Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher amount of PAC compared to mature milk. Exosomal formulation of PAC (ExoPAC) showed higher antiproliferative activity and inhibition of colony formation against A549 cells compared with PAC alone, and also showed antiproliferative activity against a drug-resistant variant of A549. To further enhance its efficacy, exosomes were attached with a tumor-targeting ligand, folic acid (FA). FA-ExoPAC given orally showed significant inhibition (\u3e50%) of subcutaneous tumor xenograft while similar doses of PAC showed insignificant inhibition. In the orthotopic lung cancer model, oral dosing of FA-ExoPAC achieved greater efficacy (55% growth inhibition) than traditional i.v. PAC (24–32% growth inhibition) and similar efficacy as i.v. Abraxane (59% growth inhibition). The FA-ExoPAC given i.v. exceeded the therapeutic efficacy of Abraxane (76% growth inhibition). Finally, wild-type animals treated with p.o. ExoPAC did not show gross, systemic or immunotoxicity. Solvent-based PAC caused immunotoxicity which was either reduced or completely mitigated by its exosomal formulations. These studies show that a tumor-targeted oral formulation of PAC (FA-ExoPAC) significantly improved the overall efficacy and safety profile while providing a user-friendly, cost-effective alternative to bolus i.v. PAC and i.v. Abraxane

Updates on the anticancer potential of garlic organosulfur compounds and their nanoformulations: Plant therapeutics in cancer management

Garlic (Allium sativum L.) possesses numerous pharmacological potential, including antibacterial, antiarthritic, antithrombotic, anticancer, hypoglycemic, and hypolipidemic effects. The anti-cancer action of garlic is likely the best researched of the many advantageous pharmacological effects, and its use offers significant protection against the risk of developing cancer. A few active metabolites of garlic have been reported to be essential in the destruction of malignant cells due to their multi-targeted activities and lack of significant toxicity. The bioactive compounds in garlic having anticancer properties include diallyl trisulfide, allicin, allyl mercaptan diallyl disulfide, and diallyl sulphide. Different garlic-derived constituents and their nanoformulations have been tested for their effects against various cancers including skin, ovarian, prostate, gastric, breast, and lung, colorectal, liver, oral, and pancreatic cancer. The objective of this review is to summarize the antitumor activity and associated mechanisms of the organosulfur compounds of garlic in breast carcinoma. Breast cancer continues to have a significant impact on the total number of cancer deaths worldwide. Global measures are required to reduce its growing burden, particularly in developing nations where incidence is increasing quickly and fatality rates are still high. It has been demonstrated that garlic extract, its bioactive compounds, and their use in nanoformulations can prevent breast cancer in all of its stages, including initiation, promotion, and progression. Additionally, these bioactive compounds affect cell signaling for cell cycle arrest and survival along with lipid peroxidation, nitric oxide synthase activity, epidermal growth factor receptor, nuclear factor kappa B (NF-κB), and protein kinase C in breast carcinoma. Hence, this review deciphers the anticancer potential of garlic components and its nanoformulations against several breast cancer thereby projecting it as a potent drug candidate for efficient breast cancer management

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices

Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% (w/w) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in control group. At the end of the study (25 weeks), the tumor incidence was 96% in the control group compared with only 70% in the caraway group. A significant reduction in tumor volume (661 ± 123 vs. 313 ± 81 mm3) and tumor multiplicity (4.2 ± 0.4 vs. 2.5 ± 0.5 tumors/animal) was also observed in the caraway group compared with the control group. Together, our data show dietary caraway can significantly delay and prevent the hormonal mammary tumorigenesis by modulating different cellular and molecular targets

Exosomes in Cancer Therapy

Exosomes or small extracellular vesicles (EVs) are natural nanoparticles and known to play essential roles in intercellular communications, carrying a cargo of a broad variety of lipids, proteins, metabolites, RNAs (mRNA, miRNA, tRNA, long non-coding RNA), and DNAs (mtDNA, ssDNA, dsDNA) [...

Antimutagenic activity of methanolic extracts of four ayurvedic medicinal plants

668-672Methanolic extracts of Acorus calamus (Rhizome), Hemidesmus indicus (Stem), Holarrhena antidysenterica (Bark) and Plumbago zeylanica (Root), were tested for their antimutagenic potential. These extracts, at tested concentrations, showed no sign of mutagenicity to Salmonella typhimurium tester strains. The extracts of the plants exhibited varying level of antimutagenicity. At a dose of 100 µg/plate, the extracts exhibited the inhibition of His+ revertants from 18.51% to 82.66 % against direct acting mutagens, methyl methanesulphonate (MMS) and sodium azide (NaN3) induced mutagenicity in Salmonella tester strains TA 97a, TA 100, TA 102 and TA 104. However, at lower concentrations (25 and 50 µg/ plate) of the plant extracts, a decrease in antimutagenic activity was recorded. Dose dependent antimutagenic activity of the extracts is also evident from linear regression analysis of the data. The over all antimutagenic potential of above four extracts was found to be in order of A. calamus > H. indicus > H. antidysenterica > P. zeylanica. Further, total phenolic content of these extracts did not correlate with its antimutagenic activity in A. calamus and P. zeylanica

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials

Biosorption of Ni, Cr and Cd by metal tolerant <i style="">Aspergillus niger </i>and <i style="">Penicillium sp.</i> using single and multi-metal solution

73-76Fungi including Aspergillus and Penicillium, resistant to Ni2+, Cd2+, and Cr6+ were isolated from soil receiving long-term application of municipal wastewater mix with untreated industrial effluents of Aligarh, India. Metal tolerance in term of minimum inhibitory concentration (MIC) was 125-550 μg/ml for Cd, 300-850 μg/ml for Ni and 300-600 μg/ml for Cr against test fungi. Two isolates, Aspergillus niger and Penicillium sp. were tested for their Cr, Ni and Cd biosorption potential using alkali treated, dried and powdered mycelium. Biosorption experiment was conducted in 100 ml of solution at three initial metal concentrations i.e., 2, 4 and 6 mM with contact time (18 hr) and pretreated fungal biomass (0.1g) at 25°C. Biosorption of all metals was found higher at 4 mM initial metal concentration as compared to biosorption at 2 and 6 mM concentrations. At 4 mM initial metal concentration, chromium biosorption was 18.05 and 19.3 mg/g of Aspergillus and Penicillium biomasses, respectively. Similarly, biosorption of Cd and Ni ions was also maximum at 4 mM initial metal concentration by Aspergillus (19.4 mg/g for Cd and 25.05 mg/g of biomass for Ni) and Penicillium (18.6 mg/g for Cd and 17.9 mg/g of biomass for Ni). In general, biosorption of metal was influenced by initial metal concentration and type of the test fungi. The results indicated that fungi of metal contaminated soil have high level of metal tolerance and biosorption properties