Polymeric Nanoparticles as Tunable Nanocarriers for Targeted Delivery of Drugs to Skin Tissues for Treatment of Topical Skin Diseases.

The topical route is the most appropriate route for the targeted delivery of drugs to skin tissues for the treatment of local skin diseases; however, the stratum corneum (SC), the foremost layer of the skin, acts as a major barrier. Numerous passive and active drug delivery techniques have been exploited to overcome this barrier; however, these modalities are associated with several detrimental effects which restrict their clinical applicability. Alternatively, nanotechnology-aided interventions have been extensively investigated for the topical administration of a wide range of therapeutics. In this review, we have mainly focused on the biopharmaceutical significance of polymeric nanoparticles (PNPs) (made from natural polymers) for the treatment of various topical skin diseases such as psoriasis, atopic dermatitis (AD), skin infection, skin cancer, acute-to-chronic wounds, and acne. The encapsulation of drug(s) into the inner core or adsorption onto the shell of PNPs has shown a marked improvement in their physicochemical properties, avoiding premature degradation and controlling the release kinetics, permeation through the SC, and retention in the skin layers. Furthermore, functionalization techniques such as PEGylation, conjugation with targeting ligand, and pH/thermo-responsiveness have shown further success in optimizing the therapeutic efficacy of PNPs for the treatment of skin diseases. Despite enormous progress in the development of PNPs, their clinical translation is still lacking, which could be a potential future perspective for researchers working in this field.

Oromucosal delivery of macromolecules: Challenges and recent developments to improve bioavailability.

Owing to their biological diversity, high potency, good tolerability, low immunogenicity, site-specific activity, and great efficacy, macromolecular drugs (i.e., proteins and peptides, antibodies, hormones, nucleic acids, vaccines, etc.) are extensively used as diagnostics, prophylactics, and therapeutics in various diseases. To overcome drawbacks associated with parenteral (invasive) delivery of macromolecules as well as to preserve their therapeutic integrity, oromucosal route (sublingual and buccal) has been proven efficient alternate port of delivery. This review aims to summarize challenges associated with oromucosal route and overtime developments in conventional delivery systems with special emphasis on most recent delivery strategies. Over the past few decades, significant efforts have been made for improving the oromucosal absorption of macromolecules by employing chemical penetration enhancers (CPE), enzyme inhibitors, chemical modification of drug structure (i.e., lipidation, PEGylation, etc.), and mucoadhesive materials in the form of buccal tablets, films (or patches), sprays, fast disintegrating tablets, and microneedles. Adaptation of adjunct strategies (e.g., iontophoresis in conjunction with CPE) has shown significant improvement in oromucosal absorption of macromolecules; however, these approaches were also associated with many drawbacks. To overcome these shortcomings and to further improve therapeutic outcomes, specialized delivery devices called "hybrid nanosystems" have been designed in recent times. This newer intervention showed promising potential for promoting oromucosal absorption and absolute bioavailability of macromolecules along with improved thermostability (cold chain free storage), enabling self-administration, site-specific activity, improving therapeutic efficacy and patient compliance. We anticipate that tailoring of hybrid nanosystems to clinical trials as well as establishing their short- and long-term safety profile would substantiate their therapeutic value as pharmaceutical devices for oromucosal delivery of macromolecules.

Hyaluronic acid functionalization improves dermal targeting of polymeric nanoparticles for management of burn wounds: In vitro, ex vivo and in vivo evaluations.

