Current Drug Metabolism - Volume 23, Issue 10, 2022

Breast cancer is the most prevalent cancer in women around the world, having a sudden spread nowadays because of the poor sedentary lifestyle of people. Comprising several subtypes, one of the most dangerous and aggressive ones is triple-negative breast cancer or TNBC. Even though conventional surgical approaches like single and double mastectomy and preventive chemotherapeutic approaches are available, they are not selective to cancer cells and are only for symptomatic treatment. A new branch called nanotechnology has emerged in the last few decades that offers various novel characteristics, such as size in nanometric scale, enhanced adherence to multiple targeting moieties, active and passive targeting, controlled release, and site-specific targeting. Among various nanotherapeutic approaches like dendrimers, lipid-structured nanocarriers, carbon nanotubes, etc., nanoparticle targeted therapeutics can be termed the best among all for their specific cytotoxicity to cancer cells and increased bioavailability to a target site. This review focuses on the types and molecular pathways involving TNBC, existing treatment strategies, various nanotechnological approaches like exosomes, carbon nanotubes, dendrimers, lipid, and carbon-based nanocarriers, and especially various nanoparticles (NPs) like polymeric, photodynamic, peptide conjugated, antibody-conjugated, metallic, inorganic, natural product capped, and CRISPR based nanoparticles already approved for treatment or are under clinical and pre-clinical trials for TNBC.

Nanoparticles have gained prominence in many areas and domains worldwide, such as metallic NP, carbon dots, quantum dots, polymeric NP, nano-suspension, nanocrystals, solid lipid nanoparticles (SLN), etc. and have been applied in the field of medicine as nanomedicine with promising results. Rise in cancer mortality rate has been an issue for a long time with female breast cancer as one of the most detected cancers. No permanent treatment has been developed till date could combat breast cancer with minimum side effects that are not long-lasting as there is no proper technique through which the anticancer drugs can recognize benign or malignant or normal cells that causes systematic toxicity. Advancement in technology has led to the discovery of many biological pathways and mechanisms. Tumor cells or cancer cells overexpress some high-affinity receptors that can be targeted to deliver the anticancer drugs at specific site using these pathways and mechanisms. Solid lipid nanoparticles (SLN) are among some of the excellent drug delivery systems, especially stealth SLN (sSLN). SLN, when conjugated with a ligand (called as sSLN), has affinity and specificity towards a specific receptor, and can deliver the drug in breast cancer cells overexpressing the receptors. Using this technique, various investigations have reported better anti-breast cancer activity than simple SLN (non-conjugated to ligand or no receptor targeting). This review includes the investigations and data on receptor-mediated targeting in breast cancer from 2010 to 2021 by searching different databases. Overall, information on SLN in different cancers is reviewed. In vivo investigations, pharmacokinetics, biodistribution, and stability are discussed to describe the efficacy of sSLN. Investigations included in this review demonstrate that sSLN delivers the drug by overcoming the biological barriers and shows enhanced and better activity than non-conjugated SLN which also verifies that a lesser concentration of drug can show anti-breast cancer activity. The efficacy of medicines could be increased with lower cancer deaths through stealth-SLN. Due to the low cost of synthesis, biocompatibility and easy to formulate, more study is needed in vitro and in vivo so that this novel technique could be utilized in the treatment of human breast cancer.

In recent times, nanotechnology has made significant advances in the field of cancer. The majority of chemotherapeutic drugs do not selectively target cancer cells, and they might cause side effects and damage to healthy cells, resulting in a variety of adverse effects. Having a thorough understanding of nanoparticles may improve drug targeting and administration. The nano-engineering of pharmacological and natural compounds can improve the diagnosis and treatment. Polymeric micelles, liposomes, and dendrimers are examples of innovative cancer therapeutic nano-formulations. It has been demonstrated that quantum dots, nano-suspensions, and gold nanoparticles can improve drug delivery. Nanomedicines may be delivered more effectively, focusing on cancerous cells instead of healthy tissues, which minimizes undesirable side effects and drug resistance to chemotherapeutic agents. However, limited water solubility, low stability, poor absorption, and quick metabolism limit their therapeutic effectiveness. Nanotechnology has generated unique formulations to optimise the potential use of phytochemicals in anticancer therapy. Nanocomposites can improve phytochemical solubility and bioavailability, extend their half-life in circulation, and even transport phytochemicals to specific locations. The progress in using phytochemical-based nanoparticles in cancer treatment is summarized in this paper.

