Sulfo-butyl ether ß-cyclodextrin inclusion complexes of bosutinib: in silico, in vitro and in vivo evaluation in attenuating the fast-fed variability.

Bosutinib (BOS) is a BCS class IV drug that shows low oral bioavailability and high fast-fed variability. Various pharmaceutical formulations have been explored thus far in order to improve its bioavailability while avoiding fast-fed variability. In the present study, we explored cyclodextrin (CD) complexation strategy to overcome the aforementioned disadvantages associated with BOS. CD complexation is a simple, versatile and economic approach that enables formation of inclusion complexes, thereby improving aqueous solubility while nullifying pH-dependent solubility and fast-fed variability for poorly soluble drugs. Initially, we performed molecular dynamics and docking studies to select appropriate CD derivative. The results of in silico studies revealed that sulfo-butyl ether ß-cyclodextrin (SBE-CD) offered superior binding affinity with BOS. Further, Job's plot revealed that 1:1 stoichiometry of BOS and CD resulted in enhancement of BOS solubility up to ~ 132.6-folds. In vitro release studies in bio-relevant media (fasted and fed state simulated gastric and intestinal fluids) revealed higher drug release while overcoming its pH-dependent solubility. In vitro studies on K562 cells demonstrated a 1.83-fold enhancement in cytotoxicity due to enhanced ROS production and G2/M phase arrest.In vivo pharmacokinetic studies in Sprague-Dawley rats revealed insignificant fast-fed variability with AUCfast/fed 0.9493 and Cmaxfast/fed 0.8291 being closer to 1 in comparison with BOS. Hence, we conclude that SBE-CD complexation could be a promising approach in diminishing fast-fed variability of BOS.

Supramolecular self-assembled peptide-engineered nanofibers: A propitious proposition for cancer therapy.

Cancer is a devastating disease that causes a substantial number of deaths worldwide. Current therapeutic interventions for cancer include chemotherapy, radiation therapy, or surgery. These conventional therapeutic approaches are associated with disadvantages such as multidrug resistance, destruction of healthy tissues, and tissue toxicity. Therefore, there is a paradigm shift in cancer management wherein nanomedicine-based novel therapeutic interventions are being explored to overcome the aforementioned disadvantages. Supramolecular self-assembled peptide nanofibers are emerging drug delivery vehicles that have gained much attention in cancer management owing to their biocompatibility, biodegradability, biomimetic property, stimuli-responsiveness, transformability, and inherent therapeutic property. Supramolecules form well-organized structures via non-covalent linkages, the intricate molecular arrangement helps to improve tissue permeation, pharmacokinetic profile and chemical stability of therapeutic agents while enabling targeted delivery and allowing efficient tumor imaging. In this review, we present fundamental aspects of peptide-based self-assembled nanofiber fabrication their applications in monotherapy/combinatorial chemo- and/or immuno-therapy to overcome multi-drug resistance. The role of self-assembled structures in targeted/stimuli-responsive (pH, enzyme and photo-responsive) drug delivery has been discussed along with the case studies. Further, recent advancements in peptide nanofibers in cancer diagnosis, imaging, gene therapy, and immune therapy along with regulatory obstacles towards clinical translation have been deliberated.

Neutrophil membrane-based nanotherapeutics: Propitious paradigm shift in the management of cancer.

Cancer is the leading cause of death across the globe, with 19.3 million new cancer cases and 10 million deaths in the year 2020. Conventional treatment modalities have numerous pitfalls, such as off-site cytotoxicity and poor bioavailability. Nanocarriers (NCs) have been explored to deliver various therapeutic moieties such as chemotherapeutic agents and photothermal agents, etc. However, several limitations, such as rapid clearance by the reticuloendothelial system, poor extravasation into the tumor microenvironment, and low systemic half-life are roadblocks to successful clinical translation. To circumvent the pitfalls of currently available treatment modalities, neutrophil membrane (NM)-based nanotherapeutics have emerged as a promising platform for cancer management. Their versatile features such as natural tumor tropism, tumor-specific accumulation, and prevention from rapid clearance owing to their autologous nature make them an effective anticancer NCs. In this manuscript, we have discussed various methods for isolation, coating and characterization of NM. We have discussed the role of NM-coated nanotherapeutics as neoadjuvant and adjuvant in different treatment modalities, such as chemotherapy, photothermal and photodynamic therapies with rationales behind their inclusion. Clinical hurdles faced during the bench-to-bedside translation with possible solutions have been discussed. We believe that in the upcoming years, NM-coated nanotherapeutics will open a new horizon in cancer management.

