Blind Spots in Development of Nanomedicines.

The field of nanomedicine demonstrates immense advantages and noteworthy expansion compared to conventional drug delivery systems like tablet, capsules, etc. Despite the innumerable advantages, it holds certain shortcomings in the form of blind spots that need to be assessed before the successful clinical translation. This perspective highlights the foremost blind spots in nanomedicine and emphasizes the challenges faced before the entry into the market, including the need for provision of safety and efficacy data by the regulatory agencies like FDA. The significant revolution of nanomedicine in the human life, particularly in patient well-being, necessitates to identify the blind spots and overcome them for effective management and treatment of ailments.

Nanodiamond-based berberine aquasomes for enhancing penetration across epidermis to treat psoriasis.

The use of berberine hydrochloride (BCS class III) has limited application in psoriasis, when given as topical drug delivery systems, due to low permeability in the skin layer. Hence, berberine hydrochloride-loaded aquasome nanocarriers were developed for skin targeting, particularly epidermis (primary site of psoriasis pathophysiology) and enhance the skin permeability of berberine hydrochloride. Aquasomes were formulated using the adsorption method and characterized by structural morphology TEM, % drug adsorption, drug release profile (in-vitro and ex-vivo), in-vivo efficacy study and stability study. The reduced particle size and higher surface charge of SKF3 formulation (263.57 ± 27.78 nm and -21.0 ± 0.43 mV) showed improved stability of aquasomes because of the development of higher surface resistance to formation of aggregates. The adsorption of hydrophilic berberine and the non-lipidic nature of aquasomes resulted in % adsorption efficiency (%AE) of 94.46 ± 0.39 %. The controlled first-order release behavior of aquasomes was reported to be 52.647 ± 14.63 and 32.08 ± 12.78 % in in-vitro and ex-vivo studies, respectively. In-vivo studies demonstrated that topical application of berberine hydrochloride loaded aquasomes significantly alleviated psoriasis symptoms like hyperkeratosis, scaling and inflammation, due to the reduction in the inflammatory cytokines (IL-17 and IL-23). Therefore, aquasome formulation exhibits an innovative approach for targeted application of berberine hydrochloride in the management of psoriasis.

BSA nanoclusters-based sensor for detection of dopamine in schizophrenia from biofluids.

OBJECTIVE: To develop nontoxic and stable fluorescent emission B-Cu nanoclusters (NCs) for the specific detection of dopamine at low concentrations in cerebrospinal fluid (CSF). SIGNIFICANCE: Fluorescent gold and copper NCs conjugated with proteins, such as bovine serum albumin (BSA), offer photostability and healthcare potential. This study focused on fabricating B-Cu NCs that exhibited superior characteristics for sensitive dopamine detection. METHODS: The study employed various instrumental techniques including attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), spectrofluorometry, and transmission electron microscopy (TEM) to characterize the formulated B-Cu NCs. The NCs were synthesized, resulting in particle size ∼300 nm. The highest observed fluorescence was recorded at 24542.81 relative fluorescence units (RFU). RESULTS: The introduction of dopamine at concentrations of 0.1, 0.2, 0.3, and 0.4 ng/mL led to decreased fluorescence in both B-Au and B-Cu NCs due to an electron transport system. This reduction in fluorescence allowed dopamine concentration analysis in phosphate buffer and biological fluids such as blood plasma and CSF. B-Cu NCs showed potential as a biosensing system for point-of-care (POC) applications, specifically for diagnosing schizophrenia. CONCLUSION: The study successfully synthesized stable and nontoxic B-Cu NCs with enhanced fluorescent emission properties. These NCs exhibited the capacity to detect dopamine at low concentrations in CSF. The study's findings hold promise for future applications, particularly in the development of a B-Cu NCs-based biosensing system for convenient POC detection of schizophrenia by both patients and clinicians. The potential impact of this technology on healthcare and biomedical fields is substantial.

Potentiation of Brain Bioavailability Using Thermoreversible Cubosomal Formulation.

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 µg/mL), Cmax (368.07 ± 0.23 µg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

Therapeutic Potential of Stem Cells in Natural Killer-Like B Cell-Associated Diseases.

