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[Display omitted] 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 PEG 1000 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Inclusion complexes of Palbociclib with β-CD and HP-β-CD developed by freeze drying method and characterized for its physiochemical properties. • Both inclusion complexes improved aqueous solubility of Palbociclib by 31.05 and 37.99-fold respectively. • In-silico studies revealed higher interaction of Palbociclib with β-CD and HP-β-CD. • In-vitro cell-based assay conclude the higher efficacy against MDA-MB-231 cells. Palbociclib (PAL) is an anti-cancer molecule that is highly selective for CDK4/6 inhibition and approved for the management of advanced breast cancer. Due to its down-and-out aqueous solubility and poor oral bioavailability, therapeutic applications have been compromised in the pharmaceutical field. The work aims to explore the physicochemical properties, aqueous solubility, dissolution rate, and in silico analysis of PAL complexed with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and to ascertain the implications of complexation on the in vitro anti-cancer activity of PAL. The two inclusion complexes (ICs) of PAL were prepared by the methodology of freeze-drying and further characterized by FT-IR, DSC, TGA, FESEM, and PXRD. The 1H NMR and 2D NMR revealed that a significant chemical shift was observed for the ICs as well and a correlation was seen between the CH 3 of HP-β-CD with protons (ring C & D) of the pyrimidine and pyridine rings respectively. A L type graph was obtained depicting the K S value to be 625.4 M−1 and 3760 M−1 respectively for PAL-β-CD and PAL-HP-β-CD. Also, the aqueous solubility of PAL was improved by 31.05 and 37.99-fold respectively by both the ICs. The stoichiometric ratio of 1:1 was established by Job's plot. Additionally, the results of in-silico studies were in correlation with the theoretical calculations. Further, it was found that the in vitro cytotoxicity investigation on MDA-MB-231 cells reported IC 50 value for PAL-β-CD IC and PAL-HP-β-CD IC a 2.33– and 3.38-fold a lower IC 50 value than PAL (IC 50 = 9.55 ppm) which indicates higher cellular toxicity for both ICs in comparison to free PAL. Additionally, PAL-β-CD IC (41.99 ± 2.63 %) and PAL-HP-β-CD IC (57.33 ± 1.58 %) showed higher apoptosis than PAL (25.17 ± 1.27 %) also the cellular internalization was seen higher for both the ICs as well as the ROS formation, and MMP depolarization was evidenced. [ABSTRACT FROM AUTHOR]

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 ΔG binding of the N-imidazopyridine-noscapinoids 7 – 11 varied from −27.45 to −36.15 kcal/mol, a much lower value than noscapine with ΔG binding −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 IC 50 concentration) ranges between 4.04 and 33.93 μM against breast cancer cells without affecting normal cells (IC 50 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. [Display omitted] • We present the regioselective modification of noscapine to produce the 9 N- imidazopyridine noscapinoids. • The top ranked molecule based on molecular docking and predictive binding energy calculation were chemically synthesized. • Compounds have shown improved anticancer activity using two breast cancer cells and panel of primary breast cancer cells. • Along with elevated ROS, there was loss of mitochondrial membrane potential, suggesting induction of apoptosis. • Compound 9 significantly regressed the implanted tumor in nude mice as xenografts of MCF-7 cells with no side-effects. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is reported to be the leading cause of mortality in females worldwide. At the beginning of the year 2021, about 7.8 million women were diagnosed with BC in past 5 years. High prevalence and poor neoadjuvant chemotherapeutic efficacy has motivated the scientists around the globe to investigate alternative management strategies. In recent years, there has been an exponential rise in the scientific studies reporting the role of tumor derived exosomes (TDEs) in the BC pathophysiology and management. TDEs play an important role in the intercellular communication and transportation of biomolecules. This manuscript reviews the role of exosomes in the BC pathophysiology, diagnosis, and therapy. Role of TDEs in the mechanistic pathways of BC metastasis, immunosuppression, migration, dormancy and chemo-resistance is extensively reviewed. We have also highlighted the epigenetic modulations orchestrated by exosomal miRNAs and long noncoding RNAs (lnc RNAs) in the BC environment. Liquid biopsies analyzing blood circulating exosomes for early and accurate detection of the BC have been discussed. Characterization of exosomes, strategies to use them in BC chemotherapy, BC immunotherapy and potential challenges that will present themselves in translating exosomes based technologies to market are discussed. [Display omitted] [ABSTRACT FROM AUTHOR]