Quality by design empowered preparation of itraconazole albumin nanoparticles for prostate cancer.

The current advent explores the potential of itraconazole (ITR) in prostate cancer (PCa), by its incorporation into albumin nanoparticles (NP). ITR as a repurposed moiety has displayed tremendous potential in various cancers. However, poor aqueous solubility poses hurdles towards its clinical translation. Amorphisation of ITR was observed post-incorporation within NP matrix which could prevent its precipitation in aqueous media. ITR NP was developed using quality by design and multivariate analysis and evaluated for cellular uptake, cell proliferation inhibition and the mechanism of PCa cell inhibition. Time and concentration-dependent serum stability and hemolytic potential revealed safety of ITR NP. Morphological changes and nuclear staining studies revealed the efficacy of ITR and ITR NP in promoting growth inhibition of PC-3 cells. Superior qualitative and quantitative uptake, reactive oxygen species (ROS) and mitochondrial impairment for ITR NP in comparison with ITR and control group was observed. Cell cycle study revealed remarkable G2/M phase inhibition in PC-3 cells. ITR NP demonstrated superior anticancer potential in 3D tumoroids mimicking the micro-metastatic lesions compared to control and ITR. Hence, ITR NP can be a favorable alternative therapeutic alternative in PCa.

Surface Functionalized Lipid Nanoparticles in Promoting Therapeutic Outcomes: An Insight View of the Dynamic Drug Delivery System.

Compared to the conventional approach, nanoparticles (NPs) facilitate a non-hazardous, non-toxic, non-interactive, and biocompatible system, rendering them incredibly promising for improving drug delivery to target cells. When that comes to accomplishing specific therapeutic agents like drugs, peptides, nucleotides, etc., lipidic nanoparticulate systems have emerged as even more robust. They have asserted impressive ability in bypassing physiological and cellular barriers, evading lysosomal capture and the proton sponge effect, optimizing bioavailability, and compliance, lowering doses, and boosting therapeutic efficacy. However, the lack of selectivity at the cellular level hinders its ability to accomplish its potential to the fullest. The inclusion of surface functionalization to the lipidic NPs might certainly assist them in adapting to the basic biological demands of a specific pathological condition. Several ligands, including peptides, enzymes, polymers, saccharides, antibodies, etc., can be functionalized onto the surface of lipidic NPs to achieve cellular selectivity and avoid bioactivity challenges. This review provides a comprehensive outline for functionalizing lipid-based NPs systems in prominence over target selectivity. Emphasis has been put upon the strategies for reinforcing the therapeutic performance of lipidic nano carriers' using a variety of ligands alongside instances of relevant commercial formulations.

Quality by design fostered fabrication of cabazitaxel loaded pH-responsive Improved nanotherapeutics against prostate cancer.

Cabazitaxel has been approved for the treatment of prostate cancer since 2010. However, its poor solubility and permeability pitfalls prevent its accumulation at the target site and promote severe adverse effects. About 90% of prostate cancer (PCa) patients suffer from bone metastasis. This advent reports the development of CBZ-loaded pH-responsive polydopamine nanoparticles (CBZ NP) against metastatic PCa cells. Quality by design (QbD) and multivariate analysis tools were employed for the optimization of CBZ NP. Amorphisation of CBZ along with metastatic microenvironment responsive release was observed thereby imparting spatial release and circumventing solubility pitfalls. CBZ NP retained its cytotoxic potential, with a significant increase in quantitative cellular uptake. Apoptotic markers observed from nuclear staining with elevated reactive oxygen species (ROS) and mitochondrial damage revealed by JC-1 staining demonstrated the efficacy of CBZ NP against PC-3 cells with good serum stability and diminished hemolysis. Cell cycle analysis revealed substantial S and G2/M phase arrest with enhancement in apoptosis was observed. Western blot studies revealed an elevation in caspase-1 and suppression in Bcl-2 indicating enhanced apoptosis compared to the control group. Substantial reduction in the diameter of 3D-Tumoroid and enhanced cell proliferation inhibition indicated the efficacy of CBZ NP in PCa. Thus, we conclude that CBZ NP could be a promising Nanotherapeutic approach for PCa.

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.

Quality by design endorsed atorvastatin-loaded nanostructured lipid carriers embedded in pH-responsive gel for melanoma.