Stem cells are undifferentiated cells possessing a remarkable capacity to develop into multiple cell types. NKB cells, referred to "natural killer-like B cells," are recently identified subtype of B lymphocytes possessing characteristics that are similar to both natural killer (NK) cells and regular B lymphocytes. NK cells are lymphocyte-like in structure and cytotoxic in nature participating in the immediate immune response to the infected or malignant cells, whereas B lymphocytes produce antibodies and participate in adaptive immune response by binding to the specific antigen. The identification of NKB cells brings up new possibilities for studying and perhaps modulating immune responses in a variety of diseases, particularly those associated with microbial infections or inflammatory responses. Further, correlation of NKB cells with interleukins allows us to understand the molecular mechanism of diseases. Stem cell research offers a better understanding of NKB cell participation and provides new insights for novel treatment methods wherein mesenchymal stem cells (MSCs) have found to be the most promising stem cell showing positive outcomes in NKB cell-associated inflammatory diseases. Additionally, the perceptions acquired from researching NKB cells in diverse diseases leads to innovative treatment options, improving our capacity to control and cure immunological dysregulation-related ailments.

Anti-CD64 Antibody-Conjugated PLGA Nanoparticles Containing Methotrexate and Gold for Theranostics Application in Rheumatoid Arthritis.

Rheumatoid arthritis, an autoimmune disorder, exerts a considerable effect on quality of life. The inflammatory mechanism involved in rheumatoid arthritis is not clearly known, and therefore the need to develop effective medicines as well as new methods for early detection is a challenge. In this study, we developed PLGA nanoparticles containing gold and methotrexate in core and anti-CD64 antibody conjugated to nanoparticle surface via coupling process. The nanoparticles were examined for their surface morphology using SEM and TEM. The mean particle size, zeta potential, and PDI values of nanoparticles were 413.6 ± 2.89 nm, -10.12 ± 2.12 mV, and 0.23 ± 0.04, respectively, indicating good stability and particle homogeneity. In vitro drug release revealed a controlled release pattern with 93.44 ± 1.60% up to 72 h of release in the presence of pH 5.8, indicating the influence of pH and NIR on drug release. In vivo results on adjuvant-induced arthritis on Wistar rats indicated that animals receiving antibody-conjugated nanoparticles showed improvement in clinical indices and arthritic score as compared to non-conjugated nanoparticles and free drugs. This innovative drug delivery system will be an excellent strategy to maximize therapeutic effectiveness by limiting dosage-related side effects.

Phthalocyanine-based glucose-responsive nanocochleates for dynamic prevention of ß-cell damage in diabetes.

Phthalocyanine is a blue-colored macrocyclic compound with excellent anti-oxidant and lipid-peroxidation abilities due to its intermolecular π-π stacking structure. Antioxidants inhibit intracellular reactive oxygen species formation and decrease oxidation defense ability of the enzymes in diabetes management. The present study aimed to fabricate concanavalin A conjugated phthalocyanine-loaded cochleates (Formulation PhConA) as a glucose-sensitive lipidic system and estimate its efficacy in streptozotocin-induced male Sprague Dawley diabetic rats for 28 days. Thin-film hydration and trapping methods were used in the preparation of liposomes and cochleates, respectively, whereas the surface was modified for concanavalin A conjugation using EDAC: NHS (1:1). Formulation PhConA with rod-shaped structures showed particle size of 415.7 ± 0.46 nm, PdI value of 0.435 ± 0.09, encapsulation efficiency of 85.64 ± 0.34%, and 84.55 ± 0.29% release of phthalocyanine for 56 h. The circular dichroism study displayed a slight deviation after the conjugation effect of concanavalin A to cochleates. The in-vivo studies of the formulation PhConA improved the blood glucose levels along with defensive effect on the liver to overcome the hyperlipidemic effect. The rigid structure of cochleates prolongs the drug elimination from systemic circulation and extends its effect for a longer duration by decreasing the blood glucose level. Thus, the glucose-sensitive formulation PhConA showed significant improvement in diabetic rats within the period of 28 days by improving the oxidative defense and protecting the pancreatic ß-cells.

Zinc-Phthalocyanine Loaded PLGA-PVA-Chitosan Nanosystem for the Enhancement of Antidiabetic Activity.

