Dasatinib loaded mucoadhesive lecithin-chitosan hybrid nanoparticles for its augmented oral delivery, in-vitro efficacy and safety.

Dasatinib (DAS) is an oral tyrosine kinase inhibitor; however, its efficacy is significantly subsided by its low oral bioavailability. The present research aimed to improve DAS's oral delivery and efficacy in triple-negative breast cancer by fabricating its mucoadhesive lecithin-chitosan hybrid nanoparticles (DAS-L/CS-NPs). DAS-L/CS-NPs were optimized using Box-Behnken design which showed mean particle size and percent entrapment efficiency of 179.7 ± 5.42 nm and 64.65 ± 0.06 %, respectively. DAS-L/CS-NPs demonstrated sustained release profile in different release media up to 48 h and showed 10 times higher apparent permeability coefficient and flux than free DAS suspension. The binding of DAS-L/CS-NPs to the mucus layer was demonstrated via ex-vivo mucoadhesion study and change in absorbance using turbidimetry. In cell culture studies, DAS-L/CS-NPs revealed a 4.14-fold decrease in IC50, significantly higher cellular uptake and mitochondrial membrane depolarization, 3.82-fold increased reactive oxygen species generation and 2.10-fold enhanced apoptosis in MDA-MB-231 cells than free DAS. In in-vivo pharmacokinetic assessment, DAS-L/CS-NPs showed a 5.08-fold and 3.74-fold rise in AUC (0-t) and Cmax than free DAS suspension, respectively. An acute toxicity study revealed a good safety profile of DAS-L/CS-NPs. In a nutshell, proposed hybrid nanoparticles are promising carriers for improved oral delivery of poorly water-soluble drugs.

Acalabrutinib as a novel hope for the treatment of breast and lung cancer: an in-silico proof of concept.

Drug repurposing is proved to be a groundbreaking concept in the field of cancer research, accelerating the pace of de novo drug discovery by investigating the anti-cancer activity of the already approved drugs. On the other hand, it got highly benefitted from the advancement in the in-silico tools and techniques, which are used to build up the initial "proof of concept" based on the drug-target interaction. Acalabrutinib (ACL) is a well-known drug for the treatment of hematological malignancies. But, the therapeutic ability of ACL against solid tumors is still unexplored. Thereby, the activity of ACL on breast cancer and lung cancer was evaluated utilizing different computational methods. A series of proteins such as VEGFR1, ALK, BCL2, CXCR-4, mTOR, AKT, PI3K, HER-2, and Estrogen receptors were selected based on their involvement in the progression of the breast as well as lung cancer. A multi-level computational study starting from protein-ligand docking to molecular dynamic (MD) simulations were performed to detect the binding potential of ACL towards the selected proteins. Results of the study led to the identification of ACL as a ligand that showed a high docking score and binding energy with HER-2, mTOR, and VEGFR-1 successively. Whereas, the MD simulations study has also shown good docked complex stability of ACL with HER2 and VEGFR1. Our findings suggest that interaction with those receptors can lead to preventive action on both breast and lung cancer, thus it can be concluded that ACL could be a potential molecule for the same purpose.Communicated by Ramaswamy H. Sarma.

Exploring the current landscape of chitosan-based hybrid nanoplatforms as cancer theragnostic.

In the last decade, investigators have put significant efforts to develop several diagnostic and therapeutic strategies against cancer. Many novel nanoplatforms, including lipidic, metallic, and inorganic nanocarriers, have shown massive potential at preclinical and clinical stages for cancer diagnosis and treatment. Each of these nano-systems is distinct with its own benefits and limitations. The need to overcome the limitations of single-component nano-systems, improve their morphological and biological features, and achieve multiple functionalities has resulted in the emergence of hybrid nanoparticles (HNPs). These HNPs integrate multicomponent nano-systems with diagnostic and therapeutic functions into a single nano-system serving as promising nanotools for cancer theragnostic applications. Chitosan (CS) being a mucoadhesive, biodegradable, and biocompatible biopolymer, has emerged as an essential element for the development of HNPs offering several advantages over conventional nanoparticles including pH-dependent drug delivery, sustained drug release, and enhanced nanoparticle stability. In addition, the free protonable amino groups in the CS backbone offer flexibility to its structure, making it easy for the modification and functionalization of CS, resulting in better drug targetability and cell uptake. This review discusses in detail the existing different oncology-directed CS-based HNPs including their morphological characteristics, in-vitro/in-vivo outcomes, toxicity concerns, hurdles in clinical translation, and future prospects.

Amphotericin B loaded nanoemulsion: Optimization, characterization and in-vitro activity against L. donovani promastigotes.

