Banashree Bondhopadhyay

In cancer research, tumour complexity and treatment resistance have become more prevalent. Especially microRNA (miRNA) modulation has recently come into light as a promising strategy in cancer immunotherapy, particularly in converting "cold" tumours with limited immune cell infiltration into "hot" tumours responsive to immunotherapy. Tumour microenvironments are influenced by miRNAs, while specific miRNAs are targeted in cold tumours to enhance the immune response, potentially improving therapeutic efficacy. A miRNA profiling approach may enable earlier cancer detection and personalized treatments, emphasizing its importance for oncology in the future. This review sheds light on miRNA's role in cold and hot tumour microenvironments, that how they can modulate depending on the tumour niche. Furthermore, therapeutic resistance might develop over time and aid to decrease the efficacy of miRNA regulation. To address the hurdles of finding relevant miRNAs to target, researchers may use high-throughput sequencing methods to characterise miRNA expression across tumour subtypes. They may also use bioinformatics tools and databases to analyse massive amounts of miRNArelated data and find prospective candidate miRNAs.

The next-generation nanoparticles overcome the drawbacks of early nanoplatforms by integrating multiple functions, such as drug delivery, controlled drug release, and combination therapy, into a single system. This study examines the biomedical applications of quantum dots, carbon nanotubes, superparamagnetic iron oxide nanoparticles, and layered double hydroxides for the delivery of breast cancer drugs. They are termed as “nextgeneration” nanoparticles, as they are advanced nanocarriers that offer a comprehensive and alternative approach towards breast cancer treatment, providing enhanced specificity and efficacy compared to their predecessors. The development of these nanoplatforms has significantly enhanced drug bioavailability and reduced toxicity. A comprehensive analysis of a nanotechnology-based drug delivery system was conducted. The keywords used for this review were “Breast Cancer”, “Targeted Drug Delivery”, “Quantum Dots”, “Carbon Nanotubes”, “Layer Double Hydroxides”, and “Superparamagnetic Iron Oxide Nanoparticles”. The inclusion criteria consisted of studies focusing on breast cancer, targeted drug delivery, and therapeutic applications of these nanocarriers. In contrast, exclusion criteria included studies focusing on the synthesis of nanocarriers and the diagnostic applications of these nanostructures. The study underscores their mechanisms, limitations, and future development directions. Additionally, the study tracks the evolution of the nanocarriers since their early discovery. Next-generation nanocarriers (QDs, CNTs, SPIONs, and LDHs) have strong therapeutic potential owing to their precisely engineered properties, such as size, shape, morphology, and surface modifications. Their trigger-initiated drug release mechanisms enable targeted delivery with a better rate of tumor penetration, while their ability to co-deliver multiple therapeutic agents addresses drug resistance issues and provides synergistic effects. Comparative analyses have revealed that these advanced nanoplatforms significantly outperform early-generation carriers in terms of bioavailability, reduced toxicity, and treatment efficacy across various breast cancer types. Next-generation nanoplatforms offer unprecedented opportunities for targeted and efficient cancer treatment. Continued research and innovation are necessary to address existing challenges and to optimize their therapeutic potential for clinical applications.

Numerous studies have previously reported the applications of carbon-based materials, in diagnostic imaging and therapies as standalone treatments. This chapter specifically explores the capable role of carbon nanostructures, to synergistically integrate both the platforms, for a combined treatment. The chapter classifies the five structural classes of carbon, and their respective physiochemical characteristics such as size, morphology, surface and optical properties. It further explores the top-down and bottom-up fabrication methods, like arc discharge, CVD, hydrothermal and detonation methods. Several studies are reported to support successful theragnostic applications such as photothermal, photodynamic and chemodynamic treatments, synergistically enabling MRI, fluorescence and photoacoustic imaging. Mechanistic roles such as EPR effect, ROS-generation, are elaborately discussed. Limitations around lack of clinical studies, long-time exposure and cost-effective functionalization are challenges to be critically evaluated to accelerate translational research.

The transformative role of polymers, biomaterials, nanomaterials, and metal ions in breast cancer treatment have highlighted their potential to enhance diagnosis and therapeutic outcomes. Traditional cancer therapies have often fallen short due to their “one-size-fits-all” approach, leading to increased patient non-responsiveness. The integration of interdisciplinary research—from biomedical science to nanotechnology—promises more precise and effective treatments. Polymers enable targeted drug delivery with reduced side effects, while biomaterials enhance regeneration and drug delivery systems. Nanomaterials improve drug accumulation in tumors and combat resistance, and metal ions disrupt cancer cell metabolism and DNA. By exploring case studies and applications of these advanced materials, this paper underscores their significant contributions to personalized cancer therapies and improved patient quality of life. Looking forward, innovations in multifunctional nanomaterials and biosensors are anticipated to further revolutionize breast cancer treatment strategies.

