Enhancing breast cancer treatment: Comprehensive study of gefitinib-loaded poloxamer 407/TPGS mixed micelles through design, development, in-silico modelling, In-Vitro testing, and Ex-Vivo characterization.

Breast cancer continues to pose a substantial global health challenge, emphasizing the critical need for the advancement of novel therapeutic approaches. Key players in the regulation of apoptosis, a fundamental process in cell death, are the B-cell lymphoma 2 (Bcl-2) family proteins, namely Bcl-2 and Bax. These proteins have garnered attention as highly promising targets for the treatment of breast cancer. Targeting the overexpressed anti-apoptotic Bcl-2 protein in breast cancer, Gefitinib (GEF), an EGFR (Epidermal Growth Factor Receptor) inhibitor, emerges as a potential solution. This study focuses on designing Gefitinib-loaded polymeric mixed micelles (GPMM) using poloxamer 407 and TPGS (D-alpha tocopherol PEG1000 succinate) for breast cancer therapy. In silico analyses unveil strong interactions between GEF- Bcl-2 and TPGS-Pgp-2 receptors, indicating efficacy against breast cancer. Molecular dynamics simulations offer insights into GEF and TPGS interactions within the micelles. Formulation optimization via Design of Experiment ensures particle size and entrapment efficiency within acceptable ranges. Characterization tools such as zeta sizer, ATR-FTIR, XRD, TEM, AFM, NMR, TGA, and DSC confirms particle size, structure, functional groups, and thermodynamic events. The optimized micelles exhibit a particle size of 22.34 ± 0.18 nm, PDI of 0.038 ± 0.009, and zeta potential of -0.772 ± 0.12 mV. HPLC determines 95.67 ± 0.34% entrapment efficiency and 1.05 ± 0.12% drug loading capacity. In-vitro studies with MDA-MB-231 cell lines demonstrate enhanced cytotoxicity of GPMM compared to free GEF, suggesting its potential in breast cancer therapy. Cell cycle analysis reveals apoptosis induction through key apoptotic proteins. Western blot results confirm GPMM's ability to trigger apoptosis in MDA-MB-231 cells by activating caspase-3, Bax, Bcl-2, and Parp. In conclusion, these polymeric mixed micelles show promise in selectively targeting cancer cells, warranting future in-vivo studies for optimized clinical application against breast cancer.

Emerging In Vitro and In Vivo Models: Hope for the Better Understanding of Cancer Progression and Treatment.

Various cancer models have been developed to aid the understanding of the underlying mechanisms of tumor development and evaluate the effectiveness of various anticancer drugs in preclinical studies. These models accurately reproduce the critical stages of tumor initiation and development to mimic the tumor microenvironment better. Using these models for target validation, tumor response evaluation, resistance modeling, and toxicity comprehension can significantly enhance the drug development process. Herein, various in vivo or animal models are presented, typically consisting of several mice and in vitro models ranging in complexity from transwell models to spheroids and CRISPR-Cas9 technologies. While in vitro models have been used for decades and dominate the early stages of drug development, they are still limited primary to simplistic tests based on testing on a single cell type cultivated in Petri dishes. Recent advancements in developing new cancer therapies necessitate the generation of complicated animal models that accurately mimic the tumor's complexity and microenvironment. Mice make effective tumor models as they are affordable, have a short reproductive cycle, exhibit rapid tumor growth, and are simple to manipulate genetically. Human cancer mouse models are crucial to understanding the neoplastic process and basic and clinical research improvements. The following review summarizes different in vitro and in vivo metastasis models, their advantages and disadvantages, and their ability to serve as a model for cancer research.

Unveiling the healing properties of 2,3-dehydrosilychristin: a potential silymarin-derived flavonolignan from Vitex negundo.

The compound 2,3-dehydrosilychristin, a flavonolignan linked to silychristin and silymarin, remains intriguing due to its challenging isolation from silymarin. While silymarin has been the exclusive source of flavonolignans - silybin, silychristin and silydianin - 2,3-dehydrosilychristin is reported in this study from Vitex negundo Linn. leaves. 2,3-Dehydrosilychristin (7) and 14 other compounds were isolated through focused extraction. Its subsequent pharmacological evaluation demonstrated potent antioxidant and in-vitro anti-inflammatory effects, notably inhibiting cytokines TNF-α, IL-6, IL-8 and VEGF. In in-vivo assessments, 2,3-dehydrosilychristin (7) revealed remarkable hepatoprotective potential by reducing liver enzyme levels AST and ALT. These findings expand the potential of 2,3-dehydrosilychristin and suggest bioprospecting Vitex species as alternate sources of bioactive flavonolignans.

