. The final drug formulation was tested for toxicity and proinflammatory responses in human cell lines. Dose deposition efficiency of the formulation was determined using Anderson Cascade Impactor.

In this work, Isoniazid (INH) (an anti-TB drug) was converted to inhalable particles using cryo-crystallization under a partial anti-solvent environment.