Zinc, one of the most common nutraceutical agents, proved to be effective for diabetes as it regulates the blood glucose level by inhibiting glucagon secretion. However, the hepatotoxicity of zinc creates necrosis, hepatic glycogen depletion, and apoptosis of hepatocytes at the concentration of 10 µg/kg. Phthalocyanine, a blue-colored compound, is an aromatic macrocyclic compound with good antioxidant ability owing to its heterocyclic nitrogen conjugation. The conjugation of zinc with phthalocyanine aimed to reduce the toxicity associated with zinc and enhance the antidiabetic activity at a lower dose. Hence, the present research work possessed the insights of the synthetic aspect of zinc with phthalocyanine along with its entrapment in the poly(lactic-co-glycolic acid) (PLGA)-chitosan nanosystem via oral administration in the treatment of diabetes. A nanoprecipitation technique was implemented for the synthesis of PLGA chitosan nanoparticles, and formulation was further optimized using a central composite design. Twenty trials provided by the software selected optimum concentrations of PLGA, poly(vinyl alcohol) (PVA), and chitosan in consideration with particle size up to 335.6 nm, zeta potential 27.87 mV, and entrapment efficiency of 75.67 ± 8.13%. Addition of chitosan to the nanocarrier system for controlling the release of the drug for 3 days was accompanied by the improvement in the glucose level within 28 days. The delivery of the nanoparticles showed enhancement in the cholesterol, triglyceride, alkaline phosphatase (ALP), urine parameters, and pro-inflammatory cytokines. The application of DoE (design of experiments) for the optimization of the nanoparticles established a controlled release formulation for diabetes, which displayed safety and effectiveness in streptozotocin (STZ)-induced diabetic rats.

Interdigitation of lipids for vesosomal formulation of ergotamine tartrate with caffeine: a futuristic trend of intranasal route.

OBJECTIVE: This research work aimed to form vesosomes using combination of two drugs ergotamine (ERG) and caffeine for synergistic activity when given intranasally resulting in faster absorption, steric stability, and controlled release. SIGNIFICANCE: The multicompartment vesicles viz., vesosomes of ERG tartrate proved to increase absorption of drugs post-intranasal administration, bypassing the blood-brain barrier via the olfactory pathway. METHODS: The phospholipids like soya lecithin, cholesterol, and dipalmitoyl phosphatidylcholine (DPPC) were used to form a multicompartment structure called vesosomes using ethanol-induced interdigitation of lipids as the preparation method. RESULTS: The formulation showed low particle size (PS) of 315.48 ± 14.27 nm with zeta potential (ZP) of -21.78 ± 4.72 mV, higher % EE of 91.13 ± 1.29%, and controlled release kinetics, when assessed for in-vitro and ex-vivo studies as 97.64 ± 5.13% and 82.25 ± 3.27% release, respectively. Vesosomes displayed several advantages over liposomes like improved stability against phospholipase-induced enzymatic degradation and higher brain uptake 3.41-fold increase of ERG via the olfactory pathway. CONCLUSIONS: The stable vesosomes prepared using interdigitation of saturated phospholipids proved to be a viable option for ERG when administered intranasally for better absorption and bioavailability coupled with ease of administration gaining wider patient acceptance.

Vesosomes as multicompartment vesicles formulated of ergotamine (ERG) and caffeine for synergistic action in migraine treatment.Ethanol induced for interdigitation of lipids in vesosomes preparation exhibited nano-size, good colloidal stability, better encapsulation efficiency, and controlled release profile.ERG vesosomes demonstrated stability against phospholipase-induced enzymatic degradation.

Competitive inhibition of nicotine acetylcholine receptors using microneedles of nicotine and varenicline for smoking withdrawal therapy.

Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 µm), width (350 µm), and tip diameter (10 µm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.

Current scenario and potential of music therapy in the management of diseases.

Over the preceding years, music therapy has gained tremendous attention due to new findings of music in management of various conditions like Alzheimer's, depression, anxiety, insomnia, etc. Music is a non-invasive, patient-friendly and pleasant form of therapy with minimal or no side effects. It activates the reward pathway of brain by influencing several processes such as dopamine release, reduction in cortisol levels, increase in estrogen and testosterone levels. This review article focuses on advantages and disadvantages of music therapy, mechanism of action of music in brain and its effective applications in the management of different diseases. The article covers history of music therapy in America, Egypt, and India with practice of music therapy. The advanced effects of music therapy in autism, cancer, post-operative pain, Parkinson's disease, selective mutism, stroke, heart problems, pregnancy, eating disorders, bone fractures and obsessive compulsive disorders are discussed. Also the effect of music therapy on the quality of sleep and brain waves has been discussed. This is an established profession in western countries like America, UK, Australia, and Canada, but not in low-income countries like India where it needs to be standardized.

Evasion of opsonization of macromolecules using novel surface-modification and biological-camouflage-mediated techniques for next-generation drug delivery.