Mahamanalactone A, a new triterpenoid from Dysoxylum malabaricum bark: a case study for rapid identification of new metabolites via LC-HRMS profiling and database mining strategy.

In this recent investigation, the focus centred on exploring the potential phytoconstituents within the bark of Dysoxylum malabaricum. A profiling strategy employing LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry) was implemented for the rapid identification of compounds from the bark extract. The crude extract underwent fractionation, resulting in the isolation of four previously known compounds (1-4) and a novel cycloartane triterpenoid named Mahamanalactone A (5). Compound 5 represents a cycloartane triterpenoid with a modified ring-A, featuring £-caprolactone fusion at positions 4 and 5, distinguishing it from other reported compounds where £-caprolactone is typically fused at positions 3 and 4. Cytotoxicity assessment revealed that the newly identified compound 5 exhibited a moderate cytotoxic profile (IC50 29 to 78 µM) against a panel of cancer cell lines.

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.

Quality by design approach-based fabrication and evaluation of self-nanoemulsifying drug delivery system for improved delivery of venetoclax.

Breast cancer is reported as one of the most prevalent non-cutaneous malignancies in women. Venetoclax (VEN) is an approved BCl-2 inhibitor for the treatment of chronic myeloid leukemia with very limited oral bioavailability and exhibits an enormous impact on breast cancer. In the current investigation, venetoclax-loaded self-nanoemulsifying drug delivery systems (VEN-SNEDDS) were designed and fabricated to improve the aqueous solubility, permeability, and anticancer efficacy of VEN. Various surface-active parameters of the reconstituted SNEDDS were determined to scrutinize the performance of the selected surfactant mixture. Central composite design (CCD) was used to optimize the VEN-SNEDDS. The globule size of reconstituted VEN-SNEDDS was 71.3 ± 2.8 nm with a polydispersity index of 0.113 ± 0.01. VEN-SNEDDS displayed approximately 3-4 fold, 6-7 fold, and 5-6 fold reduced IC50 as compared to free VEN in MDA-MB-231, MCF-7, and T47 D cells, respectively. VEN-SNEDDS showed greater cellular uptake, apoptosis, reactive oxygen species generation, and higher BAX/BCL2 ratio with decreased caspase 3 and 8 and BCL-2 levels in the MDA-MB-231 cells compared to pure VEN. VEN-SNEDDS exhibited approximately fivefold enhancement in Cmax and an improved oral bioavailability compared to VEN suspension in in vivo pharmacokinetic studies.

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.

Flavone-based dual PARP-Tubulin inhibitor manifesting efficacy against endometrial cancer.

Structural tailoring of the flavone framework (position 7) via organopalladium-catalyzed C-C bond formation was attempted in this study. The impact of substituents with varied electronic effects (phenyl ring, position 2 of the benzopyran scaffold) on the antitumor properties was also assessed. Resultantly, the efforts yielded a furyl arm bearing benzopyran possessing a 4-fluoro phenyl ring (position 2) (14) that manifested a magnificent antitumor profile against the Ishikawa cell lines mediated through dual inhibition of PARP and tubulin [(IC50 (PARP1) = 74 nM, IC50 (PARP2) = 109 nM) and tubulin (IC50 = 1.4 µM)]. Further investigations confirmed the ability of 14 to induce apoptosis as well as autophagy and cause cell cycle arrest at the G2/M phase. Overall, the outcome of the study culminated in a tractable dual PARP-tubulin inhibitor endowed with an impressive activity profile against endometrial cancer.

Rational design of novel microtubule targeting anticancer drugs N-imidazopyridine noscapinoids: Chemical synthesis and experimental evaluation based on in vitro using breast cancer cells and in vivo using xenograft mice model.