AIM: Our aim was to repurpose atorvastatin for melanoma by encapsulating in a nanostructured lipid carrier matrix to promote tumour cell internalisation and skin permeation. pH-responsive chitosan gel was employed to restrict At-NLCs in upper dermal layers. METHODS: We utilised a quality by design approach for encapsulating At within the NLC matrix. Further, cellular uptake and cytotoxicity was evaluated along with pH-responsive release and ex vivo skin permeation. RESULTS: Cytotoxicity assay showed 3.13-fold enhanced cytotoxicity on melanoma cells compared to plain drug with nuclear staining showing apoptotic markers. In vitro, release studies showed 5.9-fold rapid release in chitosan gel matrix at pH 5.5 compared to neutral pH. CONCLUSIONS: At-NLCs prevented precipitation, promoted skin permeation, and SK-MEL 28 cell internalisation. The localisation of NLCs on the upper dermal layer due to electrostatic interactions of skin with chitosan gel diminished the incidence of untoward systemic effects.

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.

Multifaceted roles of pollen in the management of cancer.

Oral drug delivery of microparticles demonstrates shortcomings like aggregation, decreased loading capacity and batch-to-batch variation, which limits its scale-up. Later, porous structures gained attention because of their large surface-to-volume ratio, high loading capacity and ability to carry biomacromolecules, which undergo degradation in GIT. But there are pitfalls like non-uniform particle size distribution, the impact of porogen properties, and harsh chemicals. To circumvent these drawbacks, natural carriers like pollen are explored in drug delivery, which withstands harsh environments. This property helps to subdue the acid-sensitive drug in GIT. It shows uniform particle size distribution within the species. On the other side, they contain phytoconstituents like flavonoids and polysaccharides, which possess various pharmacological applications. Therefore, pollen has the capability as a carrier system and therapeutic agent. This review focuses on pollen's microstructure, composition and utility in cancer management. The extraction strategies, characterisation techniques and chemical structure of sporopollenin exine capsule, its use in the oral delivery of antineoplastic drugs, and emerging cancer treatments like photothermal therapy, immunotherapy and microrobots have been highlighted. We have mentioned a note on the anticancer activity of pollen extract. Further, we have summarised the regulatory perspective, bottlenecks and way forward associated with pollen.

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.

Nanomedicine based strategies for oligonucleotide traversion across the blood-brain barrier.

Neurological disorders are considered the most prominent cause of disability worldwide. The major hurdle in the management of neurological disorders is the existence of the blood-brain barrier (BBB), which hinders the entry of several therapeutic moieties. In recent years, oligonucleotides have gained tremendous attention for their target specificity, diminished dose and adverse effects, thereby halting disease progression. However, enzymatic degradation, rapid clearance, limited circulation and availability at the bio-active site, etc., limit its clinical translation. Nanomedicine has opened up a breadth of opportunities in the delivery of oligonucleotides across the BBB. This review addresses the pitfalls associated with oligonucleotide delivery in traversing the BBB via nanotherapeutics for the management of brain disorders. Regulatory perspectives pertaining to hastening the clinical translation of oligonucleotide-loaded nanocarriers for brain delivery have been highlighted.

Paradigm of lyotropic liquid crystals in tissue regeneration.

The liquid crystalline phase has attracted tremendous attention from researchers across the globe due to its intriguing properties. In this article, we enumerate the different classes of liquid crystals. Lyotropic liquid crystals (LLCs) exhibit their liquid crystalline nature based on the surrounding solvent media, which opens novel horizons in drug delivery and tissue regeneration. The advantages of LLCs in the said fields and the thermodynamic mechanistic insights responsible for their structural stabilization have been conveyed. Various fabrication and characterization techniques, along with factors influencing the formation of LLCs, have been discussed. Applications in novel therapeutic avenues like bone extracellular matrix, cardiac remodeling, wound management, and implants have been unveiled. Also, regulatory considerations, patent, and clinical portfolios to circumvent the hurdles of clinical translation have been discussed. LLCs could be a promising approach in diverse avenues of tissue regeneration.

Nanotechnological Advances for Nose to Brain Delivery of Therapeutics to Improve the Parkinson Therapy.

Blood-Brain Barrier (BBB) acts as a highly impermeable barrier, presenting an impediment to the crossing of most classical drugs targeted for neurodegenerative diseases including Parkinson's disease (PD). About the nature of drugs and other potential molecules, they impose unavoidable doserestricted limitations eventually leading to the failure of therapy. However, many advancements in formulation technology and modification of delivery approaches have been successful in delivering the drug to the brain in the therapeutic window. The nose to the brain (N2B) drug delivery employing the nanoformulation, is one such emerging delivery approach, overcoming both classical drug formulation and delivery-associated limitations. This latter approach offers increased bioavailability, greater patient acceptance, lesser metabolic degradation of drugs, circumvention of BBB, ample drug loading along with the controlled release of the drugs. In N2B delivery, the intranasal (IN) route carries therapeutics firstly into the nasal cavity followed by the brain through olfactory and trigeminal nerve connections linked with nasal mucosa. The N2B delivery approach is being explored for delivering other biologicals like neuropeptides and mitochondria. Meanwhile, this N2B delivery system is associated with critical challenges consisting of mucociliary clearance, degradation by enzymes, and drug translocations by efflux mechanisms. These challenges finally culminated in the development of suitable surfacemodified nano-carriers and Focused- Ultrasound-Assisted IN as FUS-IN technique which has expanded the horizons of N2B drug delivery. Hence, nanotechnology, in collaboration with advances in the IN route of drug administration, has a diversified approach for treating PD. The present review discusses the physiology and limitation of IN delivery along with current advances in nanocarrier and technical development assisting N2B drug delivery.