Owing to its intricate pathophysiology, impaired wound healing is one of the substantial challenges in the treatment of burn wounds (BWs). Despite the variety of conventional therapies available, morbidities associated with BWs have not subsided. Therefore, aim of the present study was to design an advanced nanotechnology-composited therapy for effectual management of BWs. Hyaluronic acid (HA)-functionalized curcumin (CUR) and quercetin (QUE) co-loaded nanoparticle (HA-CUR-QUE-CSNPs) were fabricated, optimized, characterized and evaluated for successful co-encapsulation of drugs, morphology, stability, drug release, cell proliferation, penetration across the skin, localization in the epidermis and dermis, and in vivo wound healing efficacy. Fabricated HA-functionalized CSNPs exhibited ultra-small size (177 ± 11 nm), good zeta potential (+37.0 ± 3.2 mV), high encapsulation efficiency (EE) (QUE ∼84% and CUR ∼64%) and loading capacity (LC) (QUE ∼38% and CUR ∼43%), and spherical shape with uniformly rough surface. HA-functionalized CSNPs showed a triphasic release pattern with Fickian diffusion kinetics, a time-mannered progression in MC3T3-E1 cells proliferation, improved penetration of CUR (2414 µg/cm2) and QUE (1984 µg/cm2) through stratum corneum, and good localization of drugs in the epidermis and dermis. A superior wound healing efficacy (98% wound closure rate at day 28) with marked histological signs of minimal infiltration of inflammatory cells, re-epithelization, ECM formation, fibroblast infiltration at wound site, granulation tissue formation, angiogenesis, and collagen deposition were also evidenced. This study concludes that HA-functionalization of polymeric NPs could be a promising approach to maximize skin penetration efficiency, localization of drugs in skin tissues, tissue regeneration and BWs healing.

Smart pH-responsive Co-polymeric Hydrogels for Controlled Delivery of Capecitabine: Fabrication, Optimization and In Vivo Toxicology Screening.

BACKGROUND: Despite exhibiting promising anticancer potential, the clinical significance of capecitabine (a potent prodrug of 5-fluorouracil used for the treatment of colorectal cancer) is limited owing to its acidic and enzymatic hydrolysis, lower absorption following the oral administration, poor bioavailability, short plasma half-life, and poor patient compliance. OBJECTIVES: The present study was aimed to fabricate the capecitabine as a smart pH-responsive hydrogel network to efficiently facilitate its oral delivery while shielding its stability in the gastric media. METHODS: The smart pH-sensitive HP-ß-CD/agarose-g-poly(MAA) hydrogel network was developed using an aqueous free radical polymerization technique. The developed hydrogels were characterized for drug-loading efficiency, structural and compositional features, thermal stability, swelling behaviour, morphology, physical form, and release kinetics. The pH-responsive behaviour of developed hydrogels was established by conducting the swelling and release behaviour at different pH values (1.2 and 7.4), demonstrating significantly higher swelling and release at pH 7.4 as compared with pH 1.2. The capecitabine-loaded hydrogels were also screened for acute oral toxicity in animals by analysing the body weight, water and food intake, dermal toxicity, ocular toxicity, biochemical analysis, and histological examination. RESULTS: The characteristic evaluations revealed that capecitabine (anticancer agent) was successfully loaded into the hydrogel network. The range of capecitabine loading was from 71.22% to 90.12%. An interesting feature of hydrogel was its pH-responsive behaviour which triggers release at basic pH (94.25%). Optimum swelling (95%)was seen at pH 7.4. Based upon regression coefficient R2(0.96 - 0.99) the best-fit model was zero-order. The extensive toxicity evaluations evidenced a good safety profile with no signs of oral, dermal, or ocular toxicities, as well as no variations in blood parameters and histology of vital organs. CONCLUSION: Our findings conclusively evinced that the developed hydrogel exhibited excellent pharmaceutical and therapeutic potential and thus can be employed as a pH-responsive system for the controlled delivery of anticancer agents.

Norfloxacin Loaded Lipid Polymer Hybrid Nanoparticles for Oral Administration: Fabrication, Characterization, In Silico Modelling and Toxicity Evaluation.