Opsonization plays a pivotal role in hindering controlled drug release from nanoformulations due to macrophage-mediated nanoparticle destruction. While first and second-generation delivery systems, such as lipoplexes (50-150 nm) and quantum dots, hold immense potential in revolutionizing disease treatment through spatiotemporal controlled drug delivery, their therapeutic efficacy is restricted by the selective labeling of nanoparticles for uptake by reticuloendothelial system and mononuclear phagocyte system via various molecular forces, such as electrostatic, hydrophobic, and van der Waals bonds. This review article presents novel insights into surface-modification techniques utilizing macromolecule-mediated approaches, including PEGylation, di-block copolymerization, and multi-block polymerization. These techniques induce stealth properties by generating steric forces to repel micromolecular-opsonins, such as fibrinogen, thereby mitigating opsonization effects. Moreover, advanced biological methods, like cellular hitchhiking and dysopsonic protein adsorption, are highlighted for their potential to induce biological camouflage by adsorbing onto the nanoparticulate surface, leading to immune escape. These significant findings pave the way for the development of long-circulating next-generation nanoplatforms capable of delivering superior therapy to patients. Future integration of artificial intelligence-based algorithms, integrated with nanoparticle properties such as shape, size, and surface chemistry, can aid in elucidating nanoparticulate-surface morphology and predicting interactions with the immune system, providing valuable insights into the probable path of opsonization.

3D-to-4D Structures: an Exploration in Biomedical Applications.

3D printing is a cutting-edge technique for manufacturing pharmaceutical drugs (Spritam), polypills (guaifenesin), nanosuspension (folic acid), and hydrogels (ibuprofen) with limitations like the choice of materials, restricted size of manufacturing, and design errors at lower and higher dimensions. In contrast, 4D printing represents an advancement on 3D printing, incorporating active materials like shape memory polymers and liquid crystal elastomers enabling printed objects to change shape in response to stimuli. 4D printing offers numerous benefits, including greater printing capacity, higher manufacturing efficiency, improved quality, lower production costs, reduced carbon footprint, and the ability to produce a wider range of products with greater potential. Recent examples of 4D printing advancements in the clinical setting include the development of artificial intravesicular implants for bladder disorders, 4D-printed hearts for transplant, splints for tracheobronchomalacia, microneedles for tissue wound healing, hydrogel capsules for ulcers, and theragrippers for anticancer drug delivery. This review highlights the advantages of 4D printing over 3D printing, recent applications in manufacturing smart pharmaceutical drug delivery systems with localized action, lower incidence of drug administration, and better patient compliance. It is recommended to conduct substantial research to further investigate the development and applicability of 4D printing in the future.

A stimuli-responsive nanocarrier for diagnosis of seizures and inhibition of glutaminase in epilepsy.

Epilepsy is marked by unpredictable and recurrent episodes of seizures. It is characterized by glutamate excitotoxicity and changes in stimuli such as pH, temperature and oxidative environment. This study aimed to formulate novel nanoparticulate theranostic nanocarrier for combined effects of diagnosis and treatment of epilepsy by: i) in-situ detection of epileptic conditions through characteristic changes in pH through the synthesis of pH-responsive polymer (CS-g-PD) and ii) 'on-demand' therapeutic alleviation of epileptic seizures through an inhibitor of glutaminase, 6-diazo-5-oxo-norleucine (DON). The formulation of DON-CS-g-PD-SLNs possessed nanodimensions (∼197.56 ± 17.87) nm and zeta potential (4.19 ± 0.29), with entrapment efficiency of (80.29 ± 0.006%). The coating pH-responsive polymer showed good sensitivity for acidic conditions by releasing the drug in pH 6.4 and resisting release in higher pH 7.2. In-vivo studies in Wistar rats showed suppression of epileptic seizures, escalation in the duration latency and reduction in duration of convulsions and recovery period. Furthermore, it was also successful in reducing the levels of glutaminase (p < 0.0001) in the brain of PTZ-kindled rats, thereby leading to a decrease in glutamate levels (p < 0.01). Hence, the nanocarriers show promising potential as 'on-demand' theranostics in epilepsy by reducing both the incidence and severity of convulsions.

Dual role of autophagy for advancements from conventional to new delivery systems in cancer.

