Molecular Mechanisms and the Interplay of Important Chronic Obstructive Pulmonary Disease Biomarkers Reveals Novel Therapeutic Targets.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive, age-dependent, and unmet chronic inflammatory disease of the peripheral airways, leading to difficulty in exhalation. Several biomarkers have been tested in general towards the resolution for a long time, but no apparent success was achieved. Ongoing therapies of COPD have only symptomatic relief but no cure. Reactive oxygen species (ROS) are highly reactive species which include oxygen radicals and nonradical derivatives, and are the prominent players in COPD. They are produced as natural byproducts of cellular metabolism, but their levels can vary due to exposure to indoor air pollution, occupational pollution, and environmental pollutants such as cigarette smoke. In COPD, the lungs are continuously exposed to high levels of ROS thus leading to oxidative stress. ROS can cause damage to cells, proteins, lipids, and DNA which further contributes to the chronic inflammation in COPD and exacerbates the disease condition. Excessive ROS production can overwhelm cellular antioxidant systems and act as signaling molecules that regulate cellular processes, including antioxidant defense mechanisms involving glutathione and sirtuins which further leads to cellular apoptosis, cellular senescence, inflammation, and sarcopenia. In this review paper, we focused on COPD from different perspectives including potential markers and different cellular processes such as apoptosis, cellular senescence, inflammation, sirtuins, and sarcopenia, and tried to connect the dots between them so that novel therapeutic strategies to evaluate and target the possible underlying mechanisms in COPD could be explored.

A Proteomics Investigation of Cigarette Smoke Exposed Wistar Rats Revealed Improved Anti-Inflammatory Effects of the Cysteamine Nanoemulsions Delivered via Inhalation.

Cigarette smoking is the major cause of chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD). It is paramount to develop pharmacological interventions and delivery strategies against the cigarette smoke (CS) associated oxidative stress in COPD. This study in Wistar rats examined cysteamine in nanoemulsions to counteract the CS distressed microenvironment. In vivo, 28 days of CS and 15 days of cysteamine nanoemulsions treatment starting on 29th day consisting of oral and inhalation routes were established in Wistar rats. In addition, we conducted inflammatory and epithelial-to-mesenchymal transition (EMT) studies in vitro in human bronchial epithelial cell lines (BEAS2B) using 5% CS extract. Inflammatory and anti-inflammatory markers, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1ß, IL-8, IL-10, and IL-13, have been quantified in bronchoalveolar lavage fluid (BALF) to evaluate the effects of the cysteamine nanoemulsions in normalizing the diseased condition. Histopathological analysis of the alveoli and the trachea showed the distorted, lung parenchyma and ciliated epithelial barrier, respectively. To obtain mechanistic insights into the CS COPD rat model, "shotgun" proteomics of the lung tissues have been carried out using high-resolution mass spectrometry wherein genes such as ABI1, PPP3CA, PSMA2, FBLN5, ACTG1, CSNK2A1, and ECM1 exhibited significant differences across all the groups. Pathway analysis showed autophagy, signaling by receptor tyrosine kinase, cytokine signaling in immune system, extracellular matrix organization, and hemostasis, as the major contributing pathways across all the studied groups. This work offers new preclinical findings on how cysteamine taken orally or inhaled can combat CS-induced oxidative stress.

Technetium-99m labeled core shell hyaluronate nanoparticles as tumor responsive, metastatic skeletal lesion targeted combinatorial theranostics.

Achieving target specific delivery of chemotherapeutics in metastatic skeletal lesions remains a major challenge. Towards this, a dual drug loaded, radiolabeled multi-trigger responsive nanoparticles having partially oxidized hyaluronate (HADA) conjugated to alendronate shell and palmitic acid core were developed. While the hydrophobic drug, celecoxib was encapsulated in the palmitic acid core, the hydrophilic drug, doxorubicin hydrochloride was linked to the shell via a pH responsive imine linkage. Hydroxyapatite binding studies showed affinity of alendronate conjugated HADA nanoparticles to bones. Enhanced cellular uptake of the nanoparticles was achieved via HADA-CD44 receptor binding. HADA nanoparticles demonstrated trigger responsive release of encapsulated drugs in the presence of hyaluronidase, pH and glucose, present in excess in the tumor microenvironment. Efficacy of the nanoparticles for combination chemotherapy was established by >10-fold reduction in IC50 of drug loaded particles with a combination index of 0.453, as compared to free drugs in MDA-MB-231 cells. The nanoparticles could be radiolabeled with the gamma emitting radioisotope technetium-99m (99mTc) through a simple, 'chelator free', procedure with excellent radiochemical purity (RCP) (>90 %) and in vitro stability. 99mTc-labeled drug loaded nanoparticles reported herein constitutes a promising theranostic agent to target metastatic bone lesions. STATEMENT OF HYPOTHESES: Technetium-99m labeled, alendronate conjugated, dual targeting, tumor responsive, hyaluronate nanoparticle for tumor specific drug release and enhanced therapeutic effect, with real-time in vivo monitoring.

