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.

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.

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.

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.

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.

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.

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.

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.

Dual-action of colloidal ISCOMs: an optimized approach using Box-Behnken design for the management of breast cancer.

Neuropeptide Y (NPY) occurs in G-protein-coupled receptors and offers targeted effects at the active sites for therapeutic action in various conditions like depression, stress, obesity and cancer. Immune stimulating complexes (ISCOMs) associate peptides with the lipid systems for enhancing antigen targeting to provide site-specific action and B-cell response. The present study focused on the encapsulation of NPY in ISCOMs to comprise dual action in the form of immunity modulation and management of breast cancer by arresting G0/G1 phase. The colloidal ISCOMs were prepared by coupling method and further optimized by Box-Behnken design of Design of Experiment (DoE) software. The NPY-loaded ISCOMs (formulation ISCN) were characterized by various parameters with higher % encapsulation efficiency of 87.99 ± 1.87% and in-vitro release of 84.16±3.2% of NPY for 24 h. The study of MTT assay on MCF-7 cell line for formulation ISCN exhibited a significant decrease in the cell growth of 66.41±4.7% at 10 µg/mL compared to plain NPY (52.21±0.04%). The MCF-7 cells showed a significant reduction in cytokine levels in the presence of formulation ISCN wherein TH1(TNF-α) and TH2(IL-10) levels were found to be 25.12±3.11 pg/mL and 35.76±4.23 pg/mL, respectively. The cell cycle study demonstrated that significant cells were blocked in the G0/G1 phase with 57.8±3.02% of cell apoptosis using formulation ISCN. The formulation ISCN was found to prolong t1/2 and increase AUC than plain NPY via intravenous administration due to complex formation with phospholipid. Hence, ISCOMs-based NPY system will be a promising approach for dual action as immunomodulation and anticancer effects by controlling the release of NPY.

ß-Cyclodextrin-crosslinked synthetic neuropeptide Y-based nanosponges in epilepsy by contributing GABAergic signal.

Neuropeptide Y (NPY) is a polypeptide sequence useful in regulating physiological functions like homeostasis, feeding, etc., but its usage is restricted due to its short half-life. ß-cyclodextrin-crosslinked nanosponges improve the drug release and stability due to its wide cavity, which is helpful to deliver therapeutics. The present work aimed to formulate synthetic NPY-based nanocarriers as sponges by polymer condensation mechanism using design experiment to improve the peptide release and stability. The validated nanosponges exhibited a particle size of 423.42 ± 5.32 nm, 75.82 ± 7.43 % entrapment efficiency and 83.50 ± 6.54 % NPY release for 24 h. The NPY and ß-cyclodextrin interaction was confirmed by X-ray diffraction, Fourier transform infrared and nuclear magnetic resonance spectroscopy. The NPY-loaded nanosponges were found stable for 6 months at two conditions (5 ± 2 °C and 25 ± 2 °C). The cross-linked nanocarriers of synthetic peptide-based nanosponges powder at different doses were administered intranasally using a metered-dose inhaler in the animal model to check its antiepileptic activity. The synthetic NPY-loaded nanosponges at higher doses showed significant antiepileptic effects equivalent to the standard drug (administered orally) in maximal electroshock and chemically-induced seizures with an increase of NPY in the brain directly proportional to GABAergic signalling by increase in GABA levels resulting in convulsions attenuation.

Self-Assembled Lipid Polymer Hybrid Nanoparticles Using Combinational Drugs for Migraine Via Intranasal Route.

The objective of the current research study was to formulate the PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine for intranasal administration with higher entrapment efficiency, better permeability, desirable controlled release pattern, and significant brain uptake in animal studies. A single-step nanoprecipitation method was employed in the processing of self-assembled hybrid nanoparticles constituting polymer PLGA, lipids soya lecithin, and DPPC with PEGylation using polyethylene glycol (PEG-2000). The optimal lipid/polymer weight ratio of 15% w/w showed lower particle size of 239.46 ± 2.31 nm with good colloidal stability depicted by zeta potential (- 18.36 ± 6.59 mV), higher entrapment efficiency of 86.88 ± 1.67%, and controlled release profile when evaluated for in vitro and ex vivo studies as 97.12 ± 2.79% and 75.13 ± 5.62% release, respectively, for 48 h. The formulation showed long-term serum stability when incubated in bovine serum albumin and displayed high brain uptake (4.35-fold) offering significant permeability in the brain post-intranasal administration via olfactory route. Histopathological investigations and serotonin toxicity studies in animals confirmed the safe and non-toxic nature of the formulation while the acetic acid writhing test proved the anti-hyperalgesic activity. The PEGylated lipid polymer hybrid nanoparticles of ergotamine and caffeine showed synergistic activity with efficacious higher anti-migraine potential.

Microneedles in diagnostic, treatment and theranostics: An advancement in minimally-invasive delivery system.