Norfloxacin (NOR), widely employed as an anti-bacterial drug, has poor oral bioavailability. Nano based drug delivery systems are widely used to overcome the existing oral bioavailability challenges. Lipid-Polymer Hybrid Nanoparticles (LPHNs) exhibit the distinctive advantages of both polymeric and liposomes nanoparticles, while excluding some of their disadvantages. In the current study, NOR loaded LPHNs were prepared, and were solid amorphous in nature, followed by in vitro and in vivo evaluation. The optimized process conditions resulted in LPHNs with the acceptable particle size 121.27 nm, Polydispersity Index (PDI) of 0.214 and zeta potential of -32 mv. The addition of a helper lipid, oleic acid, and polymers, ethyl cellulose, substantially increased the encapsulation efficiency (EE%) (65% to 97%). In vitro study showed a sustained drug release profile (75% within 12 h) for NOR LPHNs. The optimized NOR LPHNs showed a significant increase (p < 0.05) in bioavailability compared to the commercial product. From the acute toxicity study, the LD50 value was found to be greater than 1600 mg/kg. The molecular modelling studies substantiated the experimental results with the best combination of polymers and surfactants that produced highly stable LPHNs. Therefore, LPHNs proved to be a promising system for the delivery of NOR, as well as for other antibiotics and hydrophobic drugs.

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.

Cell membrane cloaked nanomedicines for bio-imaging and immunotherapy of cancer: Improved pharmacokinetics, cell internalization and anticancer efficacy.

Despite enormous advancements in the field of oncology, the innocuous and effectual treatment of various types of malignancies remained a colossal challenge. The conventional modalities such as chemotherapy, radiotherapy, and surgery have been remained the most viable options for cancer treatment, but lacking of target-specificity, optimum safety and efficacy, and pharmacokinetic disparities are their impliable shortcomings. Though, in recent decades, numerous encroachments in the field of onco-targeted drug delivery have been adapted but several limitations (i.e., short plasma half-life, early clearance by reticuloendothelial system, immunogenicity, inadequate internalization and localization into the onco-tissues, chemoresistance, and deficient therapeutic efficacy) associated with these onco-targeted delivery systems limits their clinical viability. To abolish the aforementioned inadequacies, a promising approach has been emerged in which stealthing of synthetic nanocarriers has been attained by cloaking them into the natural cell membranes. These biomimetic nanomedicines not only retain characteristics features of the synthetic nanocarriers but also inherit the cell-membrane intrinsic functionalities. In this review, we have summarized preparation methods, mechanism of cloaking, and pharmaceutical and therapeutic superiority of cell-membrane camouflaged nanomedicines in improving the bio-imaging and immunotherapy against various types of malignancies. These pliable adaptations have revolutionized the current drug delivery strategies by optimizing the plasma circulation time, improving the permeation into the cancerous microenvironment, escaping the immune evasion and rapid clearance from the systemic circulation, minimizing the immunogenicity, and enabling the cell-cell communication via cell membrane markers of biomimetic nanomedicines. Moreover, the preeminence of cell-membrane cloaked nanomedicines in improving the bio-imaging and theranostic applications, alone or in combination with phototherapy or radiotherapy, have also been pondered.

Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting.

The tumor-specific targeting of chemotherapeutic agents for specific necrosis of cancer cells without affecting the normal cells poses a great challenge for researchers and scientists. Though extensive research has been carried out to investigate chemotherapy-based targeted drug delivery, the identification of the most promising strategy capable of bypassing non-specific cytotoxicity is still a major concern. Recent advancements in the arena of onco-targeted therapies have enabled safe and effective tumor-specific localization through stimuli-responsive drug delivery systems. Owing to their promising characteristic features, stimuli-responsive drug delivery platforms have revolutionized the chemotherapy-based treatments with added benefits of enhanced bioavailability and selective cytotoxicity of cancer cells compared to the conventional modalities. The insensitivity of stimuli-responsive drug delivery platforms when exposed to normal cells prevents the release of cytotoxic drugs into the normal cells and therefore alleviates the off-target events associated with chemotherapy. Contrastingly, they showed amplified sensitivity and triggered release of chemotherapeutic payload when internalized into the tumor microenvironment causing maximum cytotoxic responses and the induction of cancer cell necrosis. This review focuses on the physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems for triggered cancer chemotherapy through active and/or passive targeting. Moreover, the review also provided a brief insight into the molecular dynamic simulations associated with stimuli-based tumor targeting.

Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and future prospects.

Owing to their tremendous potential, the inference of nano-scaled materials has revolutionized many fields including the medicine and health, particularly for development of various types of targeted drug delivery devices for early prognosis and successful treatment of various diseases, including the brain disorders. Owing to their unique characteristic features, a variety of nanomaterials (particularly, ultra-fine particles (UFPs) have shown tremendous success in achieving the prognostic and therapeutic goals for early prognosis and treatment of various brain maladies such as Alzheimer's disease, Parkinson's disease, brain lymphomas, and other ailments. However, serious attention is needful due to innumerable after-effects of the nanomaterials. Despite their immense contribution in optimizing the prognostic and therapeutic modalities, biological interaction of nanomaterials with various body tissues may produce severe nanotoxicity of different organs including the heart, liver, kidney, lungs, immune system, gastro-intestinal system, skin as well as nervous system. However, in this review, we have primarily focused on nanomaterials-induced neurotoxicity of the brain. Following their translocation into different regions of the brain, nanomaterials may induce neurotoxicity through multiple mechanisms including the oxidative stress, DNA damage, lysosomal dysfunction, inflammatory cascade, apoptosis, genotoxicity, and ultimately necrosis of neuronal cells. Our findings indicated that rigorous toxicological evaluations must be carried out prior to clinical translation of nanomaterials-based formulations to avoid serious neurotoxic complications, which may further lead to develop various neuro-degenerative disorders.

Nanomedicines for improved targetability to inflamed synovium for treatment of rheumatoid arthritis: Multi-functionalization as an emerging strategy to optimize therapeutic efficacy.

Owing to its intricate autoimmune pathophysiology and significant risks of progression to other rheumatic co-morbidities (i.e., osteoporosis and osteoarthritis), a plausible therapeutic regimen is mandatory for early-stage management of rheumatoid arthritis (RA). Nevertheless, the conventional therapeutic agents particularly the corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) have shown grander success in the treatment of RA; however, long-term use of these agents is also associated with serious adverse events. To combat these issues and optimize therapeutic efficacy, nanotechnology-based interventions have been emerged as viable option. While, nanomedicines signposted superiority over the conventional pharmacological moieties; there are still many pharmacokinetic and pharmacodynamic challenges to nanomedicines following their intravenous or intra-articular administration. To circumvent these challenges, significant adaptations such as PEGylation, surface conjugation of targeting ligand(s), and site- responsive behavior (i.e., pH-, biochemical-, or thermal-responsiveness) have been implemented. Besides, multi-functionalization of nanomedicines has been emerging as an exceptional strategy to overcome pharmacokinetic challenges, improve targetability to inflamed synovium, maximise internalisation into the activated macrophages, and improved therapeutic outcomes for treatment of RA. Therefore, this review aims to conceptualize and recapitulate the substantial evidences regarding the pharmacokinetic and pharmacodynamic superiority of multi-functionalized nanomedicines over the naked nanomedicines for site-selective targeting to inflamed synovium and rational treatment of RA and other rheumatic co-morbidities. Pharmaceutical sustainability of the multi-functionalized nanomedicines for improved biocompatibility, profound interaction with the targeting tissue/cells/sub-cellular domain, and diminished systemic toxicity has also been pondered.

Eurycoma longifolia, a promising suppressor of RANKL-induced differentiation and activation of osteoclasts: An in vitro mechanistic evaluation.