Indiscriminate use of levonorgestrel, a progestin-only contraceptive, can affect breast cancer subtypes, as it can plausibly bind to steroid receptors other than Estrogen Receptor (ER) and Progesterone Receptor (PR). The ER, PR negative status of TNBC makes it important to explore other receptors of levonorgestrel. In this study glucocorticoid receptor (GR) was observed to show − 83.519 kcal/mol free energy of binding with levonorgestrel. To understand the effect of levonorgestrel on breast cancer cells, cellular assays were performed. In the cell proliferation assays, it was found that ER + PR + Her2- cell line, MCF-7, showed reduced proliferation upon treatment with levonorgestrel for 24 h. Whereas TNBC cell lines (MDA-MB-231 and MDA-MB-468) showed statistically significantly higher proliferation rate. Cellular adhesion assays displayed more adhesion in levonorgestrel-treated MCF-7 cells than in levonorgestrel-treated MDA-MB-231 and MDA-MB-468, as compared to the control. Ki67 (proliferation marker) showed upregulation in MCF-7 control. Levonorgestrel-treated MCF-7 cells demonstrated Ki67 downregulation. In contrast, the treatment triggered upregulation of Ki67 in TNBC cell lines on levonorgestrel treatment. Therefore, the study suggests that in the absence of ER and PR in TNBC, levonorgestrel may potentially show its effect through GR. The study emphasizes the need for further research, as there exist several factors, such as the consumption of oral contraceptive pills like levonorgestrel, which might worsen the status of breast cancer in women.

ROS are molecules of the cell signalling, produced during oxidative metabolism and causes various human disease as its accumulation leads to deregulation of antioxidant defence mechanism (Wang et al. 2021). ROS regulates several cell signalling pathways which are responsible for apoptosis, survival of the cell, growth and maintenance of metabolic activities of the cell. This chapter focuses on the role of reactive oxygen species in cell signalling. Cell signalling is the process through which cell communicate each other and responds to environment and stimuli through a cascade of events, ultimately leading to production of desired protein as a result. Therefore, a comprehensive understanding of mechanism of cell signalling enhances our knowledge of intrinsic cellular process and also provide insight for development therapeutic strategies for curing various diseases.

Aim: The PI3K (phosphoinositide 3-kinase)-alpha isoform is found upregulated in 30–40% of breast cancer. Currently, there are limited selective and specific drugs that target PI3K-alpha, and no natural therapeutic option is available. This study aims to develop natural hybrid antagonists of PI3K-alpha for breast cancer therapeutics. Methods: 25 pan-PI3K and PI3K-alpha targeting drugs were obtained from various sources, including the COCONUT (Collection of Open Natural Products) database. On the parent dataset, high throughput virtual screening (HTVS), standard precision (SP) docking, and extra precision (XP) docking were performed to produce Murcko scaffolds and heterogenous fragments. Murcko scaffolds are hybridized with fragments of natural compounds (Category 1) and drugs (Category 2), respectively. Hybrids are docked with HTVS, SP, and XP, followed by induced fit docking and ADME (absorption, distribution, metabolism, and excretion) prediction. MM/GBSA (molecular mechanics/generalized Born and surface area) was performed on the docked poses. Results: Highest docking scores of –13.354 kcal/mol and –12.670 kcal/mol were achieved by hybrids in Category 1 and Category 2, respectively. MM/GBSA free energy ranged from –51.14 kcal/mol to –72.66 kcal/mol. In terms of binding docking, pharmacological properties, and Lipinski’s rule of five, the natural hybrids outperformed the parent drugs. Conclusions: PI3K-alpha kinase proteins can be targeted with natural-drug hybrid antagonists for breast cancer treatment. Hybrid molecules, such as NH-01 and NH-06, show better binding with promising ADME properties. Thus, in vivo and in vitro testing is necessary to prove the value of such hybrids.

Despite the widespread use of traditional cancer therapies such as surgery, chemotherapy, and radiation, these approaches often suffer from significant drawbacks. Nanomaterials (NMs) are a promising alternative due to their distinct nanoscale properties which enable more precise drug delivery and reduced off-target effects. Recently, cuproptosis and ferroptosis have emerged as novel forms of programmed cell death regulated by metal ions, offering novel pathways for cancer therapy. Cuproptosis, caused by copper ion accumulation, leads to mitochondrial dysfunction, while ferroptosis, driven by iron-mediated lipid peroxidation, disrupts cellular integrity through oxidative stress. Here, we propose to explore how NMs can be harnessed to induce metalloptosis, for advanced cancer treatment strategies. Variations in NM size, morphology, and the synergistic effects of composite NMs complicate the identification of individual mechanisms. Use of NMs in cancer therapy, requires focusing on the precise design and regulation of metalloptosis pathways.

The effectiveness of the conventional treatment strategies is falling, as tumors are gradually becoming chemoresistant. Breast cancer cells are persistently overexposed to therapeutic agents, leading them to develop multidrug resistance. Molecular mechanisms causing Multidrug Resistance (MDR) include the overexpression of drug efflux transporters, evasion of apoptosis, activation of NF-κB and other signaling pathways supporting tumor proliferation, dysregulation of DNA repair mechanisms, epigenetic modulations and tumor-supportive microenvironment. This present study explores the biomedical applications of nanoparticles to combat multidrug resistance (MDR) in breast cancer. We focus on nanoparticles that can bypass drug efflux pumps, deliver agents precisely, co-deliver siRNA/miRNA for DNA repair, and release drugs responsively. Looking ahead, we identify future research opportunities in multi-targeting pathways, hypoxia/enzyme-triggered drug release, genetic/epigenetic modulation, personalized medicines, and AI-driven optimization of nanoparticle properties. ‎