Nanoparticulate strategies for the delivery of miRNA mimics and inhibitors in anticancer therapy and its potential utility in oral submucous fibrosis

MicroRNAs (miRNAs) are naturally occurring noncoding RNAs with multiple functionalities. They are dysregulated in several conditions and can serve as disease biomarkers, therapeutic targets and therapeutic agents. Translation of miRNA therapeutics to the clinic poses several challenges related to the safe and effective delivery of these agents to the site of action. Nanoparticulate carriers hold promise in this area by enhancing targeting efficiency and reducing off-target effects. This paper reviews recent advances in the delivery strategies of miRNAs in anticancer therapy, with a focus on lipid-based, polymeric, inorganic platforms, cell membrane-derived vesicles and bacterial minicells. Additionally, this review explores the potentiality of miRNAs in the treatment of oral submucous fibrosis, a potentially premalignant condition of the oral cavity with no definitive treatment to date.

pH-responsive size-shrinkable mesoporous silica-based nanocarrier for improved tumor penetration and therapeutic efficacy

Poor tumor penetration is a major obstacle to nanomedicine for achieving effective anticancer therapy. Tumor microenvironment-induced nanomedicine size shrinkage is a promising strategy to overcome the drug penetration barrier across...

Modern combined treatment of multiple cerebral and visceral metastases of skin melanoma on the example of clinical observation

Introduction. The article discusses modern methods of combined treatment of patients with cerebral and visceral metastases of melanoma, including drug therapy and radiation therapy, the place of neurosurgery, and also discusses a clinical case of long-term relapse-free survival after effective treatment of multiple intracerebral and extracranial metastases of non-pigmented melanoma without a driver mutations. Purpose. Analysis of the results of the application of modern methods of antitumor treatment of melanoma with metastases to the brain and their effect on survival on the example of a clinical case of a patient with metastatic non-pigmented melanoma without an identified primary focus without driver mutations with multiple metastases to the brain, single metastases to the cervical lymph node and left adrenal gland. Materials and methods. Using a clinical example, a possible sequence of an individual approach to the treatment of a patient with multiple intracerebral metastases of non-pigmented melanoma without a primary identified focus without driver mutations and metastasis to the left adrenal gland is considered, the place of modern methods of treatment and examination. Results. The use of a combination of modern methods of anticancer therapy, including immunotherapy, stereotactic radiosurgery and radiation therapy, has increased the overall and relapse-free survival of patients with metastases of melanoma to the brain and visceral organs, and, moreover, reduces the need in neurosurgical interventions. As confirmation of this, the patient is alive for more than 25 months from the moment of progression with a life expectancy of 3-6 months. Conclusions. Modern methods of anticancer therapy can significantly increase the survival rate of patients with metastases of melanoma to the brain and visceral organs, and the accumulation of clinical experience will contribute to the optimization of approaches in the combined and sequential treatment of metastatic melanoma.

Iron chelates in the anticancer therapy

Iron plays a significant role in the metabolism of cancer cells. In comparison with normal cells, neoplastic ones exhibit enhanced vulnerability to iron. Ferric ions target tumor via the ferroptotic death pathway—a process involving the iron-mediated lipid oxidation. Ferric ion occurs in complex forms in the physiological conditions. Apart from iron, ligands are the other factors to affect the biological activity of the iron complexes. In recent decades the role of iron chelates in targeting the growth of the tumor was extensively examined. The ligand may possess a standalone activity to restrict cancer’s growth. However, a wrong choice of the ligand might lead to the enhanced cancer cell’s growth in in vitro studies. The paper aims to review the role of iron complex compounds in the anticancer therapy both in the experimental and clinical applications. The anticancer properties of the iron complex rely both on the stability constant of the complex and the ligand composition. When the stability constant is high, the properties of the drug are unique. However, when the stability constant remains low, both components—ferric ions and ligands, act separately on the cells. In the paper we show how the difference in complex stability implies the action of ligand and ferric ions in the cancer cell. Iron complexation strategy is an interesting attempt to transport the anticancer Fe2+/3+ ions throughout the cell membrane and release it when the pH of the microenvironment changes. Last part of the paper summarizes the results of clinical trials and in vitro studies of novel iron chelates such as: PRLX 93,936, Ferumoxytol, Talactoferrin, DPC, Triapine, VLX600, Tachypyridine, Ciclopiroxamine, Thiosemicarbazone, Deferoxamine and Deferasirox.

Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective

Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain ‘undruggable’ through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials.

Galactose Oxidase Enables Modular Assembly of Conjugates from Native Antibodies with High Drug-to-Antibody Ratios

The potential of antibody conjugates with high drug loading in anticancer therapy has recently been highlighted by the approval of Trastuzumab deruxtecan and Sacituzumab govitecan. These biopharmaceutical approaches have spurred interest in bioconjugation strategies with high and defined degrees antibody-to-drug (DAR) ratios, in particular on native antibodies. Here we report a glycoengineering methodology to generate antibody drug conjugates with DAR of up to eight, by combining highly selective enzymatic galactosylation and oxidation with biorthogonal tandem Knoevenagel-Michael addition chemistry. This three step approach offers a selective route to conjugates from native antibodies with high drug loading, and thus illustrates how biocatalysis can be used for the generation of biopharmaceuticals using mild reaction conditions.