RESUMO
Cancer is a complex disease that displays physiomorphological transformation in different surrounding microenvironments. Therefore, the single treatment modalities are relatively less effective, and their efficiency varies with tumor cell physiology, leading to the development of tumor resistance. Combinatorial therapeutic approaches, such as chemo-photothermal therapy, are promising for efficiently mitigating tumor progression irrespective of cancer physiology. Nanotechnology has played a significant role in this regard. Therefore, the present study reports the synthesis of poly(acrylic acid)-tetraethylene glycol (PAA-TEG)-coated BaSO4 nanoparticles (NPs) with enhanced solubility, dispersibility, and X-ray attenuation. Next, nanocomposites (NCs) are synthesized by loading BaSO4 NPs with the therapeutic drug triiodobenzoic acid (Tiba) and the photosensitizer IR780 using a lipid coating. These fabricated NCs are analyzed for dual-modal imaging (fluorescence and X-ray-based imaging) properties and chemo-phototherapeutic ability against two-dimensional (2D) and three-dimensional (3D) cultures of A549 cells. Furthermore, A549 cells are morphologically and physiologically aggravated into potent malignant cells using tobacco leaf extract (TE), and the variation in the therapeutic effect of NCs compared to cisplatin is determined. The synthesized NCs display enhanced encapsulation and excellent synergistic anticancer activity through the generation of reactive oxygen species (ROS), mitochondrial damage, and genotoxicity. Also, the NCs are more potent in inhibiting cancer cell growth than cisplatin, and their impact is unaltered in the presence or absence of TE pretreatment of A549 cells. The present study holds significant potential for various theranostic applications, which are highly desired for laparoscopic image-guided lung cancer therapy.
RESUMO
The rapid metastasis & heterogenic constitution of triple negative breast cancer (TNBC) limits drug entry to the tumor, reducing treatment effectiveness. To address this, we have synthesized Casein nanoparticles (Cn NPs) with attached glutathione (GSH), a natural ligand for cancer cell overexpressed γ-glutamyl transpeptidase (GGT). Cn NPs encapsulated with Camptothecin and NIR dye IR 797 (CCN NPs) for combinatorial therapy of TNBC. The GSH-CCN nanoparticles (CCNG NPs) act as a Nano-Trojan to deceive the cancer cells by delivering therapeutic payloads directly to specific target cells. In this study, Casein Nano-Trojan is equipped with GSH as a targeting ligand for GGT. The binding of CCNG NPs with cell surface receptors switched the anionic charge to catanionic, prompting the target cell to engulf the nanoparticles. The Casein Nano-Trojan releases its therapeutic payload inside the target cell, potentially inhibiting proliferation & inducing a high percentage of cell death (85 ± 7 %). Disintegration of mitochondrial membrane potential, inhibition of both migration & re-growth were observed. Immunofluorescence, acridine orange/ethidium bromide stain, and nuclear fragmentation assay further confirmed the substantial DNA damage induced by the high expression of γH2AX and p53. Significant therapeutic efficacy was observed in the 3D spheroids of 4T1 cells and in vivo breast cancer mice model (BALB/c). These findings demonstrate that CCNG NPs could be an effective treatment approach for highly metastatic triple negative breast cancer.
Assuntos
Camptotecina , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Caseínas/uso terapêutico , Ligantes , Linhagem Celular Tumoral , GlutationaRESUMO
RNA interference (RNAi) has increased the possibility of restoring RNA drug targets for cancer treatment. Small interfering RNA (siRNA) is a promising therapeutic RNAi tool that targets the defective gene by inhibiting its mRNA expression and stopping its translation. However, siRNAs have flaws like poor intracellular trafficking, RNase degradation, rapid kidney filtration, off-targeting, and toxicity, which limit their therapeutic efficiency. Nanocarriers (NCs) have been designed to overcome such flaws and increase antitumor activity. Combining siRNA and anticancer drugs can give synergistic effects in cancer cells, making them a significant gene-modification tool in cancer therapy. Our discussion of NCs-mediated siRNA delivery in this review includes their mechanism, limitations, and advantages in comparison with naked siRNA delivery. We will also discuss organic NCs (polymers and lipids) and inorganic NCs (quantum dots, carbon nanotubes, and gold) that have been reported for extensive delivery of therapeutic siRNA to tumor sites. Finally, we will conclude by discussing the studies based on organic and inorganic NCs-mediated siRNA drug delivery systems conducted in the years 2020 and 2021.
Assuntos
Nanotubos de Carbono , Neoplasias , RNA Interferente Pequeno/genética , Sistemas de Liberação de Fármacos por Nanopartículas , Interferência de RNA , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
BACKGROUND: Cancer remains a major world health issue due to its high morbidity and mortality rate. Plant based natural products (NPs) have played vital role in discovery of valuable anti-cancer drugs. Darjeeling Himalayan region has a rich diversity of therapeutic plants that can be utilized for development of novel drugs. AIM: We previously reported cytotoxic potential of rhizome extract of A.rivularis, a Darjeeling himalayan herb. Present study reports isolation and characterization of a phytosteroid from the plant rhizome in a bioassay-guided approach and evaluation of its anti-tumorigenic potential. RESULTS: The phytosteroid was characterized as stigmasta-5(6), 22(23)-dien-3-beta-yl acetate (A11) by various spectrometric techniques (IR, NMR, MS etc.). The catalytic inhibition and structural alteration of human dihydrofolate reductase (hDHFR) by A11 was evaluated using methotrexate (MTX), a DHFR inhibitor anticancer drug as a reference. A11 inhibited hDHFR activity with IC50 values of 1.20 µM A11 caused concentration dependent quenching of tryptophan fluorescence of hDHFR suggesting its effect on alteration of enzyme structure. Molecular docking of A11 on crystal structure of hDHFR revealed significant interaction with free energy of binding and Ki values of -10.86 kcal/mol and 11 nM, respectively. Subsequent in vitro studies at cellular level showed a relatively greater cytotoxic effect of A11 against human kidney (ACHN, IC50 60 µM) and liver (HepG2, IC5070 µM) cancer cells than their respective normal cells (HEK-293, IC50 350 µM and WRL-68, IC50 520 µM). Scanning electron microscopy of A11 treated cells revealed the morphological feature of apoptosis, like cell rounding and surface detachment, membrane blebbing, loss of cilia and increased number of pores of decreased sizes. A11 mediated apoptosis of cancer cells was found to be correlated with induction of intracellular of reactive oxygen species (ROS) level and fragmentation of genomic DNA.