Biopolymer Coating Imparts Sustainable Self-Disinfecting and Antimicrobial Properties to Fabric: Translated to Protective Gears for the Pandemic and Beyond.

The global pandemic of COVID-19 and emerging antimicrobial drug resistance highlights the need for sustainable technology that enables more preparedness and active control measures. It is thus important to have a reliable solution to avert the present situations as well as preserve nature for habitable life in the future. One time use of PPE kits is promoting the accumulation of nondegradable waste, which may pose an unforeseen challenge in the future. We have developed a biocompatible, biodegradable, and nonirritating nanoemulsion coating for textiles. The study focused on coating cotton fabric to functionalize it with broad spectrum antimicrobial, antibiofilm, and anti-SARS-CoV-2 activity. The nanoemulsion comprises spherical particles of chitosan, oleic acid, and eugenol that are cross-linked to fibers. The nanoemulsion caused complete destruction of pathogens even for the most rigid biofilms formed by drug resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans on the surface of the coated fabric. The secondary coat with beeswax imparts super hydrophobicity and 20 wash cycle resistance and leads to enhanced barrier properties with superior particulate filtration, bacterial filtration, and viral penetration efficiency as compared to an N95 respirator. The coated fabric qualifies as per standard parameters like breathability, flammability, splash resistance, and filtration efficiency for submicrometer particles, bacteria, and viruses. The scaleup and bulk manufacturing of the coating technology on fabric masks complied with standards. The consumer feedback rated the coated mask with high scores in breathability and comfortability as compared to an N95. The strategy promises to provide a long-term sustainable model compared to single use masks and PPE that will remain a nondegradable burden on the ecosystem for years to come.

Targeted nano-delivery of chemotherapy via intranasal route suppresses in vivo glioblastoma growth and prolongs survival in the intracranial mouse model.

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood-brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therapeutic delivery stages. The objective of this research is to fabricate lipid nanoparticles (LNPs) for the co-delivery of paclitaxel (PTX) and miltefosine (HePc) a proapoptotic agent decorated with transferrin (Tf-PTX-LNPs) and investigate its anti-glioma activity both in vitro and in vivo orthotopic NOD/SCID GBM mouse model. The present study demonstrates the anti-glioma effect of the dual drug combination of PTX and proapoptotic HePc lipid-based transferrin receptor (TfR) targeted alternative delivery (direct nose to brain transportation) of the nanoparticulate system (Tf-PTX-LNPs, 364 ± 5 nm, -43 ± 9 mV) to overcome the O6-methylguanine-DNA methyltransferase induce drug-resistant for improving the effectiveness of GBM therapy. The resulting nasally targeted LNPs present good biocompatibility, stability, high BBB transcytosis through selective TfR-mediated uptake by tumor cells, and effective tumor penetration in the brain of GBM induced mice. We observed markedly enhanced anti-proliferative efficacy of the targeted LNPs in U87MG cells compared to free drug. Nasal targeted LNPs had shown significantly improved brain concentration (Cmax fivefold and AUC0-24 4.9 fold) with early tmax (0.5 h) than the free drug. In vivo intracranial GBM-bearing targeted LNPs treated mice exhibited significantly prolonged survival with improved anti-tumor efficacy accompanied by reduced toxicity compared to systemic Taxol® and nasal free drug. These findings indicate that the nasal delivery of targeted synergistic nanocarrier holds great promise as a non-invasive adjuvant chemotherapy therapy of GBM.

Lectin-Functionalized Chitosan Nanoparticle-Based Biosensor for Point-of-Care Detection of Bacterial Infections.