The present work aimed to develop and evaluate AmB-loaded nano-emulsion (AmB-NE) which will augment the solubility of AmB and lead to enhanced anti-leishmanial activity. The composition of AmB-NE was optimized by systematic screening followed by DoE-extreme vertices mixture design. The optimized NE revealed mean droplet size and PDI of 44.19 ± 5.5 nm, 0.265 ± 0.0723, respectively. The NE could efficiently encapsulate AmB with drug content and efficiency 83.509 ± 0.369% and 81.659 ± 0.013%, respectively. The presence of cholesterol and stearyl amine retarded the release (P < 0.0001) of AmB significantly compared to AmB suspension. The AmB-NE and pure AmB suspension demonstrated the IC50 of 0.06309 µg/mL and 0.3309 µg/mL against L.donovani promastigotes after 48 h incubation. The formulation was robust at all exaggerated stability conditions such as freeze-thaw and centrifugation. These findings indicate that AmB-NE is an attractive approach to treat visceral leishmaniasis with improved activity.

Chitosan functionalized PCL nanoparticles bearing tyrosine kinase inhibitor osimertinib mesylate for effective lung cancer therapy.

Lung cancer ranks second position among the cancer-related deaths. Osimertinib mesylate (OSM) is a tyrosine-kinase-inhibitor which can effectively treat non-small cell lung cancer (NSCLC), but still there are certain limitations and side effects which could be circumvented by polymeric nanoparticles approach. Hence, this research was aimed to develop drug-loaded biodegradable polycaprolactone nanoparticles (PCL-NPs) such as OSM-loaded PCL-NPs (PCL-OSM-NPs) and chitosan fabricated OSM-loaded PCL-NPs (CS-PCL-OSM-NPs) to achieve active-targeting of OSM in the cancerous lung tissue. Thus, CS-PCL-OSM-NPs enhance the anticancer efficacy due to active targeting nature and thereby reduces off-target side effects of OSM in the NSCLC treatment. Blank PCL-NPs, PCL-OSM-NPs, and CS-PCL-OSM-NPs were prepared by nanoprecipitation method. Optimized blank PCL-NPs, PCL-OSM-NPs, and CS-PCL-OSM-NPs exhibited the mean particle size of 90.2 ± 4.7 nm, 167.7 ± 2.9 nm, and 233.7 ± 4.8 nm respectively. The encapsulation efficiency % (%EE) of PCL-OSM-NPs was found to be 68.4 ± 3.2%. In vitro drug release study demonstrated sustained release profile of 69.5 ± 5% and 65.7 ± 1.5% for OSM from both the PCL-OSM-NPs and CS-PCL-OSM-NPs, respectively. The PCL-OSM-NPs and CS-PCL-OSM-NPs demonstrated the inhibition of 82.2 ± 0.5% and 81.9 ± 0.2% in A549 cancer cells respectively which clearly signified the improved efficacy. Moreover, the PCL-OSM-NPs and CS-PCL-OSM-NPs exhibited significantly less hemolysis than OSM indicating safety of the formulation. These findings indicate that biohemocompatible CS-PCL-OSM-NPs is an attractive option to treat NSCLC with enhanced anticancer activity and reduced side effects.

Self-nanoemulsifying drug delivery system (SNEDDS) of docetaxel and carvacrol synergizes the anticancer activity and enables safer toxicity profile: optimization, and in-vitro, ex-vivo and in-vivo pharmacokinetic evaluation.

Docetaxel (DTX) is a first-line chemotherapeutic molecule with a broad-spectrum anticancer activity. On the other hand, carvacrol (CV) has anti-inflammatory, antioxidant, cytotoxic, and hepatoprotective properties that could reduce undue toxicity caused by DTX chemotherapy. Thus, in order to overcome the challenges posed by DTX's poor aqueous solubility, low permeability, hepatic first pass, and systemic toxicities, we have developed a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) co-loaded with DTX and CV. In the present investigation, liquid-SNEDDS (L-SNEDDS) were fabricated using Nigella sativa oil, Cremophor RH 40, and Ethanol which was converted into solid by lyophilization using Aerosil 200. The reconstituted CV-DTX-S-SNEDDS showed an average globule size of < 200 nm with promising flow properties (angle of repose θ: 33.22 ± 0.06). Additionally, 2.3-fold higher dissolution of DTX was observed from CV-DTX-S-SNEDDS after 6 h as compared to free DTX. Similar trend was followed in dialysis release experiments with 1.5-fold higher release within 24 h. Ex vivo permeation studies demonstrated significantly increased permeation of 1077.02 ± 12.72 µg/cm2 of CV-DTX-S-SNEDDS after 12 h. In vitro cell cytotoxicity studies revealed 5.2-fold reduction in IC50 as compared to free DTX in MDA-MB-231 cells. Formulation was able to induce higher apoptosis in cells treated with CV-DTX-S-SNEDDS as compared to free DTX and CV. It was evident from toxicity studies that CV-DTX-S-SNEDDS was well tolerated at higher dose where CV was able to manage the toxic effects of free DTX. In vivo pharmacokinetic study showed 3.4-fold increased Cmax and improved oral bioavailability as compared to free DTX. Thus, CV-DTX-S-SNEDDS could be an encouraging option for facilitating DTX oral therapy.

Traversing the diverse avenues of exopolysaccharides-based nanocarriers in the management of cancer.