BACKGROUND: Eurycoma longifolia (E. longifolia) has gained remarkable recognition due to its promising efficacy of stimulating bone formation in androgen-deficient osteoporosis. Numerous in vivo studies have explored the effects of E. longifolia on osteoporosis; however, the in vitro cellular mechanism was not discovered yet. OBJECTIVES: The present study was aimed to investigate the effect of E. longifolia on the proliferation, differentiation and maturation of osteoclasts and the translational mechanism of inhibition of osteoclastogenesis using RAW 264.7 cells as an in vitro osteoclastic model. MATERIALS AND METHODS: Having assessed cytotoxicity, the cell viability, cell proliferation rate and osteoclastic differentiation capacity of E. longifolia was investigated by evaluating the tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclasts. Taken together, the time-mannered expression of osteoclast-related protein biomarkers such as matrix metallopeptidase-9 (MMP-9), cathepsin-K, TRAP, nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), superoxide (free radicals) generation and superoxide dismutase activity were also measured to comprehend the mechanism of osteoclastogenesis. RESULTS: E. longifolia did not show significant effects on cytotoxicity and cell proliferation of RAW 264.7 cells; however, a significant inhibition of cells differentiation and maturation of osteoclasts was observed. Moreover, a significant down-regulation of RANKL-induced TRAP activity and expression of MMP-9, cathepsin-K, TRAP, NFATc1 and generation of superoxide and enhanced superoxide dismutase activity was observed in E. longifolia treated cell cultures. CONCLUSION: We anticipated that E. longifolia that enhances bone regeneration on the one hand and suppresses osteoclast's maturation on the other hand may have great therapeutic value in treating osteoporosis and other bone-erosive diseases such as rheumatoid arthritis and metastasis associated with bone loss.

Synergistic effects of combined therapy of curcumin and Fructus Ligustri Lucidi for treatment of osteoporosis: cellular and molecular evidence of enhanced bone formation.

OBJECTIVE: The present study explored the effects of the combined herbal therapy consisting of curcumin (CUR) and Fructus Ligustri Lucidi (FLL) on aspects of bone regeneration. METHODS: Prior to analyzing the ability of this novel combined herbal therapy to promote aspects of bone regeneration, its cytotoxicity was determined using MC3T3-E1 cells (pre-osteoblast model). Cell proliferation was evaluated using phase-contrast microscopy and cell differentiation was estimated using alkaline phosphatase activity. The effect of the combined herbal therapy (CUR + FLL) was also assessed in terms of mineralization in the extracellular matrix (ECM) of cultured cells. Further, to explore the molecular mechanisms of bone formation, time-dependent expression of bone-regulating protein biomarkers was also evaluated. RESULTS: Combined herbal therapy (CUR + FLL) significantly upregulated the viability, proliferation and differentiation of MC3T3-E1 cells compared to the monotherapy of CUR or FLL. The magnitude of ECM mineralization (calcium deposition) was also higher in MC3T3-E1 cells treated with combined therapy. The time-dependent expression of bone-forming protein biomarkers revealed that the tendency of expression of these bone-regulating proteins was remarkably higher in cells treated with combined therapy. CONCLUSION: The co-administration of CUR and FLL had superior promotion of elements of bone regeneration in cultured cells, thus could be a promising alternative herbal therapy for the management of bone erosive disorders such as osteoporosis.

Current Updates on Bone Grafting Biomaterials and Recombinant Human Growth Factors Implanted Biotherapy for Spinal Fusion: A Review of Human Clinical Studies.

BACKGROUND: Owing to their great promise in the spinal surgeries, bone graft substitutes have been widely investigated for their safety and clinical potential. By the current advances in the spinal surgery, an understanding of the precise biological mechanism of each bone graft substitute is mandatory for upholding the induction of solid spinal fusion. OBJECTIVE: The aim of the present review is to critically discuss various surgical implications and level of evidence of most commonly employed bone graft substitutes for spinal fusion. METHOD: Data was collected via electronic search using "PubMed", "SciFinder", "ScienceDirect", "Google Scholar", "Web of Science" and a library search for articles published in peer-reviewed journals, conferences, and e-books. RESULTS: Despite having exceptional inherent osteogenic, osteoinductive, and osteoconductive features, clinical acceptability of autografts (patient's own bone) is limited due to several perioperative and postoperative complications i.e., donor-site morbidities and limited graft supply. Alternatively, allografts (bone harvested from cadaver) have shown great promise in achieving acceptable bone fusion rate while alleviating the donor-site morbidities associated with implantation of autografts. As an adjuvant to allograft, demineralized bone matrix (DBM) has shown remarkable efficacy of bone fusion, when employed as graft extender or graft enhancer. Recent advances in recombinant technologies have made it possible to implant growth and differentiation factors (bone morphogenetic proteins) for spinal fusion. CONCLUSION: Selection of a particular bone grafting biotherapy can be rationalized based on the level of spine fusion, clinical experience and preference of orthopaedic surgeon, and prevalence of donor-site morbidities.