The WHO estimates an average of 10 million deaths per year due to the increasing number of infections and the predominance of drug resistance. To improve clinical outcomes and contain the spread of infections, the development of newer diagnostic tools is imperative to reduce the time and cost involved to reach the farthest population. The current study focuses on the development of a point-of-care technology that uses crystal violet entrapped, lectin functionalized chitosan nanoparticles to detect the presence of clinically relevant bacterial infections. Spherical nanoparticles of <200 nm in diameter make up the biosensing nanomaterial, showed specific clumping in the presence of bacteria to form visible aggregates as compared to a nonbacterial sample. Visible agglutination confirmed the presence of bacteria in the samples. The devices require just 100 µL of sample and were tested with various bacteria-spiked saline, simulated urine, artificial sputum, and simulated respiratory and wound swabs. The developed device did not require any sample preparation or sophisticated instruments while enabling rapid differentiation between bacterial and nonbacterial infections within 10 min. The in vitro results with bacteria-spiked simulated samples reveal 100% sensitivity and specificity with a limit of detection of 105 cfu/mL. The nanomaterial developed was found to be stable for more than 90 days at accelerated conditions. The developed device can be a screening tool for home-based or clinical assessment and follow the treatment accordingly, reducing exposure to broad-spectrum antibiotics in the case of nonbacterial infections.

Bio-polymeric transferrin-targeted temozolomide nanoparticles in gel for synergistic post-surgical GBM therapy.

Spatiotemporal targeting of anti-glioma drugs remains a pressing issue in glioblastoma (GBM) treatment. We challenge this issue by developing a minimally invasive in situ implantable hydrogel implant comprising transferrin-targeted temozolomide-miltefosine nanovesicles in the surgically resected GBM cavity (tumour bed). Injection of the "nanovesicle in hydrogel system" in orthotopic GBM-bearing mice improved drug penetration into the peri-cavitary region (∼4.5 mm in depth) with the potential to act as a bridge therapy in the immediate postoperative period, before the initiation of adjuvant radiotherapy. The controlled and sustained release of temozolomide over a month in the surgical cavity eradicated the microscopic GBM cells present within the tumour bed, thereby augmenting the efficacy of adjuvant therapy. The drug (temozolomide and miltefosine) combination was tolerable and efficiently inhibited tumour growth, causing significant prolongation of the survival of tumour-bearing mice compared to that with the free drug. Direct implantation at the target site in the brain resulted in spatiotemporal anti-glioma activity with minimal extracranial and systemic distribution. Nanovesicle in flexible hydrogel systems can be used as potential platforms for the post-surgical management of GBM before initiating adjuvant radiation therapy.

Nanotechnology Approaches for Rapid Detection and Theranostics of Antimicrobial Resistant Bacterial Infections.

As declared by WHO, antimicrobial resistance (AMR) is a high priority issue with a pressing need to develop impactful technologies to curb it. The rampant and inappropriate use of antibiotics due to the lack of adequate and timely diagnosis is a leading cause behind AMR evolution. Unfortunately, populations with poor economic status and those residing in densely populated areas are the most affected ones, frequently leading to emergence of AMR pathogens. Classical approaches for AMR diagnostics like phenotypic methods, biochemical assays, and molecular techniques are cumbersome and resource-intensive and involve a long turnaround time to yield confirmatory results. In contrast, recent emergence of nanotechnology-assisted approaches helps to overcome challenges in classical approaches and offer simpler, more sensitive, faster, and more affordable solutions for AMR diagnostics. Nanomaterial platforms (metallic, quantum-dot, carbon-based, upconversion, etc.), nanoparticle-based rapid point-of-care platforms, nano-biosensors (optical, mechanical, electrochemical), microfluidic-assisted devices, and importantly, nanotheranostic devices for diagnostics with treatment of AMR infections are examples of rapidly growing nanotechnology approaches used for AMR management. This review comprehensively summarizes the past 10 years of research progress on nanotechnology approaches for AMR diagnostics and for estimating antimicrobial susceptibility against commonly used antibiotics. This review also highlights several bottlenecks in nanotechnology approaches that need to be addressed prior to considering their translation to clinics.

Levonorgestrel Microneedle Array Patch for Sustained Release Contraception: Formulation, Optimization and In Vivo Characterization.