Exopolysaccharides are unique polymers generated by living organisms such as algae, fungi and bacteria to protect them from environmental factors. After a fermentative process, these polymers are extracted from the medium culture. Exopolysaccharides have been explored for their anti-viral, anti-bacterial, anti-tumor, and immunomodulatory effects. Specifically, they have acquired massive attention in novel drug delivery strategies owing to their indispensable properties like biocompatibility, biodegradability, and lack of irritation. Exopolysaccharides such as dextran, alginate, hyaluronic acid, pullulan, xanthan gum, gellan gum, levan, curdlan, cellulose, chitosan, mauran, and schizophyllan exhibited excellent drug carrier properties. Specific exopolysaccharides, such as levan, chitosan, and curdlan, have demonstrated significant antitumor activity. Moreover, chitosan, hyaluronic acid and pullulan can be employed as targeting ligands decorated on nanoplatforms for effective active tumor targeting. This review shields light on the classification, unique characteristics, antitumor activities and nanocarrier properties of exopolysaccharides. In addition, in vitro human cell line experiments and preclinical studies associated with exopolysaccharide-based nanocarriers have also been highlighted.

Core-Shell Type Lipidic and Polymeric Nanocapsules: the Transformative Multifaceted Delivery Systems.

Amongst the several nano-drug delivery systems, lipid or polymer-based core-shell nanocapsules (NCs) have garnered much attention of researchers owing to its multidisciplinary properties and wide application. NCs are structured core-shell systems in which the core is an aqueous or oily phase protecting the encapsulated drug from environmental conditions, whereas the shell can be lipidic or polymeric. The core is stabilized by surfactant/lipids/polymers, which control the release of the drug. The presence of a plethora of biocompatible lipids and polymers with the provision of amicable surface modifications makes NCs an ideal choice for precise drug delivery. In the present article, multiple lipidic and polymeric NC (LNCs and PNCs) systems are described with an emphasis on fabrication methods and characterization techniques. Far-reaching applications as a carrier or delivery system are demonstrated for oral, parenteral, nasal, and transdermal routes of administration to enhance the bioavailability of hard-to-formulate drugs and to achieve sustained and targeted delivery. This review provide in depth understanding on core-shell NC's mechanism of absorption, surface modification, size tuning, and toxicity moderation which overshadows the drawbacks of conventional approaches. Additionally, the review shines a spotlight on the current challenges associated with core-shell NCs and applications in the foreseeable future.

Applications of lipid-engineered nanoplatforms in the delivery of various cancer therapeutics to surmount breast cancer.

Breast cancer (BC) is the most extensively accounted malignancy among the women across the globe and is treatable in 70-80% of patients with early-stage, non-metastatic cancer. The current available therapies have been found to be less effective to treat distant organ metastases and advanced breast cancers. The clinical efficacy hugely suffers from chemoresistance, non-specific toxicity, relapse and other associated adverse effects. Furthermore, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Nanotechnology based approaches have been widely used over the period as they are nanometric, offer controlled and site-specific drug release along with reduced toxicity, improved half-life, and stability. Lipid-based nanoplatforms have grabbed a tremendous attention for delivering cancer therapeutics as they are cost-effective, scalable and provide better entrapment efficiency. In this review, all the promising applications of lipid-engineered nanotechnological tools for breast cancer will be summarized and discussed. Subsequently, BC therapy achieved with the aid of chemotherapeutics, phytomedicine, genes, peptides, photosensitizers, diagnostic and immunogenic agents etc. will be reviewed and discussed. This review gives tabular information on all the results obtained pertaining to the physicochemical properties of the lipidic nanocarrier, in vitro studies conferring to mechanistic drug release profile, cell viability, cellular apoptosis and in vivo studies referring to cellular internalisation, reduction of tumor volume, PK-PD profile, bioavailability achieved and anti-tumor activity in detail. It also gives complete information on the most relevant clinical trials done on lipidic nanoplatforms over two decades in tabular form. The review highlights the current status and future prospects of lipidic nanoplatforms with streamlined focus on cancer nanotherapeutics.

Nano-lipidic formulation and therapeutic strategies for Alzheimer's disease via intranasal route.

AIM: The inability of drug molecules to cross the 'Blood-Brain Barrier' restrict the effective treatment of Alzheimer's disease. Lipid nanocarriers have proven to be a novel paradigm in brain targeting of bioactive by facilitating suitable therapeutic concentrations to be attained in the brain. METHODS: The relevant information regarding the title of this review article was collected from the peer-reviewed published articles. Also, the physicochemical properties, and their in vitro and in vivo evaluations were presented in this review article. RESULTS: Administration of lipid-based nano-carriers have abilities to target the brain, improve the pharmacokinetic and pharmacodynamics properties of drugs, and mitigate the side effects of encapsulated therapeutic active agents. CONCLUSION: Unlike oral and other routes, the Intranasal route promises high bioavailability, low first-pass effect, better pharmacokinetic properties, bypass of the systemic circulation, fewer incidences of unwanted side effects, and direct delivery of anti-AD drugs to the brain via circumventing 'Blood-Brain Barrier'.