It is demonstrated that fasting can alter the biodistribution of radiopharmaceuticals in nuclear medicine. Various studies have highlighted that fasting is interpreted to be easy for physicians during PET study, fasting is one of the most important factors determining the usefulness of this protocol. It is well documented that fasting can suppress normal ¹⁸F-FDG PET uptake during nuclear cardiology. However, there is no consensus about the usefulness of fasting on radiopharmaceuticals, especially on ¹⁸F-FDG in PET imaging, but special attention should be paid to the setting of the fasting duration. Nevertheless, it does seem we still need extensive clinical studies in the future. The present study aims to review the various aspects of fasting, especially metabolic alteration on radiopharmaceutical biodistribution. In this study, we focused more on the effect of fasting on ¹⁸F-FDG biodistribution, which alters its imaging contrast in cardiology and cancer imaging. Therefore, shifting substrate metabolism from glucose to free fatty acids during fasting can be an alternative approach to suppress physiological myocardial uptake.

Background: Numerous herbs are reported to have anti-hyperglycemic activity and are frequently used in combination with prescription drugs to lower the blood glucose levels in diabetic patients, without proper knowledge about the possibility of herb-drug interaction. Objectives: To investigate the effect of cumin and garden cress on pharmacokinetics (PK) and pharmacodynamics (PD) of gliclazide (GLZ) in nicotinamide-streptozotocin diabetic model. Methods: Diabetic animals of groups II-IV were treated with GLZ, cumin, ‘cumin + GLZ’, garden cress and ‘garden cress + GLZ’. Herb’s treatments were given for two weeks, and GLZ was administered in a single dose. Blood glucose levels (BGLs) were measured at pre-determined time points. Plasma samples of pharmacokinetic study were analyzed using UPLC-MS/MS. GLZ fragment at m/z 324.1>127 was monitored. Results: Cumin and garden cress have shown 15.3% and 15.9% reduction in mean BGL (1-24h) (p-value < 0.001), respectively. GLZ reduced mean BGL by 30.0%, which was significantly better than cumin and garden cress (pvalue <0.05). Concurrently administered “garden cress + GLZ” demonstrated the highest reduction in mean BGL (by 40.46%) and showed a prolonged effect. There was no significant advantage of simultaneously administered ‘cumin + GLZ’. Cumin did not affect PK of GLZ. Garden cress has significantly enhanced AUC0-t (by 69.8%, pvalue 0.0013), but other PK parameters Cmax, Tmax, and Kel were close to the control group. Conclusion: PK/PD-based herb-drug interaction was observed. Concurrently administered garden cress + GLZ showed improved antidiabetic effect and has enhanced GLZ bioavailability.

Background: Vadadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor, is a substance which carries a lifetime ban in both horse racing and equestrian competition. A comprehensive metabolic study of vadadustat in horses has not been previously reported. Objective: Metabolism and elimination profiles of vadadustat in equine plasma and urine were studied for the purpose of doping control. Methods: A nasoesophageal administration of vadadustat (3 g/day for 3 days) was conducted on three thoroughbred mares. Potential metabolites were comprehensively detected by differential analysis of full-scan mass spectral data obtained from both in vitro studies with liver homogenates and post-administration samples using liquid chromatography high-resolution mass spectrometry. The identities of metabolites were further substantiated by product ion scans. Quantification methods were developed and validated for the establishment of the excretion profiles of the total vadadustat (free and conjugates) in plasma and urine. Results: A total of 23 in vivo and 14 in vitro metabolites (12 in common) were identified after comprehensive analysis. We found that vadadustat was mainly excreted into urine as the parent drug together with some minor conjugated metabolites. The elimination profiles of total vadadustat in post-administration plasma and urine were successfully established by using quantification methods equipped with alkaline hydrolysis for cleavage of conjugates such as methylated vadadustat, vadadustat glucuronide, and vadadustat glucoside. Conclusion: Based on our study, for effective control of the misuse or abuse of vadadustat in horses, total vadadustat could successfully be detected for up to two weeks after administration in plasma and urine.