Solid Lipid Nanoparticles: Applications and Prospects in Cancer Treatment.

Recent advancements in drug delivery technologies paved a way for improving cancer therapeutics. Nanotechnology emerged as a potential tool in the field of drug delivery, overcoming the challenges of conventional drug delivery systems. In the field of nanotechnology, solid lipid nanoparticles (SLNs) play a vital role with a wide range of diverse applications, namely drug delivery, clinical medicine, and cancer therapeutics. SLNs establish a significant role owing to their ability to encapsulate hydrophilic and hydrophobic compounds, biocompatibility, ease of surface modification, scale-up feasibility, and possibilities of both active and passive targeting to various organs. In cancer therapy, SLNs have emerged as imminent nanocarriers for overcoming physiological barriers and multidrug resistance pathways. However, there is a need for special attention to be paid to further improving the conceptual understanding of the biological responses of SLNs in cancer therapeutics. Hence, further research exploration needs to be focused on the determination of the structure and strength of SLNs at the cellular level, both in vitro and in vivo, to develop potential therapeutics with reduced side effects. The present review addresses the various modalities of SLN development, SLN mechanisms in cancer therapeutics, and the scale-up potential and regulatory considerations of SLN technology. The review extensively focuses on the applications of SLNs in cancer treatment.

C-Glucosyl Xanthone derivative Mangiferin downregulates the JNK3 mediated caspase activation in Almal induced neurotoxicity in differentiated SHSY-5Y neuroblastoma cells.

INTRODUCTION: C-Glucosyl Xanthone derivatives were assessed to inhibit the JNK3 mediated Caspase pathway in Almal (Aluminum Maltolate) induced neurotoxicity in SHSY-5Y cells. METHODS: Mangiferin was selected among 200 C-Glucosyl Xanthones based on molecular interaction, docking score (-10.22 kcal/mol), binding free energy (-71.12 kcal/mol), ADME/tox properties and by molecular dynamic studies. Further, it was noticed that glycone moiety of Mangiferin forms H-bond with ASN 194, SER 193, GLY 76, and OH group in the first position of the aglycone moiety shows interaction at Met 149 which is exceptionally crucial for JNK3 inhibitory activity. RESULTS AND DISCUSSION: Mangiferin (0.5, 1, 10, 20 and 30 µM) and standard SP600125 (20 µM) treatment increased the cell survival rate against Almal 200 µM, with EC50 of Mangiferin (8 µM) and standard SP600125 (4.9 µM) respectively. Mangiferin significantly impedes kinase activation, indicating suppression of JNK3 signaling with IC50 (98.26 nM). Mangiferin (10 and 15 µM) dose-dependently inhibits the caspase 3, 8, and 9 enzyme activation in comparison to Almal group. CONCLUSION: Mangiferin demonstrated neuroprotection in SHSY-5Y cells against apoptosis induced by Almal by adapting the architecture of the neurons and increasing their density. Among all Xanthone derivatives, Mangiferin could improve neuronal toxicity by inhibiting JNK3 and down-regulating the Caspase activation.

Molecule(s) of Interest: I. Ionic Liquids-Gateway to Newer Nanotechnology Applications: Advanced Nanobiotechnical Uses', Current Status, Emerging Trends, Challenges, and Prospects.

Ionic liquids are a potent class of organic compounds exhibiting unique physico-chemical properties and structural compositions that are different from the classical dipolar organic liquids. These molecules have found diverse applications in different chemical, biochemical, biophysical fields, and a number of industrial usages. The ionic liquids-based products and procedural applications are being developed for a number of newer industrial purposes, and academic uses in nanotechnology related procedures, processes, and products, especially in nanobiotechnology and nanomedicine. The current article overviews their uses in different fields, including applications, functions, and as parts of products and processes at primary and advanced levels. The application and product examples, and prospects in various fields of nanotechnology, domains of nanosystem syntheses, nano-scale product development, the process of membrane filtering, biofilm formation, and bio-separations are prominently discussed. The applications in carbon nanotubes; quantum dots; and drug, gene, and other payload delivery vehicle developments in the nanobiotechnology field are also covered. The broader scopes of applications of ionic liquids, future developmental possibilities in chemistry and different bio-aspects, promises in the newer genres of nanobiotechnology products, certain bioprocesses controls, and toxicity, together with emerging trends, challenges, and prospects are also elaborated.

Formulation development of cream with mupirocin and essential oils for eradication of biofilm mediated antimicrobial resistance.