We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔGbinding of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔGbinding -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC50 concentration) ranges between 4.04 and 33.93 µM against breast cancer cells without affecting normal cells (IC50 value > 952 µM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers.

Unravelling the flexibility of Mycobacterium tuberculosis: an escape way for the bacilli.

The persistence of Mycobacterium tuberculosis makes it difficult to eradicate the associated infection from the host. The flexible nature of mycobacteria and their ability to adapt to adverse host conditions give rise to different drug-tolerant phenotypes. Granuloma formation restricts nutrient supply, limits oxygen availability and exposes bacteria to a low pH environment, resulting in non-replicating bacteria. These non-replicating mycobacteria, which need high doses and long exposure to anti-tubercular drugs, are the root cause of lengthy chemotherapy. Novel strategies, which are effective against non-replicating mycobacteria, need to be adopted to shorten tuberculosis treatment. This not only will reduce the treatment time but also will help prevent the emergence of multi-drug-resistant strains of mycobacteria.

Multifunctional targetable liposomal drug delivery system in the management of leukemia: Potential, opportunities, and emerging strategies.

The concern impeding the success of chemotherapy in leukemia treatment is descending efficacy of drugs because of multiple drug resistance (MDR). The previous failure of traditional treatment methods is primarily responsible for the present era of innovative agents to treat leukemia effectively. The treatment option is a chemotherapeutic agent in most available treatment strategies, which unfortunately leads to high unavoidable toxicities. As a result of the recent surge in marketed products, theranostic nanoparticles, i.e., multifunctional targetable liposomes (MFTL), have been approved for improved and more successful leukemia treatment that blends therapeutic and diagnostic characteristics. Since they broadly offer the required characteristics to get past the traditional/previous limitations, such as the absence of site-specific anti-cancer therapeutic delivery and ongoing real-time surveillance of the leukemia target sites while administering therapeutic activities. To prepare MFTL, suitable targeting ligands or tumor-specific antibodies are required to attach to the surface of the liposomes. This review exhaustively covered and summarized the liposomal-based formulation in leukemia treatment, emphasizing leukemia types; regulatory considerations, patents, and clinical portfolios to overcome clinical translation hurdles have all been explored.

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.

Nanomedicine in therapeutic warfront against estrogen receptor-positive breast cancer.

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Almost 70-80% of cases of BC are curable at the early non-metastatic stage. BC is a heterogeneous disease with different molecular subtypes. Around 70% of breast tumors exhibit estrogen-receptor (ER) expression and endocrine therapy is used for the treatment of these patients. However, there are high chances of recurrence in the endocrine therapy regimen. Though chemotherapy and radiation therapy have substantially improved survival rates and treatment outcomes in BC patients, there is an increased possibility of the development of resistance and dose-limiting toxicities. Conventional treatment approaches often suffer from low bioavailability, adverse effects due to the non-specific action of chemotherapeutics, and low antitumor efficacy. Nanomedicine has emerged as a conspicuous strategy for delivering anticancer therapeutics in BC management. It has revolutionized the area of cancer therapy by increasing the bioavailability of the therapeutics and improving their anticancer efficacy with reduced toxicities on healthy tissues. In this article, we have highlighted various mechanisms and pathways involved in the progression of ER-positive BC. Further, different nanocarriers delivering drugs, genes, and natural therapeutic agents for surmounting BC are the spotlights of this article.

Chemometric-Based Analysis of Metabolomics Studies of Bioactive Fractions of Pleurotus osteratus and Their Correlation with In Vitro Anti-Cancer Activity.