Autophagy, a programmed cell-lysis mechanism, holds significant promise in the prevention and treatment of a wide range of conditions, including cancer, Alzheimer's, and Parkinson's disease. The successful utilization of autophagy modulation for therapeutic purposes hinges upon accurately determining the role of autophagy in disease progression, whether it acts as a cytotoxic or cytoprotective factor. This critical knowledge empowers scientists to effectively manipulate tumor sensitivity to anti-cancer therapies through autophagy modulation, while also circumventing drug resistance. However, conventional therapies face limitations such as low bioavailability, poor solubility, and a lack of controlled release mechanisms, hindering their clinical applicability. In this regard, innovative nanoplatforms including organic and inorganic systems have emerged as promising solutions to offer stimuli-responsive, theranostic-controlled drug delivery systems with active targeting and improved solubility. The review article explores a variety of organic nanoplatforms, such as lipid-based, polymer-based, and DNA-based systems, which incorporate autophagy-inhibiting drugs like hydroxychloroquine. By inhibiting the glycolytic pathway and depriving cells of essential nutrients, these platforms exhibit tumor-suppressive effects in advanced forms of cancer such as leukemia, colon cancer, and glioblastoma. Furthermore, metal-based, metal-oxide-based, silica-based, and quantum dot-based nanoplatforms selectively induce autophagy in tumors, leading to extensive cancer cell destruction. Additionally, this article discusses the current clinical status of autophagy-modulating drugs for cancer therapy with valuable insights of progress and potential of such approaches.

Design and Characterization of Nanoflowers-based Biosensor for Estimation of Bilirubin in Jaundice.

Nanoflowers (NFs) are flower-shaped nanoparticulate systems with a higher surface-to-volume ratio and good surface adsorption. Jaundice indicates yellow discoloration of skin, sclera, and mucus membrane and is a clinical indication of bilirubin accumulation in the blood which occurs as a consequence of the incapability of the liver to excrete bilirubin in the biliary tree or conjugate bilirubin and higher production of bilirubin in the body. Several methods have been developed so far for bilirubin estimation in jaundice like the spectrophotometric method, chemiluminescence method, etc., but biosensing methods provide advantages over traditional methods concerning the surface area, adsorption, particle size, and functional characteristics. The primary objective of the present research project was to formulate and examine the adsorbent nanoflowers-based biosensor for accurate, precise, and sensitive detection of bilirubin in jaundice. The particle size of adsorbent nanoflowers was found to be in the range of 300-600nm with the surface charge (zeta potential) in the range of -1.12 to -15.42 mV. Transmission electron microscopy and scanning electron microscopy images confirmed the flower-like morphological structure of adsorbent NFs. The adsorption efficiency of NFs for bilirubin adsorption was maximum at 94.13%. Comparative studies of bilirubin estimation in the pathological sample with adsorbent NFs and diagnostic kit displayed bilirubin concentration to be 1.0 mg/dL in adsorbent nanoflowers and 1.1 mg/dL with diagnostic kit indicating effective detection of bilirubin with adsorbent NFs. The nanoflower-based biosensor acts as a smart approach to elevate adsorption efficiency on the surface of nanoflower due to a higher surface-to-volume (SV) ratio. Graphical Abstract.

In-vivo processing of nanoassemblies: a neglected framework for recycling to bypass nanotoxicological therapeutics.

The proof-of-concept of nanomaterials (NMs) in the fields of imaging, diagnosis, treatment, and theranostics shows the importance in biopharmaceuticals development due to structural orientation, on-targeting, and long-term stability. However, biotransformation of NMs and their modified form in human body via recyclable techniques are not explored owing to tiny structures and cytotoxic effects. Recycling of NMs offers advantages of dose reduction, re-utilization of the administered therapeutics providing secondary release, and decrease in nanotoxicity in human body. Therefore, approaches like in-vivo re-processing and bio-recycling are essential to overcome nanocargo system-associated toxicities such as hepatotoxicity, nephrotoxicity, neurotoxicity, and lung toxicity. After 3-5 stages of recycling process of some NMs of gold, lipid, iron oxide, polymer, silver, and graphene in spleen, kidney, and Kupffer's cells retain biological efficiency in the body. Thus, substantial attention towards recyclability and reusability of NMs for sustainable development necessitates further advancement in healthcare for effective therapy. This review article outlines biotransformation of engineered NMs as a valuable source of drug carriers and biocatalyst with critical strategies like pH modification, flocculation, or magnetization for recovery of NMs in the body. Furthermore, this article summarizes the challenges of recycled NMs and advances in integrated technologies such as artificial intelligence, machine learning, in-silico assay, etc. Therefore, potential contribution of NM's life-cycle in the recovery of nanosystems for futuristic developments require consideration in site-specific delivery, reduction of dose, remodeling in breast cancer therapy, wound healing action, antibacterial effect, and for bioremediation to develop ideal nanotherapeutics.