Recent Advances in Antibacterial, Antiprotozoal and Antifungal Trends of Eurycoma longifolia: A Review of Therapeutic Implications and Future Prospects.

BACKGROUND: Eurycoma longifolia (E. longifolia) has gained widespread recognition due to its versatile pharmacological activities including aphrodisiac, anticancer, antimicrobial, antioxidant, anti-inflammatory, anxiolytic, anti-diabetic, ergogenic, insecticidal, anti-rheumatism, bone protection, and anti-ulcer effects. OBJECTIVE: This review was aimed to critically overview the literature and summarizes the antibacterial, antiprotozoal, and antifungal trends of E. longifolia and its medicinally active components. RESULTS: Besides its well-documented safety, efficacy, and tolerability, a plethora of in vitro, in vivo, and human clinical studies has evidenced the antimicrobial efficacy of E. longifolia and its bioactive constituents. Phytochemical screening of various types of extracts (methanolic, ethyl acetate, and nbutanolic) from different parts (roots, stem, and leaves) of E. longifolia displayed a dose-dependent antibacterial, antiprotozoal, and antifungal responses. Comparative analysis revealed that the root extract of E. longifolia exhibited the highest antimicrobial efficacy compared to other parts of the plant. Bioactivity-guided fractionation identified that among all of the medicinal compounds isolated/ extracted from different parts of E. longifolia, eurycomanone displayed the strongest antibacterial, antiprotozoal and antifungal activities. CONCLUSION: Based on the critical analysis of the literature, we identified that E. longifolia exhibits promising antibacterial, antiprotozoal, and antifungal efficacies against various pathogenic microbes and thus can be considered as a potential complementary and alternative antimicrobial therapy.

Nanomedicines guided nanoimaging probes and nanotherapeutics for early detection of lung cancer and abolishing pulmonary metastasis: Critical appraisal of newer developments and challenges to clinical transition.

Lung cancer (LC) is the second most prevalent type of cancer and primary cause of mortality among both men and women, worldwide. The most commonly employed diagnostic modalities for LC include chest X-ray (CXR), magnetic-resonance-imaging (MRI), computed tomography (CT-scan), and fused-positron-emitting-tomography-CT (PET-CT). Owing to several limitations associated with the use of conventional diagnostic tools such as radiation burden to the patient, misleading diagnosis ("missed lung cancer"), false staging and low sensitivity and resolution, contemporary diagnostic regimen needed to be employed for screening of LC. In recent decades, nanotechnology-guided interventions have been transpired as emerging nanoimaging probes for detection of LC at advanced stages, while producing signal amplification, better resolution for surface and deep tissue imaging, and enhanced translocation and biodistribution of imaging probes within the cancerous tissues. Besides enormous potential of nanoimaging probes, nanotechnology-based advancements have also been evidenced for superior efficacy for treatment of LC and abolishing pulmonary metastasis (PM). The success of nanotherapeutics is due to their ability to maximise translocation and biodistribution of anti-neoplastic agents into the tumor tissues, improve pharmacokinetic profiles of anti-metastatic agents, optimise target-specific drug delivery, and control release kinetics of encapsulated moieties in target tissues. This review aims to overview and critically discuss the superiority of nanoimaging probes and nanotherapeutics over conventional regimen for early detection of LC and abolishing PM. Current challenges to clinical transition of nanoimaging probes and therapeutic viability of nanotherapeutics for treatment for LC and PM have also been pondered.