Microneedle (MN) technology plays an important role in biomedical engineering for their less intrusive access to the skin due to minimally or painless penetration, enhancement of drug permeability, improvement of detectability of biomolecules in the epidermal and dermal layers with therapeutic efficacy and safety. Furthermore, MNs possess some major disadvantages like difficulty in scale-up technique, variation in drug delivery pattern with respect to external environment of skin, blockage of arrays due to dermal tissues, induction of inflammation or allergy at the site of administration and restriction of dosing range based on the size of active. Additionally, microneedle acts as a transdermal theranostic device for monitoring the physiological parameters in clinical studies. The investigation of drug transfer mechanisms through microneedles includes coat and poke, poke and flow, poke and patch and poke and release method. This review article discusses different categories of microneedles with fabrication methods such as photolithography, laser cutting, 3D printing, etc. in therapeutic applications for treating cancer, diabetes, arthritis, obesity, neurological disorders, and glaucoma. Biosensing devices based on microneedles may detect target analytes directly in the interstitial fluid by penetrating the stratum corneum of the skin and thus microneedles-based devices can be considered as a single tool in diagnostic sensing and therapeutic administration of drugs inside the body. Moreover, the clinical status and commercial availability of microneedle devices are discussed in this review article to offer new insights to researchers and scientists. Continuous monitoring particularly for the determination of blood glucose concentration is one of the most important requirements for the development of next-generation healthcare devices. The aim of this review article focuses mainly on the theranostic applications of microneedles in various medical conditions such as malaria, glaucoma, cancer, etc.

Enhancement of immunopotentiation using tetanus toxoid-based nanoparticulate dissolvable microneedles.

The main objective of the present study was to prepare and evaluate dissolvable microneedle patch containing nanoparticles of tetanus toxoid without the use of any adjuvant and its immunopotentiation activity. Immunization with microneedles is a novel approach in vaccines delivery with advantages such as convenience, simple, and non-invasive therapy. The gelatin nanoparticles were prepared by a layer-by-layer coating method using polystyrene sulfonate (PSS), polyallylamine hydrochloride (PLA), and PLGA. The filtered gelatin nanoparticles were later dispersed in the aqueous PVP K10 solution and integrated into a mold to develop microneedles. The nanoparticles and their dissolvable microneedle patches were evaluated using particle size, surface charge, entrapment efficiency, SEM analysis, in-vitro, and in-vivo studies. The particle size was found in the order of PLGA-coated nanoparticles > layered gelatin nanoparticles > aminated gelatin nanoparticles > gelatin nanoparticles and aminated gelatin nanoparticles showed maximum entrapment efficiency (92.6 ± 3.25%). The microscopic SEM images showed the spherical-shaped particle formation, verifies that the nanoparticles were formed. The gelatin nanoparticles followed the prolonged release for the period of 8 h whereas the nanoparticle-loaded dissolvable microneedles showed the controlled release pattern for 24 h. Aminated nanoparticulate microneedle showed the highest antibody production against tetanus toxoid. Hence, the nanoparticulate dissolvable microneedles-based immunopotentiation can be used as an alternative for delivery of tetanus toxoid.

Potential of Chimeric Antigen Receptor T-Cells in Cancer Therapy.

Novel approaches for targeted delivery like nanoparticles, liposomes, polymer conjugates, etc. with better safety profile needs to be developed for cancer treatment. Chimeric antigen receptors (CAR) with modified thymus cells (T-cells) showed greater potential as a therapy due to its direct effect on immune system responsible for destruction of pathogens and said equivalent to the living drug. On activation of T-cell, it binds to the antigen domains treating refractory or relapsed cancers. The receptors are termed chimeric as it consists of T-cells functioning as well as antigen-binding combined in sole receptor. This therapy showed positive success towards hematological cancers and engineered for specific protein targeting. Though the therapy is associated to several challenges like incompetence towards tumor lysis and cytokine release rate, termination of cytotoxic activity after completion of tumor eradication, etc. The control mechanisms used by CAR T-cells are apoptosis by suicide genes, dual-antigen receptor, ON-switch tumor attack and bispecific molecules as activation switch. In solid tumors, CAR T-cell therapy showed promising signs of efficacy becoming a game-changing cell therapy. CAR T-cells are optimized using different engineering resolutions and lead to broadways for therapy adoption to benefit the cancer patients.

Polyplexes of retinoic acid: an in vitro study of complex nanostructures against colorectal cancer cell line (HCT-15).

Despite recent advances in the treatment of human colon cancer, the chemotherapeutic efficacy against colon cancer is still unsatisfactory. The complexity in colorectal cancer treatment leads to new research in combination therapy to overcome multidrug resistance in cancer and increase apoptosis. The objective of the present research work was to develop polyplexes for co-delivery of plasmid DNA with retinoic acid against colorectal cancer cell line (HCT-15). Plain polyplexes were prepared using chitosan and hyaluronic acid solution (0.1% w/v), whereas retinoic acid polyplexes were prepared using ethanol: water (1:9 v/v) system. The particle size was observed in the order of chitosan solution > blank polyplex > retinoic acid-loaded polyplex. Encapsulation efficiency of retinoic acid was found to be 81.51 ± 4.33% for retinoic acid-loaded polyplex formulation. The drug release was observed to be in a controlled pattern with 72.23 ± 1.32% release of retenoic acid from polyplex formulation. Cell line studies of the formulation displayed better cell inhibition and low cytotoxicity for the retinoic acid-loaded polyplexes in comparison to pure retinoic acid, thus demonstrating better potential action against colorectal cancer cell line HCT-15. Retinoic acid-loaded polyplexes indicated higher potential for the delivery of the active whereas the cell line studies displayed the efficacy of the formulation against colorectal cancer cell line HCT-15.