Staphylococcus aureus (S.aureus) is both a colonizer as well as a human pathogen that causes a variety of diseases. Mupirocin is a topical antimicrobial agent which is very effective against S.aureus infection. However, treating the S.aureus infection using mupirocin could be complicated due to biofilm formation. Consequently, resistance to mupirocin occurs and leads to chronic infection. The combination of mupirocin with a compound that has biofilm eradicating effect would be an ideal solution for effectively treating biofilm infections. Therefore, in this study, we have investigated the biofilm inhibitory and eradication effect of mupirocin with three essential oils (Cinnamon Oil (CO), Eugenol (EU) and Eucalyptus Oil (EO)) against sessile S.aureus. From these preliminary results, it was found that the mupirocin-CO (0.2 µg/ml-5.218 mg/ml) combination has a better synergistic antibiofilm effect against sessile S.aureus and the fractional inhibitory concentration index was found to be 0.458. The best combination of mupirocin with CO was loaded into a non-greasy O/W cream. The physico-chemical and microbiological evaluations were carried out for the prepared cream. The prepared cream has better biofilm eradication activity (40%) when compared to a marketed cream (20%).

The effect of physical stability and modified gastrointestinal tract behaviour of resveratrol-loaded NLCs encapsulated alginate beads.

Nanostructured lipid carriers (NLC) have low storage and gastrointestinal stability, limiting their applicability. The work aimed to elevate the stability and behaviour of NLC in the alimentary tract by creating an alginate bead. Through the extrusion dropping procedure, Resveratrol (RES)-loaded NLC were efficiently integrated into alginate beads. The incorporation had no significant impact on the particle size, morphology, or inner structure of NLC, as assessed using DLS (Dynamic Light Scattering), SEM (Scanning Electron Microscopy), Differential Scanning Calorimetry (DSC) and FT-IR (Fourier Transform Infra-Red). Incorporating NLC into alginate beads improves its physical stability compared to dispersion of NLC as well as NLC-Sol. An in vitro release investigation found that the NLC-alginate beads released RES more slowly than optimized NLC formulation (RES-NLCs-opt) and NLC-alginate sol. Research on simulated in vitro digestive models revealed that just a small amount of integrated NLC may permeate stomach fluid due to its tiny size. The slow diffusion of NLC from alginate to intestinal fluid prevented aggregation and allowed for gentle hydrolysis of the lipid matrix. Incorporating NLC in alginate beads shows promise for improving stability, modifying gastrointestinal behaviour, and controlling release throughout the process of digestion.

A Perspective on Therapeutic Applications and Strategies to Mitigate Toxicity of Metallic Nanoparticles.

Metallic nanoparticles (MNPs) have been widely used for diagnostic and therapeutic purposes in clinical practice. A number of MNP formulations are being investigated in clinical trials for various applications. This increase in the use of NPs results in higher exposure to humans, leading to toxicity issues. Hence, it is necessary to determine the possible undesirable effects of the MNPs after in-vivo application and exposure. One of the main reasons for the toxicity of MNPs is the release of their respective metallic ions throughout the body. Many research studies are in progress investigating the various strategies to reduce the toxicity of MNPs. These research studies aim to change the size, dose, agglomeration, release, and excretion rates of MNPs. In this perspective review, we discussed the possible strategies to improve the therapeutic effects of MNPs through various processes, with lessons learned from the studies involving silver nanoparticles (AgNPs). We also discussed the ways to manage the toxicity of MNPs by purification, surface functionalization, synergistic effect, and targeted therapy approach. All these strategies could reduce the dose of the MNPs without compromising their therapeutic benefits, which could decrease the toxicity of MNPs. Additionally, we briefly discussed the market and toxicology testing for FDA-regulated MNPs.

The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. PD is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Present therapies for PD provide only symptomatic relief by restoring the dopamine (DA) level. However, they are not disease modifying agents and so they do not delay the disease progression. Alpha-synuclein aggregation, oxidative stress, mitochondrial dysfunction and chronic inflammation are considered to be the major pathological mechanisms mediating neurodegeneration in PD. To resist oxidative stress, the human body has an antioxidant defence mechanism consisting of many antioxidants and cytoprotective genes. The expression of those genes are largely controlled by the Kelch-like ECH-associated protein 1/Nuclear factor - erythroid - 2 - related factor 2/Antioxidant response element (Keap1/Nrf2/ARE) signalling pathway. The transcription factor Nrf2 is activated in response to oxidative or electrophilic stress and protects the cells from oxidative stress and inflammation. Nrf2 has been widely considered as a therapeutic target for neurodegeneration and several drugs are now being tested in clinical trials. Regulation of the Keap1/Nrf2/ARE pathway by small molecules which can act as Nrf2 activators could be effective for treating oxidative stress and neuroinflammation in PD. In this review, we had discussed the principal molecular mechanisms behind the neuroprotective effects of Keap1/Nrf2/ARE pathway in PD. Additionally, we also discussed the small molecules and phytochemicals that could activate the Nrf2 mediated anti-oxidant pathway for neuroprotection in PD.