Quality by design endorsed fabrication of Ibrutinib-loaded human serum albumin nanoparticles for the management of leukemia.

Ibrutinib (IB), a BCS class II drug suffers from limited aqueous solubility, short half-life and extensive first-pass metabolism. In this project, we aim to recruit the desirable properties of human serum albumin (HSA) as a biocompatible drug carrier to circumvent nanoparticle-associated drawbacks. Quality by design and multivariate analysis was used for the optimization of IB-NPs. Cell culture studies performed on the K562 cell line revealed that the Ibrutinib-loaded HSA NPs demonstrated improved cytotoxicity, drug uptake, and reactive oxygen species generation in the leukemic K562 cells. Cell cycle analysis revealed G2/M phase retention of the leukemia cells. In vitro protein corona and hemolysis studies revealed superior hematological stability compared to the free drug which showed greater than 40 % hemolysis. In vitro drug release studies showed prolonged release profile till 48 h. Pharmacokinetic studies demonstrated a 2.31-fold increase in AUC and an increase in half-life from 0.43 h to 2.887 h with a tremendous reduction in clearance and elimination rate indicating prolonged systemic circulation which is desirable in leukemia. Hence, we conclude that IB-loaded albumin nanoparticles could be a promising approach for the management of leukemia.

Multifaceted applications of ulvan polysaccharides: Insights on biopharmaceutical avenues.

Ulvans are water-soluble sulfated polysaccharides predominantly found in the cell wall of green algae. They hold unique characteristics that are attributed to their 3D conformation, functional groups along with the presence of saccharides and sulfate ions. Traditionally, ulvans are widely used as food supplements and probiotics owing to the high content of carbohydrates. Despite their widespread usage in food industry, an in-depth understanding is required for extrapolating their potential application as a nutraceutical and medicinal agent which could be beneficial in promoting human health and well-being. This review emphasizes novel therapeutic avenues where ulvan polysaccharides can be used beyond their nutritional applications. A collection of literature points towards multifarious applications of ulvan in various biomedical fields. Structural aspects along with extraction and purification methods have been discussed. The underlying molecular mechanisms associated with its biomedical potential in different therapeutic fields like oncology, infectious diseases, inflammation, neuroprotection and tissue engineering, etc. have been unravelled. Challenges associated with clinical translation and future perspectives have been deliberated.

The portrayal of macrophages as tools and targets: A paradigm shift in cancer management.

Macrophages play a major role in maintaining an organism's physiology, such as development, homeostasis, tissue repair, and immunity. These immune cells are known to be involved in tumor progression and modulation. Monocytes can be polarized to two types of macrophages (M1 macrophages and pro-tumor M2 macrophages). Through this article, we aim to emphasize the potential of targeting macrophages in order to improve current strategies for tumor management. Various strategies that target macrophages as a therapeutic target have been discussed along with ongoing clinical trials. We have discussed the role of macrophages in various stages of tumor progression epithelial-to-mesenchymal transition (EMT), invasion, maintaining the stability of circulating tumor cells (CTCs) in blood, and establishing a premetastatic niche along with the role of various cytokines and chemokines involved in these processes. Intriguingly macrophages can also serve as drug carriers due to their tumor tropism along the chemokine gradient. They surpass currently explored nanotherapeutics in tumor accumulation and circulation half-life. We have emphasized on macrophage-based biomimetic formulations and macrophage-hitchhiking as a strategy to effectively target tumors. We firmly believe that targeting macrophages or utilizing them as an indigenous carrier system could transform cancer management.

Albumin-hitchhiking: Fostering the pharmacokinetics and anticancer therapeutics.