Microneedle system: a modulated approach for penetration enhancement.

The microneedles show advantages over transdermal drug delivery systems on account of better skin permeation bypassing the stratum corneum. To increase the flux of permeation, penetration enhancement techniques like physical and chemical methods are combined with a trans-epidermal delivery system across the skin causing minimal pain. These techniques include iontophoresis, sonophoresis, and electroporation for physical enhancement of drug delivery via topical route by either disrupting the structure of the stratum corneum or by creating pores/micro-channels within the skin. The use of chemical penetrants such as ethanol, lipids, surfactants, and terpenes improves the release kinetics by mechanisms like fluidization of lipids, denaturation of proteins, etc. A combination of microneedles and these techniques show a significant increase in the permeability of drugs across the skin by 5-10 times compared to microneedles alone. This review article focuses on various advanced strategies like the use of drug-polymer complexes, application of ultrasound frequency or tolerable electric current, formation of nano-formulations, etc. with microneedle delivery for transportation of high payload of actives, macromolecules, antibodies, gene, proteins, and peptides. In the near future, microneedle systems will offer potential targeted drug delivery, self-sealable administration across the skin, and minimally invasive vaccine transportation in cancer, diabetes, Alzheimer's, and cardiovascular diseases.HighlightsPhysical penetration enhancement techniques: iontophoresis, electroporation, and sonophoresis.Chemical penetration enhancers: polymers, lipids, surfactants.Strategies to use microneedle system with penetration enhancement techniques.The significant difference in the penetration ability of high payload actives.

3D Printed Personalized Medicine for Cancer: Applications for Betterment of Diagnosis, Prognosis and Treatment.

Cancer treatment is challenging due to the tumour heterogeneity that makes personalized medicine a suitable technique for providing better cancer treatment. Personalized medicine analyses patient-related factors like genetic make-up and lifestyle and designs treatments that offer the benefits of reduced side effects and efficient drug delivery. Personalized medicine aims to provide a holistic way for prevention, diagnosis and treatment. The customization desired in personalized medicine is produced accurately by 3D printing which is an established technique known for its precision. Different 3D printing techniques exhibit their capability in producing cancer-specific medications for breast, liver, thyroid and kidney tumours. Three-dimensional printing displays major influence on cancer modelling and studies using cancer models in treatment and diagnosis. Three-dimensional printed personalized tumour models like physical 3D models, bioprinted models and tumour-on-chip models demonstrate better in vitro and in vivo correlation in drug screening, cancer metastasis and prognosis studies. Three-dimensional printing helps in cancer modelling; moreover, it has also changed the facet of cancer treatment. Improved treatment via custom-made 3D printed devices, implants and dosage forms ensures the delivery of anticancer agents efficiently. This review covers recent applications of 3D printed personalized medicine in various cancer types and comments on the possible future directions like application of 4D printing and regularization of 3D printed personalized medicine in healthcare.

22 factorial design-based biocompatible microneedle arrays containing artemether co-loaded with lumefantrine nanoparticles for transepidermal delivery.

The present study was intended to enhance the permeation of artemether and lumefantrine by encapsulating in dissolvable microneedle arrays for extended action. Lumefantrine-nanoparticles were synthesized using chitosan mediated gelation and optimized by 22 factorial designs. The particle size, zeta potential and % entrapment efficiency of the optimized nanoparticles F5 were 105 ± 3.64 nm, 24.4 ± 0.54 mV and 83.94 ± 1.71%, respectively. The nanoparticles showed a controlled-release of 79.15 ± 2.45% for lumefantrine after 24 h and stability for 6 months. A combination of biocompatible polymers (PVA and PVP K - 12) was used to develop dissolvable microneedle of artemether co-loaded lumefantrine nanoparticles. The SEM and TEM analysis confirmed the needle-shaped morphology with a size of 672 ± 0.99 µm. The in-vitro release of microneedle showed biphasic release pattern for both artemether and lumefantrine, with an initial burst followed by controlled-release profile. The ex-vivo study of optimized formulation showed 70.94 ± 2.45% and 65.87 ± 1.94% permeation for artemether and lumefantrine, respectively, after 24 h. Thus, microneedle-based delivery provides an alternative to painful intravenous administration and a promising approach to increase the penetration of drugs across the skin barrier. Graphical abstract Fabrication of microneedle arrays of artemether co-loaded with lumefantrine nanoparticles.