Self-nanoemulsifying drug delivery system of aqueous leaf extracts of Justicia adhatoda and Psidium guajava to enhance platelet count.

Self-nanoemulsifying drug delivery system (SNEDDS) containing aqueous leaf extracts of Justicia adhatoda (JA) and Psidium guajava (PG), was designed to evaluate their ability to enhance platelet count. The ternary phase diagram was constructed to identify the self-emulsifying regions and nanoemulsion prepared using clove oil, tween 80 and transcutol. The globule size of the prepared SNEDDS formulation at different folds of dilution in buffers of various pH was evaluated. The average globule size of the optimized JA2- and PG2-loaded SNEDDS at different folds of dilutions was in the range of 103.4 ± 7.1 to 238.3 ± 5.4 nm and 240.2 ± 7.9 to161.7 ± 3.7 nm, respectively. The viscosity of JA2 and PG2 loaded SNEDDS formulations were found to be 621 and 642 centipoise, respectively with no observed signs of phase separation, turbidity or precipitation during the freeze-thaw process. Oral administration of combined JA2 and PG2 loaded SNEDDS formulation to Wistar rats depleted with platelets showed a significant increase in platelet count when compared to a marketed tablet Caripill. Pharmacodynamic studies in platelet-depleted Wistar rats enhanced the platelet count after administration of SNEDDS containing lyophilized aqueous extracts JA2 and PG2.

Exploring combined herbal extract-loaded phytoniosomes for antimalarial and antibacterial activity against methicillin-resistant Staphylococcus aureus.

Antibiotic resistance in the context of treating malarial infections is a major challenge in India. Home remedies such as thulasi leaves (Ocimum tenuiflorum), black pepper seeds (Piper nigrum), clove buds (Syzygium aromaticum), cinnamon bark (Cinnamomum verum), and nilavembu whole plant powder (Andrographis paniculata) were taken to explore antimalarial and methicillin-resistant Staphylococcus aureus (MRSA) activity. Among the five extracts, the best two extracts, C. verum and P. nigrum extract, showed the presence of Quercetin. Phytoniosomes were prepared by simple probe sonication with the two extracts and the resultant vesicles were in the size range of (319.7 nm). They showed significant (P < 0.001) antimalarial potency IC50 at 5.25 µg/ml against P. falciparum 3D7. In addition, their cytotoxicity (TC50) against Vero cell line was found to be > 100 µg/ml. The therapeutic index was found to be > 32 µg/ml. Phytoniosomes were converted to a capsule dosage form by lyophilization and this capsule was stable up to 90 days.

Building and behavior of a pH-stimuli responsive chitosan nanoparticles loaded with folic acid conjugated gemcitabine silver colloids in MDA-MB-453 metastatic breast cancer cell line and pharmacokinetics in rats.

The pH-stimuli release behavior of nanoformulations may enhance the success rate of chemotherapeutic drugs in cancers by site-specific delivery of drugs to cancer tissues. The aim of the present study was to prepare chitosan (CS) nanoparticles (NPs) with previously synthesized folic acid (FA) capped silver nanoparticles (AgNPs) loaded with the anti-cancer drug gemcitabine (GEM) (FA-GEM-AgNPs). The CS-FA-GEM-AgNPs (CS-NPs) were characterized with dynamic light scattering (DLS), transmission electron microscopy (TEM), energy dispersive x-ray analysis (EDAX), selected area electron diffraction (SAED), and differential scanning calorimetric (DSC) analyses. The in-vitro drug release of GEM was evaluated in media of different pH. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cytotoxic effects of the prepared nanoformulations in media with various pH. The time- and pH-dependent apoptotic cell death induced by CS-NPs with MDA-MB-453 human breast cancer cell line was observed using acridine orange (AO)/ethidium bromide (EtBr) staining. The pharmacokinetic parameters were studied with high-performance liquid chromatography (HPLC) and atomic absorption spectroscopy (AAS). Two batches of CS-NPs formulations were prepared, one with AgNPs of particle size 143 nm and the other with 244 nm. The particle size for CS-NPs-I (FA-GEM-AgNPs-143 nm) and CS-NPs-II (FA-GEM-AgNPs-244 nm) was found to be 425 and 545 nm, respectively. The zeta potential was found to be 36.1 and 37.5 mV for CS-NPs-I and CS-NPs-II, respectively. CS-NPs-I and CS-NPs-II showed a polydispersity index (PDI) of 0.240 and 0.261, respectively. A TEM study confirmed the spherical nature of the NPs. The nanoformulations exerted pH-dependant effect against MDA-MB-453 cells with relatively higher cytotoxicity at the lower pH than at higher pH levels. The pharmacokinetic profile and tissue distribution of CS-NPs in rats exerted drug release in a pH-dependent manner with enhanced excretion of Ag+. An optimized nanoformulation for pH-stimuli responsive release of GEM was successfully developed for future therapeutic exploration.