BACKGROUND: The goal of this work was to develop a levonorgestrel liposome-loaded microneedle array patch for contraception. METHODS: Levonorgestrel-loaded liposome was formulated by a solvent injection technique, characterized, and studied. RESULTS: The formulated liposomes were characterized for particle size (147 ± 8 nm), polydispersity index (0.207 ± 0.03), zeta potential (-23 ± 4.25 mV), drug loading (18 ± 3.22%) and entrapment efficiency (85 ± 4.34%). A cryo high-resolution transmission electron microscopy and cryo field emission gun scanning electron microscopy study showed spherical shaped particles with a smooth surface. The in vitro drug release and in vivo pharmacokinetic study showed sustained behaviour of Levonorgestrel for 28 days. CONCLUSION: The levonorgestrel liposome-loaded microneedle array patch showed better contraception than the drug-loaded microneedle array patch.

Wearable and implantable devices for drug delivery: Applications and challenges.

Poor adherence to drug dosing schedule is responsible for ∼50% of hospitalization cases. Most patients fail to adhere to a strict dosing schedule due to invasive drug administration, off-target toxicities, or medical conditions like dementia. The emerging concept of wearable devices (WDs), implantable devices (IDs) and combined wearable and implantable devices (WIDs) for drug delivery has created new opportunities for treating patients with chronic diseases needing repeated and long-term medical attention like diabetes, ocular disorders, cancer, wound healing, cardiovascular diseases, and contraception. WDs, worn on the body surface have created appealing non-invasive, self-administrable drug delivery platforms which receive huge patient compliance. Microneedle-skin patches, wound healing patches, drug-eluting contact lenses, mouth guards, intra-vaginal rings, pharmaceutical jewelry, and drug-loaded self-care textiles are popular WDs explored in drug delivery. In contrast, IDs are surgically placed inside body tissue allowing higher payload and enhanced localized effect for an extended duration. Hormone micropumps, hydrogel/nanofibrous depot, coronary stents, intravitreal devices, and intrauterine devices are some representative examples of IDs. In this review, we have described the past 10 years of research progress on drug-delivering WDs and IDs in the context of treating diseases that demand repeated and long-term medication, especially those affecting soft tissues. We highlighted several technical challenges that need to be addressed before considering the translation of such technologies to clinics.

Poly ε-Caprolactone Nanoparticles for Sustained Intra-Articular Immune Modulation in Adjuvant-Induced Arthritis Rodent Model.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder with synovitis and articular pathology as its primary expositions. Leflunomide (Lfd) is an anti-rheumatic drug that is effective in the treatment of RA, but displays severe side effects upon prolonged systemic administration. Local therapy might represent a promising strategy to treat rheumatoid arthritis without eliciting systemic adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) nanoparticles (Lfd-NPs) were prepared and assessed as a local drug delivery system capable of alleviating RA-associated inflammation. Lfd-NPs were optimized using the Quality by Design (QbD) approach, applying a 32 full factorial design. In vitro drug release from NPs was examined in simulated synovial fluid. In addition, the in vivo efficacy of Lfd-NPs was evaluated in the Adjuvant Induced Arthritis (AIA) rodent model. Sustained drug release in simulated synovial fluid was observed for up to 168 h. A gradual reduction in paw volume and knee diameter was observed over the course of treatment, indicating the regression of the disease. In addition, significant reductions in serum proinflammatory markers and cytokines, including the C-reactive protein (CRP), rheumatoid factor (RF), TNF-α, IL1-ß, and IL-6, were verified upon treatment with Lfd-NPs, suggesting the modulation of immune responses at the pathological site. Most importantly, no remarkable signs of toxicity were observed in Lfd-NP-treated animals. Collectively, intra-articularly administered Lfd-NPs might represent a potential therapeutic alternative to systemically administered drugs for the treatment of rheumatoid arthritis, without eliciting systemic adverse effects.

Loco-regional radiosensitizing nanoparticles-in-gel augments head and neck cancer chemoradiotherapy.