Instigation of the epoch of nanovaccines in cancer immunotherapy.

Cancer is an unprecedented proliferation of cells leading to abnormalities in differentiation and maturation. Treatment of primary and metastatic cancer is challenging. In addition to surgery, chemotherapy and radiation therapies have been conventionally used; however, they suffer from severe toxicity and non-specificity. Immunotherapy, the science of programming the body's own defense system against cancer has gained tremendous attention in the last few decades. However, partial immunogenic stimulation, premature degradation and inability to activate dendritic and helper T cells has resulted in limited clinical success. The era of nanomedicine has brought about several breakthroughs in various pharmaceutical and biomedical fields. Hereby, we review and discuss the interplay of tumor microenvironment (TME) and the immunological cascade and how they can be employed to develop nanoparticle-based cancer vaccines and immunotherapies. Nanoparticles composed of lipids, polymers and inorganic materials contain useful properties suitable for vaccine development. Proteinaceous vaccines derived from mammalian viruses, bacteriophages and plant viruses also have unique advantages due to their immunomodulation capabilities. This review accounts for all such considerations. Additionally, we explore how attributes of nanotechnology can be utilized to develop successful nanomedicine-based vaccines for cancer therapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

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.

Exploration of novel drug delivery systems in topical management of osteoarthritis.

Osteoarthritis is one of the foremost disabling disorders in the world. There is no definitive treatment to prevent the progression of osteoarthritis. Hence, palliative treatment aims at minimizing pain, disability and improving function, performance and quality of life. Oral administration of nonsteroidal anti-inflammatory drug is associated with number of adverse effects and reduced therapeutic efficacy. Intra-articular injection has been the preferred route of drug administration. However, the clearance of drug from the arthritic site, risk of infections, cost and the pain associated with frequent injections make this route highly non-compliant to patients. Since osteoarthritis is a chronic condition which requires treatment for prolonged duration, there is an urgent need for another administration route which circumvents the hindrances linked with intra-articular route. Transdermal route across the skin locally at the osteoarthritis site could help in surpassing the disadvantages associated with intra-articular route. However, traversing skin barrier and reaching the chondrocytes with sufficient amount of the drug is extremely difficult. Nanocarrier-based approaches could hold an answer to the said shortcomings owing to their reduced size, targeting tunability and site specificity. In this article, we discuss the pathophysiology of osteoarthritis, molecular targets, and utilization of nanocarrier-based approaches to strategize the treatment of osteoarthritis in a new direction, i.e. topical delivery of nanocarriers in osteoarthritis.

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.

Quality by design (QbD) assisted Fabrication & evaluation of Simvastatin loaded Nano-Enabled thermogel for melanoma therapy.

Melanoma is a form of skin cancer that starts in melanocytes. Rampant chemo-resistance, metastasis, and inability to cross the skin barriers and accumulate within the tumor microenvironment render the conventional chemotherapeutic approaches ineffective. Simvastatin (SIM), a cholesterol synthesis inhibitor, has shown tremendous anticancer potential. Due to the lack of therapeutic alternatives, repositioning SIM in melanoma could be beneficial. Incorporating SIM within the nanoparticles promoted increased melanoma cell internalization, apoptosis, and sustained release profile. Further, the incorporation of nanoparticles into the thermogel facilitated depot formation over the upper dermal layers. Sol-to-gel transition at 34 °C was observed with a 14.03-fold increase in viscosity. This could be fruitful in limiting systemic exposure and preventing adverse effects. Entrapment of SIM in the PLGA NPs enhanced the cytotoxicity by 9.38-fold (p less than 0.05). Nuclear staining with DAPI showed blebbing, membrane shrinkage, and apoptosis confirmed by DCFDA and acridine orange/ethidium bromide staining. Ex vivo diffusion studies revealed the accumulation of C-6 loaded nanoparticles incorporated within the thermogel onto the upper dermal layer and depot formation up to 6 h. Thus, we conclude that SIM-loaded nanoparticulate thermogel could be an efficacious therapeutic alternative for melanoma.

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.