Enhancement of in-vitro anti-oral cancer activities of silymarin using dispersion of nanostructured lipid carrier in mucoadhesive in-situ gel.

Silymarin (SME) shows multiple therapeutic actions against several cancers, however, low aqueous solubility and poor bioavailability issues restrict its clinical use. In this study, SME was loaded in nanostructured lipid carriers (NLCs) and further incorporated in mucoadhesive in-situ gel (SME-NLCs-Plx/CP-ISG) for localized treatment of oral cancer. Using a 33 Box-Behnken design (BBD), an optimized SME-NLC formula was developed with the ratios of solid lipids, surfactant concentration, and sonication time as independent variables, while particle size (PS), polydispersity index (PDI), and % encapsulation efficiency (EE) as dependent variables, resulting in 315.5 ± 0.1 nm PS, 0.341 ± 0.01 PDI, and 71.05 ± 0.05 % EE. Structural studies confirmed the formation of SME-NLCs. SME-NLCs incorporated in-situ gel demonstrated a sustained release for SME, indicating enhanced retention on the buccal mucosal membrane. The in-situ gel containing SME-NLCs showed a marked decrease in IC50 value (24.90 ± 0.45 µM) than SME-NLCs (28.40 ± 0.89 µM) and plain SME (36.60 ± 0.26 µM). The studies demonstrated that Reactive oxygen species (ROS) generation potential and SME-NLCs-Plx/CP-ISG induced apoptosis at Sub-G0 phase owing to higher penetration of SME-NLCs led to higher inhibition against human KB oral cancer cells. Therefore, SME-NLCs-Plx/CP-ISG can be the alternative to chemotherapy and surgery with site-specific delivery of SME to oral cancer patients.

Potential of nanocarriers using ABC transporters for antimicrobial resistance.

Some existing therapies such as antimicrobial regimens, drug combinations, among others, are employed for the treatment of infections that are a threat to the healthcare industry owing to low drug efficacy, increasing dosage regimes, mutation in bacteria and poor pharmacokinetics/pharmacodynamics properties of drugs. Overuse of antibiotics is fostering the emergence and spread of inherent microorganisms that confer temporary and permanent resistance. Nanocarriers accompanying the ABC transporter efflux mechanism are considered 'magic bullets' (i.e., effective antibacterial agents) and can traverse the multidrug-resistant obstacle owing to their multifunctional capabilities (e.g., nanostructure, variability in in vivo functions, etc.) by interfering with normal cell activity. This review focuses on novel applications of the ABC transporter pump by nanocarriers to overcome the resistance caused by the various organs of the body.

Use of 3D applicator for intranasal microneedle arrays for combinational therapy in migraine.

The objective of current research work was to fabricate dissolving microneedles combining ergotamine and caffeine for synergistic action using controlled release kinetics with better permeability. The method of preparation for microneedles utilized multiple emulsion (w/o/w) approach by solvent-diffusion-evaporation process wherein the nano-emulsion of ergotamine and caffeine prepared using PLGA polymer and PVA as a stabilizer. The PLGA nanospheres were further loaded in polymer matrix of PVA and PVP K-90 and the final mixture poured in sterile silicon molds of microneedles. The PLGA nanospheres exhibited particle size in narrow range of 280.34 ± 6.61 to 416.0 ± 9.67 nm and good colloidal stability with negative zeta potential ranging between -19.08 ± 8.77 to -22.49 ± 8.09 mV. Higher entrapment efficiency (86.21 ± 4.52 %) for ergotamine and controlled release pattern (49.79 ± 4.16 % at 48 h) displayed by PLGA nanospheres. Similarly, the dissolving microneedles loaded with PLGA nanospheres showed controlled release pattern for in-vitro and ex-vivo drug release studies with 52.01 ± 5.71 % for ERM and 87.04 ± 2.44 % for CFE at 48 h whereas ex-vivo release studies illustrated similar results of 51.08 ± 3.56 % for ERM and 69.2 ± 2.16 % for CFE. The anti-hyperalgesic capability of microneedles was verified by the acetic acid writhing test, and the non-toxicity of synthetic microneedles was confirmed by histopathology and serotonin toxicity studies. The novel 3D applicator effectively delivered the microneedle array into the nasal cavity for systemic action. Therefore, the fabricated rapid dissolving microneedles combining two drugs ergotamine and caffeine with use of 3D applicator proved to be a coherent technique for intranasal delivery of ergotamine in the treatment of migraine.