Richness in nutrients with an ample of the myco-bioactive molecules makes Pleurotus osteratus preferential mushroom. In this paper, we conducted a preliminary study on bio-assay-guided fractionation of dichloromethane:ethanol crude extract (1:1, v/v) of P. osteratus (CD) against human breast cancer cell line (MDA-MB-231). Later, CD and its potent hexane (H) and ethyl acetate (EA) fraction were screened against a panel of a human cancer cell lines. H fraction possesses higher cytotoxicity followed by EA and CD. Literature review revealed that polyphenol and ergosterol are the biomarkers found in P. osteratus and could responsible for its cytotoxic potential. Accordingly, hyphenated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based polyphenol and ergosterol-targeted myco-metabolite profiling of CD, H, and EA fractions were carried out. Despite being significantly rich in polyphenol and ergosterol content, EA fraction showed moderate cytotoxicity. Considering this, liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF/MS)-based untargeted myco-metabolite profiling of CD, H and EA fractions was further conducted to identify a new biomarker. Tentatively, 20 myco-metabolites were identified, belonging to the class of steroids, alkaloid, terpenoid, fatty alcohol, and polyketide. The myco-metabolite variabilities among potent samples in correlation to their in vitro anti-cancer activity was explored using the different chemometric tools: principal component analysis (PCA), hierarchical clustering analysis (HCA), and partial least square (PLS). A probable synergistic action among identified myco-metabolites (betulin, solanocapsine, ophiobolin F, linoleoyl ethanolamide, (13R,14R)-7-labdene-13,14,15-triol, asterosterol, cholest-5-ene, (3b,6b,8a,12a)-8,12-epoxy-7(11)-eremophilene-6,8,12-trimethoxy-3-ol, beta-obscurine, myxalamid B, momordol, and avocadyne 4-acetate) may be responsible for the observed cytotoxicity potential of H fraction of P. osteratus.

Isolation of a new cytotoxic colchinoid from Gloriosa superba roots.

A new colchinoid compound, identified as N-deacetyl-N-formylcornigerine (1), named glorigerine was isolated from the roots of Gloriosa superba, along with two known compounds. The structures of isolated compounds were elucidated by 1 D and 2 D NMR and HRMS experiments. Glorigerine (1) differed from cornigerine (6) by the presence of an N-formyl group instead of the N-acetyl group. Glorigerine (1) was found to have moderate cytotoxicity when tested against four human cancer cell lines.

Tracing the Anti-cancer Mechanism of Pleurotus osteratus by the Integrative Approach of Network Pharmacology and Experimental Studies.

The present study identified the probable mechanism behind the anti-cancer activity of the hexane fraction of Pleurotus osteratus (HFPO) using network pharmacology and experimental validation. HFPO myco-metabolites targets and targets related to the cancer were mined from the online web server, and overlapping targets were screened. Out of the 74 overlapping targets, 33 targets were identified in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of cancer. Furthermore, the main active myco-metabolites and hub targets were identified by network analysis of the compound-targets network and protein-protein interaction (PPI), respectively. Molecular docking results showed good binding affinity of the hub targets with their respective myco-metabolites. HFPO induced in-vitro anti-cancer activity by affecting the PI3K-AKT-mTOR pathway, besides time-dependent cell cytotoxicity and apoptotic cell body formation. Additionally, tumor volume reduction was observed in HFPO-treated Ehrlich ascites carcinoma (EAC) bearing Swiss albino mice. Overall, HFPO induces anti-cancer potential by modulating the PI3K-AKT-mTOR signaling pathway.

LCMS-DNP based dereplication of Araucaria cunninghamii Mudie gum-resin: identification of new cytotoxic labdane diterpene.

As a part of natural defense, plants initiate the secretion of gum containing numerous pharmacologically active essential metabolites. A fraction of such gum-resin from Araucaria cunninghamii Mudie, when screened against human cancer cell lines, was found to be active. Further, it was subjected to an LCMS-DNP (Dictionary of Natural Products) based dereplication study followed by a detailed phytochemical investigation to obtain pure metabolites. Also, the gum resin of A. cunninghamii was found to be a rich source of abietanes and labdanes. The LCMS-DNP-based dereplication study identified many known metabolites, which were isolated for the first time from this plant as well as a new labdane diterpenoid (9). The compounds were characterized via spectroscopic techniques, which were subsequently compared with the already existing literature data. The metabolites were screened against seven human cancer cell lines. The anticancer activity was further supported by molecular docking studies.

Design, Fabrication and Evaluation of Stabilized Polymeric mixed micelles for Effective Management in Cancer Therapy.

PURPOSE: Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored. METHODS: The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer). RESULTS: Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09 nm, 0.078 ± 0.009 and -4.29 ± 0.24 mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314 µg/ml at 24, 48, and 72 h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 0.85, 0.13, 0.008 µg/ml at 24, 48 and 72 h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells. CONCLUSION: The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models.