The therapeutic gain in loco-regionally advanced unresectable head and neck squamous cell carcinoma (HNSCC) is limited with the traditional use of concurrent chemoradiotherapy (CRT) owing to dose-limiting toxicities of systemic clinical radiosensitizers. Delivery through regional platforms is challenging due to limited drug permeation but allows spatio-temporal control of combinatorial regimens locally to overcome drug resistance. We address these challenges by developing biodegradable gellan- and lipid-based dual nanocarriers-in-ion-triggered porous mucoadhesive hydrogels for enhanced site-specific delivery of clinically relevant radiosensitizers i.e. cisplatin and paclitaxel. Interestingly, the nanoparticle-in-gel prolonged the tumor bioaccumulation of both the chemotherapeutic drugs with reduced systemic absorption, thereby improving in vivo efficacy which was confirmed by PET-CT imaging and safety as compared to systemic commercial formulations approved for HNSCC chemoradiotherapy. The nanoparticles facilitated intracellular radiosensitizer uptake and cell arrest to synergistically enhance radiation-induced DNA nicks and apoptosis. Our findings suggest the clinical potential of the present platform in the loco-regional management of HNSCC requiring curative CRT.

Phospholipid and menthol based nanovesicle impregnated transdermal patch for nutraceutical delivery to diminish folate and iron deficiency.

Adequate micronutrient availability is particularly important in women, children and infants. Micronutrient deficiencies are the major cause of maternal and neonatal morbidity. To overcome this, WHO recommends the use of folic acid and iron supplements for reducing anaemia and improving the health of the mother and infants. Oral intake of supplements for nutritional deficiencies are associated with gastric irritation, nausea, constipation and non-patient compliance due to associated taste. In case of absorption deficiency nutrients administered orally pass-through digestive tract unabsorbed. In the present study, we propose transdermal delivery of nutraceuticals to avoid the limitations associated with oral intake. Transdermal delivery has limited use because of the closely packed barrier of the stratum corneum that limits the permeability of molecules across skin. Here, we have used biomimetic nanovesicles impregnated in transdermal patches for delivery of folic acid and iron. Nanovesicles are prepared using an abundant component of cell membrane, phosphatidyl choline and a permeation enhancer. Further these nanovesicles are impregnated onto polyacrylate based transdermal patch.In vitrostudies have shown the ability of nanovesicles to fluidise skin lipids and penetrate into deeper skin.In vivoapplication of transdermal patches gradually increased the systemic concentration of nutraceuticals. Post application of the patch, five-fold increase in plasma folic acid concentration and 1.5-fold increase in plasma iron concertation was achieved in 6 h. Developed nanovesicles were compatible with keratinocytes and fibroblasts as testedin vitroand have the potential to enhance the cellular uptake of molecules. Skin irritation studies on human volunteers have confirmed the safety of nutraceutical loaded nanovesicles. Thus, the developed nutraceutical loaded transdermal patches provide a potential, easy to use platform for micronutrient delivery in infants and mothers.

Nanoparticle platforms for dermal antiaging technologies: Insights in cellular and molecular mechanisms.

Aging is a continuous process defined by a progressive functional decline in physiological parameters. Skin, being one of the most vulnerable organs, shows early signs of aging which are predominantly affected by intrinsic factors like hormone, gender, mood, enzymes, and genetic predisposition, and extrinsic factors like exposure to radiation, air pollution, and heat. Visible morphological and anatomical changes associated with skin aging occur due to underlying physiological aberrations governed by numerous complex interactions at cellular and subcellular levels. Nanoparticles are perceived as a powerful tool in the cosmeceutical industry both for augmenting the efficacy of existing agents and as a novel standalone therapy. Both organic and inorganic nanoparticles have been extensively investigated in antiaging applications. The use of nanoparticles helps to enhance the activity of antiaging molecules by selectively targeting cellular and molecular pathways. On the other hand, the nanoparticle platforms also gained increasing popularity as the skin protectant against extrinsic factors such as UV radiation and pollutants. This review comprehensively discusses skin aging and its mechanism by highlighting the impact on cellular, subcellular, and epigenetic elements. Importantly, the review elaborates on the examples of organic and inorganic nanoparticle-based formulations developed for antiaging application and provides mechanistic insights on how they modulate the mechanisms of skin aging. The clinical progress of nanoparticle antiaging technologies and factors that impact clinical translation are also explored. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Non-invasive transferrin targeted nanovesicles sensitize resistant glioblastoma multiforme tumors and improve survival in orthotopic mouse models.