Nanotherapeutics demonstrate poor accumulation in the tumor microenvironment due to poor extravasation and penetration into the tumor. Therapeutics such as oligonucleotides, peptides and other biologicals suffer from low systemic half-life and rapid degradation. Albumin-hitchhiking has emerged as an effective strategy to enhance tumor-specific accumulation of various therapeutics. Hitchhiking on serum albumin (SA) have shown to improve biological half-life of various therapeutics including nanocarriers (NCs), biologics, oligonucleotides, vaccines, etc. In addition, passive and active accumulation of SA-riding therapeutics in the tumor, site-specific drug release, and SA-mediated endosomal escape have improved the potential of various anticancer modalities such as chemo-, immune-, vaccine, and gene therapies. In this review, we have discussed the advantages of employing SA-hitchhiking in anticancer therapies. In addition, vaccine strategies employing inherent lymph-nodes accumulating property of albumin have been discussed. We have presented a clinical overview of SA-hitchhiked formulations along with possible bottlenecks for improved clinical outcomes. We have also discussed the role of physiologically based pharmacokinetics (PBPK) modelling for efficient characterization of anti-cancer nanotherapeutics.

Immune cell-camouflaged surface-engineered nanotherapeutics for cancer management.

Nanocarriers (NCs) have shown potential in delivering hydrophobic cytotoxic drugs and tumor-specific targeting. However, the inability to penetrate the tumor microenvironment and entrapment by macrophages has limited their clinical translation. Various cell-based drug delivery systems have been explored for their ability to improve circulation half-life and tumor accumulation capabilities. Tumors are characterized by high inflammation, which aids in tumor progression and metastasis. Immune cells show natural tumor tropism and penetration inside the tumor microenvironment (TME) and are a topic of great interest in cancer drug delivery. However, the TME is immunosuppressive and can polarize immune cells to pro-tumor. Thus, the use of immune cell membrane-coated NCs has gained popularity. Such carriers display immune cell-specific surface receptors for tumor-specific accumulation but lack cell machinery. The lack of immune cell machinery makes them unaffected by the immunosuppressive TME, meanwhile maintaining the inherent tumor tropism. In this review, we discuss the molecular mechanism behind the movement of various immune cells toward TME, the preparation and characterization of membrane-coated NCs, and the efficacy of immune cell-mimicking NCs in tumor therapy. Regulatory guidelines and the bottlenecks in clinical translation are also highlighted. STATEMENT OF SIGNIFICANCE: Nanocarriers have been explored for the site-specific delivery of chemotherapeutics. However, low systemic circulation half-life, extensive entrapment by macrophages, and poor accumulation inside the tumor microenvironment prevent the clinical translation of conventional nanotherapeutics. Immune cells possess the natural tropism towards the tumor along the chemokine gradient. Hence, coating the nanocarriers with immune cell-derived membranes can improve the accumulation of nanocarriers inside the tumor. Moreover, coating with membranes derived autologous immune cells will prevent engulfment by the macrophages.

Tumor-promoting aftermath post-chemotherapy: A focus on breast cancer.

Chemotherapy is an important tool for the management of solid tumors including breast cancers (BC). Its neo-adjuvant and adjuvant use is important for shrinking tumor size and neutralizing the disseminated cancer cells. Initial chemotherapy administration often leads to a reduction in tumor size and pathological complete response. However, chemotherapy-induced tumor-free survival is not durable in BC patients. Chemotherapy is the prominent treatment for the management of triple-negative BC (TNBC), the most aggressive subtype of the BC. Various factors such as the emergence of multidrug resistance (MDR), the appearance of dormant and tolerant clones, and remodeling of the tumor microenvironment (TME) in response to chemotherapy-induced stress are responsible for tumor relapse. In current review, the authors have highlighted various cytokines and growth factors, and underlying signaling pathways such as NF-κB and PI3k/AkT, responsible for the emergence of chemo-resistance and metastasis in the TME. The present review potentially explores the role of epithelial-mesenchymal transition (EMT) in eliciting metastasis and providing stem-like phenotypes to the BC cells. The appearance of drug-tolerant sub-populations such as persister cells and BC stem cells has been discussed with mechanistic pathways. Through the current review, authors have significantly explained the mechanistic pathways of the chemotherapy-induced transformation of the tumor microenvironment (TME) constituents responsible for tumor progression. Potential therapeutic targets have been highlighted.