Current Pharmaceutical Design - Volume 29, Issue 44, 2023

Breast cancer is a heterogeneous disease and a leading malignancy around the world. It is a vital cause of untimely mortality among women. Drug resistance is the major challenge for effective cancer therapeutics. In contrast, cancer stem cells (CSCs) are one of the reasons for drug resistance, tumor progression, and metastasis. The small population of CSCs present in each tumor has the ability of self-renewal, differentiation, and tumorigenicity. CSCs are often identified and enriched using a variety of cell surface markers (CD44, CD24, CD133, ABCG2, CD49f, LGR5, SSEA-3, CD70) that exert their functions by different regulatory networks, i.e., Notch, Wnt/β-catenin, hedgehog (Hh), and Hippo signaling pathways. Particularly the Hippo signaling pathway is the emerging and very less explored cancer stem cell pathway. Here, in this review, the Hippo signaling molecules are elaborated with respect to their ability of stemness as epigenetic modulators and how these molecules can be targeted for better cancer treatment and to overcome drug resistance.

Contemporary medical research increasingly focuses on the blood-brain barrier (BBB) to maintain homeostasis in healthy individuals and provide solutions for neurological disorders, including brain cancer. Specialized in vitro modules replicate the BBB's complex structure and signalling using micro-engineered perfusion devices and advanced 3D cell cultures, thus advancing the understanding of neuropharmacology. This research explores nanoparticle-based biomolecular engineering for precise control, targeting, and transport of theranostic payloads across the BBB using nanorobots. The review summarizes case studies on delivering therapeutics for brain tumors and neurological disorders, such as Alzheimer's, Parkinson's, and multiple sclerosis. It also examines the advantages and disadvantages of nano-robotics. In conclusion, integrating machine learning and AI with robotics aims to develop safe nanorobots capable of interacting with the BBB without adverse effects. This comprehensive review is valuable for extensive analysis and is of great significance to healthcare professionals, engineers specializing in robotics, chemists, and bioengineers involved in pharmaceutical development and neurological research, emphasizing transdisciplinary approaches.

Background: Over the past ten years, tremendous progress has been made in microbubble-based research for a variety of biological applications. Microbubbles emerged as a compelling and dynamic tool in modern drug delivery systems. They are employed to deliver drugs or genes to targeted regions of interest, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials.Objective: The objective of this article is to review the microbubble compositions and physiochemical characteristics in relation to the development of innovative biomedical applications, with a focus on molecular imaging and targeted drug/gene delivery.Methods: The microbubbles are prepared by using various methods, which include cross-linking polymerization, emulsion solvent evaporation, atomization, and reconstitution. In cross-linking polymerization, a fine foam of the polymer is formed, which serves as a bubble coating agent and colloidal stabilizer, resulting from the vigorous stirring of a polymeric solution. In the case of emulsion solvent evaporation, there are two solutions utilized in the production of microbubbles. In atomization and reconstitution, porous spheres are created by atomising a surfactant solution into a hot gas. They are encapsulated in primary modifier gas. After the addition of the second gas or gas osmotic agent, the package is placed into a vial and sealed after reconstituting with sterile saline solution.Results: Microbubble-based drug delivery is an innovative approach in the field of drug delivery that utilizes microbubbles, which are tiny gas-filled bubbles, act as carriers for therapeutic agents. These microbubbles can be loaded with drugs, imaging agents, or genes and then guided to specific target sites.Conclusion: The potential utility of microbubbles in biomedical applications is continually growing as novel formulations and methods. The versatility of microbubbles allows for customization, tailoring the delivery system to various medical applications, including cancer therapy, cardiovascular treatments, and gene therapy.

Nanogels are three-dimensional networks at the nanoscale level that can be fabricated through physical or chemical processes using polymers. These nanoparticles’ biocompatibility, notable stability, efficacious drug-loading capacity, and ligand-binding proficiency make them highly suitable for employment as drug-delivery vehicles. In addition, they exhibit the ability to react to both endogenous and exogenous stimuli, which may include factors such as temperature, illumination, pH levels, and a diverse range of other factors. This facilitates the consistent administration of the drug to the intended site. Alginate biopolymers have been utilized to encapsulate anticancer drugs due to their biocompatible nature, hydrophilic properties, and cost-effectiveness. The efficacy of alginate nano gel-based systems in cancer treatment has been demonstrated through multiple studies that endorse their progress toward clinical implementation. This paper comprehensively reviews alginate and its associated systems in drug delivery systems.

HER2 is the membrane receptor tyrosine kinase showing overexpression in several human malignancies, particularly breast cancer. HER2 overexpression causes the activation of Ras- MAPK and PI3K/Akt/ NF-ΚB cellular signal transduction pathways that lead to cancer development and progression. HER2 is, therefore, presumed as one of the key targets for the development of tumor-specific therapies. Several preclinical have been developed that function by inhibiting the HER2 tyrosine kinase activity through the prevention of the dimerization process. Most HER2 inhibitors act as ATP competitors and prevent the process of phosphorylation, and abort the cell cycle progression and proliferation. In this review, the clinical drug candidates and potent pre-clinical newly developed molecules are described, and the core chemical scaffolds typically responsible for anti-HER2 activity are deciphered. In addition, the monoclonal antibodies that are either used in monotherapy or in combination therapy against HER2-positive cancer are briefly described. The identified key moieties in this study could result in the discovery of more effective HER2-targeted anticancer drug molecules and circumvent the development of resistance by HER2-specific chemotherapeutics in the future.

Background: In a previous work, an IL-2Rβγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems.Objective: In this study, PEGylation was employed to improve the pharmacokinetic and antitumoral properties of the novel protein.Methods: Pegylated IL-2noα was characterized by polyacrylamide gel electrophoresis, size exclusion chromatography, in vitro cell proliferation and in vivo cell expansion bioassays, and pharmacokinetic and antitumor studies.Results: IL-2noα-conjugates with polyethylene glycol (PEG) of 1.2 kDa, 20 kDa, and 40 kDa were obtained by classical acylation. No significant changes in the secondary and tertiary structures of the modified protein were detected. A decrease in biological activity in vitro and a significant improvement in half-life were observed, especially for IL-2noα-PEG20K. PEGylation of IL-2noα with PEG20K did not affect the capacity of the mutant to induce preferential expansion of T effector cells over Treg cells. This pegylated IL-2noα exhibited a higher antimetastatic effect compared to unmodified IL-2noα in the B16F0 experimental metastases model, even when administered at lower doses and less frequently.Conclusion: PEG20K was selected as the best modification strategy, to improve the blood circulation time of the IL-2noα with a superior antimetastatic effect achieved with lower doses.