Synthesis and Characterization of Folic Acid Conjugated Gemcitabine Tethered Silver Nanoparticles (FA-GEM-AgNPs) for Targeted Delivery.

BACKGROUND: Silver nanoparticles (AgNPs) have attracted considerable interest in the medical industry due to their physicochemical properties, small size, and surface plasmon behavior. Their smaller particle size and instability in blood circulation leads to toxicity due to its aggregation as Ag+ ions and accumulation at the deepseated organ. In the present study, we aimed at reducing the toxicity of AgNPs by conjugation with an anticancer drug GEM and to improve their internalization through folate receptors-mediated endocytosis by capping the nanoparticles with folic acid (FA). METHODS: One-pot facile synthesis of FA capped silver nanoparticles (FA-AgNPs) has been achieved by using FA as a reducing agent. FA-AgNPs were mixed with Gemcitabine (GEM) to obtain tethered FA-GEM-AgNPs. Nanoparticles were characterized by Dynamic Light Scattering (DLS), UV-Visible spectroscopy, Transmission Electron Microscopy (TEM), Energy Dispersive X-ray Analysis (EDAX), Selected Area Electron Diffraction (SAED), and Atomic Absorption Spectroscopy (AAS). The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cytotoxic effect of the prepared nanoformulations. The apoptotic cell death induced by FA-GEM-AgNPs in breast cancer cells were monitored with Acridine orange (AO)/Ethidium Bromide (EtBr) staining. CONCLUSION: Compared to GEM and AgNPs, FA-GEM-AgNPs showed enhanced cytotoxic effect and internalization in MDA-MB-453 breast cancer cell line. FA-GEM-AgNPs could be an ideal candidate for targeting cancer cells via folate receptor-mediated endocytosis.

Phytochemical screening and cytotoxicity evaluation of crude extracts: Toxicity comparison of crude extracts and its ethosomal formulations.

BACKGROUND: Combined plant extracts of Phyllanthus niruri, Croton tiglium, and Zingiber officinale are reported to have potential pharmacological applications. Ethosomes have a unique ability of encapsulating drugs or plant extracts with varying hydrophobicities in the phospholipid bilayer. AIM: To explore cytotoxicity of the combined plant extracts and ethosome loaded combined plant extracts for topical delivery. To study effect of ethosomes loaded combined plant extracts using HaCaT cells model treated with testosterone. METHODS: Dried powder of plant was extracted with ethanol using Soxhlet and cold macerations. Total phenolic and flavonoid contents were also determined using established methods. The combined extract loaded ethosome formulation was prepared by solvent dispersion method. RESULTS: The plant extracts loaded ethosomes formulation with a vesicle size range 1524.6-167.7 nm was prepared. HaCaT cells treated with testosterone negative control showed an IC50 value of 27 ± 1.0. Thw standard marketed topical minoxidil (1% solution) treated cells with testosterone showed an IC50 value 33 ± 1.0 and the combined plant extracts loaded ethosomes with testosterone showed an IC50 value 30 ± 1.0. Morphological alterations of rat skin exposed to the combined plant extract loaded ethosomes solution were assessed and compared with untreated skin and negative control. CONCLUSION: The preclinical safety was investigated employing an in vitro cytotoxicity and histopathological study. The cell line study results confirmed that the combined plant extracts loaded ethosomes inhibits testosterone and increase cell viability closer to that of standard drug minoxidil. According to our histopathological study, the combined plant extract loaded ethosomal formulations did not cause any damage to the rat skin layer.