The blood-brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen. Despite several anti-glioma drug delivery strategies, the lack of adequate chemotherapeutic bioavailability in gliomas has led to a suboptimal therapeutic gain in terms of improvement in survival and increased systemic toxicities. This has paved the way for designing highly specific and non-invasive drug delivery approaches for treating GBM. The intranasal (IN) route is one such delivery strategy that has the potential to reach the brain parenchyma by circumventing the BBB. We recently showed that in situ hydrogel embedded with miltefosine (HePc, proapoptotic anti-tumor agent) and temozolomide (TMZ, DNA methylating agent) loaded targeted nanovesicles prevented tumor relapses in orthotopic GBM mouse models. In this study, we specifically investigated the potential of a non-invasive IN route of TMZ delivered from lipid nanovesicles (LNs) decorated with surface transferrin (Tf) and co-encapsulated with HePc to reach the brain by circumventing the BBB in glioma bearing mice. The targeted nanovesicles (228.3 ± 10 nm, -41.7 ± 4 mV) exhibited mucoadhesiveness with 2% w/v mucin suggesting their potential to increase brain drug bioavailability after IN administration. The optimized TLNs had controlled, tunable and significantly different release kinetics in simulated cerebrospinal fluid and simulated nasal fluid demonstrating efficient release of the payload upon reaching the brain. Drug synergy (combination index, 0.7) showed a 6.4-fold enhanced cytotoxicity against resistant U87MG cells compared to free drugs. In vivo gamma scintigraphy of 99mTc labeled LNs showed 500- and 280-fold increased brain concentration post 18 h of treatment. The efficacy of the TLNs increased by 1.8-fold in terms of survival of tumor-bearing mice compared to free drugs. These findings suggested that targeted drug synergy has the potential to intranasally deliver a high therapeutic dose of the chemotherapy agent (TMZ) and could serve as a platform for future clinical application.

Ultrasound augments on-demand breast tumor radiosensitization and apoptosis through a tri-responsive combinatorial delivery theranostic platform.

Advanced inoperable triple-negative breast cancer (TNBC) comprises aggressive tumors with a modest pathological response to neoadjuvant chemotherapy. The concomitant use of chemoradiotherapy improves the pathological response rates. However, the dose-dependent systemic toxicity of clinical radiosensitizers with poor circulation half-life and limited passive bioavailability limits their clinical utility. We address these challenges by rationally designing a stealth and tumor microenvironment responsive nano-conjugate platform for the ultrasound-mediated on-demand spatio-temporal delivery of plant flavonoid curcumin as a combinatorial regimen with clinically approved paclitaxel for the neoadjuvant chemoradiotherapy of locally advanced triple-negative breast cancer (TNBC). Interestingly, the focused application of ultrasound at the orthotopic TNBC xenograft of NOD-SCID mice facilitated the immediate infiltration of nano-conjugates at the tumor interstitium, and conferred in vivo safety over marketed paclitaxel formulation. In addition, curcumin significantly potentiated the in vivo chemoradiotherapeutic efficacy of paclitaxel upon loading into nano-conjugates. This gets further enhanced by the concurrent pulse of ultrasound, as confirmed by PET-CT imaging, along with a significant improvement in the mice survival. The quadrapeutic apoptotic effect by the combination of paclitaxel, curcumin, radiation, and ultrasound, along with a reduction in the tumor microvessel density and cell proliferation marker, confers the broad chemo-radiotherapeutic potential of this regimen for radio-responsive solid tumors, as well as metastatic niches.

Efficacy of transdermal delivery of liposomal micronutrients through body oil massage on neurodevelopmental and micronutrient deficiency status in infants: results of a randomized placebo-controlled clinical trial.