Recent Advances in Polymer-based Wound Dressings for the Treatment of Diabetic Foot Ulcer: An Overview of State-of-the-art.

BACKGROUND: Diabetic foot ulcers (DFUs) are the chronic, non-healing complications of diabetic mellitus which compels a significant burden to the patients and the healthcare system. Peripheral vascular disease, diabetic neuropathy, and abnormal cellular and cytokine/chemokine activity are among the prime players which exacerbate the severity and prevent wound repair. Unlike acute wounds, DFUs impose a substantial challenge to the conventional wound dressings and demand the development of novel and advanced wound healing modalities. In general, an ideal wound dressing should provide a moist wound environment, offer protection from secondary infections, eliminate wound exudate and stimulate tissue regeneration. OBJECTIVE: To date, numerous conventional wound dressings are employed for the management of DFUs but there is a lack of absolute and versatile choice. The current review was therefore aimed to summarize and critically discuss the available evidences related to pharmaceutical and therapeutic viability of polymer-based dressings for the treatment of DFUs. RESULTS: A versatile range of naturally-originated polymers including chitosan (CS), hyaluronic acid (HA), cellulose, alginate, dextran, collagen, gelatin, elastin, fibrin and silk fibroin have been utilized for the treatment of DFUs. These polymers have been used in the form of hydrogels, films, hydrocolloids, foams, membranes, scaffolds, microparticles, and nanoparticles. Moreover, the wound healing viability and clinical applicability of various mutually modified, semi-synthetic or synthetic polymers have also been critically discussed. CONCLUSION: In summary, this review enlightens the most recent developments in polymer-based wound dressings with special emphasis on advanced polymeric biomaterials, innovative therapeutic strategies and delivery approaches for the treatment of DFUs.

Eurycoma longifolia, A Potential Phytomedicine for the Treatment of Cancer: Evidence of p53-mediated Apoptosis in Cancerous Cells.

BACKGROUND: Eurycoma longifolia is a well-documented herbal medicine that has gained widespread recognition due to its versatile pharmacological activities including anticancer, antimalarial, antimicrobial, antioxidant, aphrodisiac, anti-inflammatory, anxiolytic, anti-diabetic, antirheumatism and anti-ulcer. Plethora of in vitro and in vivo studies evidenced their excellent antiproliferative and anticancer efficacy against various types of human cancers. OBJECTIVE: This review was aimed to critically analyze the therapeutic viability and anticancer efficacy of Eurycoma longifolia in the treatment of cancer and also to propose its molecular and translational mechanism of cytotoxicity against cancerous cells. RESULTS: Among a range of medicinally active compounds isolated from various parts (roots, stem, bark and leaves) of Eurycoma longifolia, 16 compounds have shown promising anti-proliferative and anticancer efficacies. Eurycomanone, one of the most active medicinal compounds of Eurycoma longifolia, displayed a strong dose-dependent anticancer efficacy against lung carcinoma (A-549 cells) and breast cancer (MCF-7 cells); however, showed moderate efficacy against gastric (MGC-803 cells) and intestinal carcinomas (HT-29 cells). The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced. CONCLUSION: Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and thus can be considered as potential complementary therapy for the treatment of various types of human cancers.

Exploring molecular mechanism of bone-forming capacity of Eurycoma longifolia: Evidence of enhanced expression of bone-related biomarkers.

BACKGROUND: Among the numerous well-documented medicinal herbs, Eurycoma longifolia (EL) has gained remarkable recognition due to its promising efficacy of stimulating bone formation in androgen-deficient osteoporosis. Though numerous animal studies have explored the bone-forming capacity of EL, the exact mechanism was yet to be explored. OBJECTIVE(S): The present study was aimed to investigate the mechanism of bone-forming capacity of EL using MC3T3-E1 as an in vitro osteoblastic model. MATERIALS AND METHODS: The cell differentiation capacity of EL was investigated by evaluating cell growth, alkaline phosphatase (ALP) activity, collagen deposition and mineralization. Taken together, time-mannered expression of bone-related mediators which include bone morphogenic protein-2 (BMP-2), ALP, runt-related transcription factor-2 (Runx-2), osteocalcin (OCN), type I collagen, osteopontin (OPN), transforming growth factor-ß1 (TGF-ß1) and androgen receptor (AR) were measured to comprehend bone-forming mechanism of EL. RESULTS: Results demonstrated a superior cell differentiation efficacy of EL (particularly at a dose of 25 µg/mL) that was evidenced by dramatically increased cell growth, higher ALP activity, collagen deposition and mineralization compared to the testosterone. Results analysis of the bone-related protein biomarkers indicated that the expression of these mediators was well-regulated in EL-treated cell cultures compared to the control groups. These findings revealed potential molecular mechanism of EL for the prevention and treatment of male osteoporosis. CONCLUSION: The resulting data suggested that EL exhibited superior efficacy in stimulating bone formation via up-regulating the expression of various mitogenic proteins and thus can be considered as a potential natural alternative therapy for the treatment of osteoporosis.

New developments and clinical transition of hyaluronic acid-based nanotherapeutics for treatment of cancer: reversing multidrug resistance, tumour-specific targetability and improved anticancer efficacy.

This review aims to overview and critically analyses recent developments in achieving tumour-specific delivery of anticancer agents, maximizing anticancer efficacy, and mitigating tumour progression and off-target effects. Stemming from critical needs to develop target-specific delivery vehicles in cancer therapy, various hyaluronic acid (HA)-conjugated nanomedicines have been fabricated owing to their biocompatibility, safety, tumour-specific targetability of drugs and genes, and proficient interaction with cluster-determinant-44 (CD44) receptors over-expressed on the surface of tumour cells. HA-based conjugation or surface modulation of anticancer drugs encapsulated nanocarriers have shown promising efficacy against the various types of carcinomas of liver, breast, colorectal, pancreatic, lung, skin, ovarian, cervical, head and neck and gastric. The success of this emerging platform is assessed in achieving the rapid internalization of anticancer payloads into the tumour cells, impeding cancer cells division and proliferation, induction of cancer-specific apoptosis and prevention of metastasis (tumour progression). This review extends detailed insight into the engineering of HA-based nanomedicines, characterization, utilization for the diagnosis or treatment of CD44 over-expressing cancer subtypes and emphasizing the transition of nanomedicines to clinical cancer therapy.

Hyaluronic acid, an efficient biomacromolecule for treatment of inflammatory skin and joint diseases: A review of recent developments and critical appraisal of preclinical and clinical investigations.

Hyaluronic acid (HA) plays multifaceted role in regulating various biological processes and maintaining homeostasis into the body. Numerous researches evidenced the biomedical implications of HA in skin repairmen, cancer prognosis, wound healing, tissue regeneration, anti-inflammatory, immunomodulation. The present review was aimed to summarize and critically appraise the recent developments and efficacy of HA for treatment of inflammatory skin and joint diseases. A thorough analysis of the literature revealed that HA based formulations (i.e., gels, creams, autologous graft, thin sheets, soaked gauze, gauze pad, tincture, injection) have shown remarkable efficacy in treating a wide range of inflammatory skin diseases. The safety, tolerability, and efficacy of HA (as intra-articular injection) have also been well-documented for treatment of various types of joint disease including knee osteoarthritic, joint osteoarthritis, canine osteoarthritis, and meniscal swelling. Intra-articular injection of HA produces remarkable reduction in joint pain, synovial inflammation, and articular swelling. A remarkable improvement in chondrocyte density, territorial matrix appearance, reconstitution of superficial amorphous layer of the cartilage, collagen remodelling, and regeneration of meniscus have also been evident in patients treated with HA. Conclusively, we validate that the application/administration of HA is a promising pharmacotherapeutic regimen for treatment of inflammatory skin and joint diseases.