BACKGROUND: Micronutrient deficiency is a known cause of adverse neurodevelopment and growth. Poor adherence to oral regimes of micronutrient supplements is a known challenge during the implementation of supplementation programs. The present study evaluates the benefits of liposomal encapsulated micronutrient fortified body oils (LMF oil) that can be used for infant body massage in terms of neurodevelopment and prevention of deficiency. STUDY DESIGN: Double-blind randomized clinical trial. METHODS: A total of 444 healthy infants aged 4-7 weeks were randomized to receive either LMF oil (containing iron, vitamin D, folate, and vitamin B12) or placebo oil for gentle body massage till 12 months of age. Blood samples were collected at 6 and 12 months for transferrin saturation (TSAT), hemoglobin, and 25-hydroxy vitamin (25-OH-D) levels. Mental and motor development was assessed at 12 months using developmental assessment for Indian Infants (DASII). RESULTS: A total of 391 infants completed the study. There was no significant improvement in the hemoglobin in the intervention group at 12 months of age as compared to the placebo group [- 0.50 vs.-0.54 g%]. There was a marginally significant improvement in 25-OH-D at 12 months in the LMF oil group [+ 1.46vs.-0.18 ng/ml, p = 0.049]. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age [adjusted mean change + 0.11vs.-0.51 g%, p = 0.043]. The mental or motor developmental quotients in the intervention group were not significantly different from those in the placebo group. CONCLUSION: Use of LMF oil for prevention of nutritional deficiency did not offer significant protection against nutritional anemia but prevented vitamin D deficiency to some extent with improvement in 25-OH-D at 12 months. In the subgroup of infants with moderate anemia, the intervention prevented the decline in hemoglobin at 12 months of age. The intervention did not result in significant improvement in mental or motor development. Further evaluation with increased doses needs to be undertaken. TRIAL REGISTRATION: CTRI no: CTRI/2017/11/010710 ; dated 30/11/2017.

Development of smart core-shell nanoparticle-based sensors for the point-of-care detection of alpha amylase in diagnostics and forensics.

Smart biocompatible materials, responsive to various external stimuli, hold immense potential in the development of biosensors for low-cost diagnostics. The present paper outlines the development of smart enzyme-responsive core-shell nanoparticle-based sensors as low-cost diagnostics for alpha amylase detection. The biocompatible core-shell nanoparticles of 200-250 nm size consisted of a chitosan-tripolyphosphate core formed by ionic gelation coated with a starch-iodine shell. In the presence of specific concentrations of amylase, the starch-iodine shell was disrupted and resulted in the exposure of core. This application herein describes a visible switch in color from blue to red towards the point-of-care detection of salivary alpha amylase (sAA). Stress and other autonomic disturbances can be diagnosed by measuring this biomarker. Also, alpha amylase can be used in the detection of latent saliva at crime scenes for forensic investigations. Using the present platform technology, a paper-based diagnostic was developed for detection of salivary alpha amylase that demonstrated a limit of detection (LoD) of 140 units/ml (70 mg/ml) at 5 minutes while a coated swab developed from the nanoparticles for crime scene investigations could achieve an LoD of 2.5 units/ml (1.25 mg/ml) over 30 minutes. The nanoparticles demonstrated stability and reproducibility with no interference seen with other substances in saliva. The present paper provides a proof-of-concept technology underscoring the utility of smart nanoparticles in affordable, versatile biosensing platforms like paper-based and swab-based formats for such diverse applications as diagnostics for stress and in forensics.

Immunomodulatory nanosystems for treating inflammatory diseases.

Inflammatory disease (ID) is an umbrella term encompassing all illnesses involving chronic inflammation as the central manifestation of pathogenesis. These include, inflammatory bowel diseases, hepatitis, pulmonary disorders, atherosclerosis, myocardial infarction, pancreatitis, arthritis, periodontitis, psoriasis. The IDs create a severe burden on healthcare and significantly impact the global socio-economic balance. Unfortunately, the standard therapies that rely on a combination of anti-inflammatory and immunosuppressive agents are palliative and provide only short-term relief. In contrast, the emerging concept of immunomodulatory nanosystems (IMNs) has the potential to address the underlying causes and prevent reoccurrence, thereby, creating new opportunities for treating IDs. The IMNs offer exquisite ability to precisely modulate the immune system for a therapeutic advantage. The nano-sized dimension of IMNs allows them to efficiently infiltrate lymphatic drainage, interact with immune cells, and subsequently to undergo rapid endocytosis by hyperactive immune cells (HICs) at inflamed sites. Thus, IMNs serve to restore dysfunctional or HICs and alleviate the inflammation. We identified that different IMNs exert their immunomodulatory action via either of the seven mechanisms to modulate; cytokine production, cytokine neutralization, cellular infiltration, macrophage polarization, HICs growth inhibition, stimulating T-reg mediated tolerance and modulating oxidative-stress. In this article, we discussed representative examples of IMNs by highlighting their rationalization, design principle, and mechanism of action in context of treating various IDs. Lastly, we highlighted technical challenges in the application of IMNs and explored the future direction of research, which could potentially help to overcome those challenges.