Breast cancer (BC) is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) in which the three major receptors i.e. estrogen receptor (ER), progesterone receptor (PR) and ...human epidermal growth factor receptor 2 (HER2), are absent is known to express the most aggressive phenotype and increased metastasis which results in the development of resistance to chemotherapy. It offers various therapeutic advantages in treating BC and TNBC. Nanotechnology offers various unique characteristics such as small size (nanometric), active and passive targeting, and the ability to attach multiple targeting moieties, controlled release, and site-specific targeting. This review focuses on conventional drug therapies, recent treatment strategies, and unique therapeutic approaches available for BC and TNBC. The role of breast cancer stem cells in the recurrence of BC and TNBC has also been highlighted. Several chemotherapeutic agents delivered using nanocarriers such as polymeric nanoparticles/micelles, metallic/inorganic NPs, and lipid-based NPs (Liposome, solid-lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs)), etc. with excellent responses in the treatment of BC/TNBC along with breast cancer stem cells have been discussed in details. Moreover, the application of nanomedicine including CRISPR nanoparticle, exosomes for the treatment of BC/TNBC and other molecular targets available such as poly (ADP-ribose) polymerase (PARP), epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), etc. for further exploration have also been discussed.
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•BC and TNBC prevalence & recurrence attributed to tumor heterogeneity & individual variations.•The identification of the role of stem cells in tumor progression and metastasis is the need of the era.•Nanotechnology-based approaches offer significant potential to address the unmet needs of cancer treatments.•Phytoconstituents can offer broad spectrum of solutions to target multiple pathways involved in breast cancer progression.•The future of BC therapy lies in close collaboration among phytochemists, molecular biologists, & formulation scientists.
Objective
To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug ...development.
Methods
GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (C
max
) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of
in vitro
experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model.
Results
GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, C
max
, and AUC from the clinical studies.
Conclusions
This work shows the value of GSA utilization in early development to guide
in vitro
experimentation and build more confidence in identifying the critical parameters for the mathematical models.
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•Polymeric micelles (PMs) offer several advantages in targeting anticancer drugs.•Active targeting in PMs utilizes receptor mediated endocytosis.•The reduction sensitive PMs release ...the drug into cytoplasm.•pH responsive PMs exploit low pH environment of cancer cell due to glycolysis.•Thermo-sensitive PMs achieve temporal delivery of drugs.
The concerns impeding the success of chemotherapy in cancer is descending efficacy of drugs due to the development of multiple drug resistance (MDR). The current efforts employed to overcome MDR have failed or are limited to only preliminary in-vitro investigations. Nanotechnology is at the forefront of the drug delivery research, playing pivotal role in chemotherapy and diagnosis, thereby providing innovative approaches for the management of the disease with minimal side effects. Recently, polymeric micelles (PMs) have witnessed significant developments in cancer therapy. PMs are self-assembled colloidal particles, with a hydrophilic head and a long hydrophobic tail, which enhance the solubility, permeability and bioavailability of drugs, due to the unique features of reaching higher concentration in the biological system, above critical micellar concentration. One of the effective approaches to improve the efficacy of chemotherapy and overcome drug resistance would be to employ multifunctional approach (combination of stimuli-responsive, utilization of drug resistance modulators and combination therapy) using PMs as drug delivery systems. Actively targeted, stimuli-sensitive and multifunctional approaches involve using single and/or combination of approaches (pH-responsive, temperature regulated, reduction-sensitive, ultrasound etc.) to combat drug resistant. The review will describe PMs, types of copolymers used in PMs, preparation and characterization of PMs. A comprehensive list of PMs tested in clinical trials is discussed. Lastly, this review covers stimuli-sensitive and multifunctional approaches to overcome MDR in cancer utilizing PMs.
Poorly water-soluble weak base molecules such as cinnarizine often exhibit pH-dependent solubility within the gastrointestinal tract. This means that their solubility can be influenced by the pH of ...the surrounding environment, and this can affect their oral absorption. The differential pH solubility between the fasted-state stomach and intestine is an important consideration when studying the oral absorption of cinnarizine. Cinnarizine has moderate permeability and is known to exhibit supersaturation and precipitation in fasted-state simulated intestinal fluid (FaSSIF), which can significantly impact its oral absorption. The present work is aimed at studying the precipitation behavior of cinnarizine in FaSSIF using biorelevant
in vitro
tools and GastroPlus
®
modeling, to identify the factors contributing to the observed variability in clinical plasma profiles. The study found that cinnarizine demonstrated variable precipitation rates under different bile salt concentrations, which could impact the concentration of the drug available for absorption. The results also showed that a precipitation-integrated modeling approach accurately predicted the mean plasma profiles from the clinical studies. The study concluded that intestinal precipitation may be one of the factors contributing to the observed variability in
C
max
but not the AUC of cinnarizine. The study further suggests that the integration of experimental precipitation results representing a wider range of FaSSIF conditions would increase the probability of predicting some of the observed variability in clinical results. This is important for biopharmaceutics scientists, as it can help them evaluate the risk of
in vivo
precipitation impacting drug and/or drug product performance.
New and improved vaccines are needed against challenging diseases such as malaria, tuberculosis, Ebola, influenza, AIDS, and cancer. The majority of existing vaccine adjuvants lack the ability to ...significantly stimulate the cellular immune response, which is required to prevent the aforementioned diseases. This study designed a novel particulate based pathogen-mimicking vaccine delivery system (PMVDS) to target antigen-presenting-cells (APCs) such as dendritic cells. The uniqueness of PMVDS is that the polymer used to prepare the delivery system, Inulin Acetate (InAc), activates the innate immune system. InAc was synthesized from the plant polysaccharide, inulin. PMVDS provided improved and persistent antigen delivery to APCs as an efficient vaccine delivery system, and simultaneously, activated Toll-Like Receptor-4 (TLR-4) on APCs to release chemokine's/cytokines as an immune-adjuvant. Through this dual mechanism, PMVDS robustly stimulated both the humoral (>32 times of IgG1 levels vs alum) and the cell-mediated immune responses against the encapsulated antigen (ovalbumin) in mice. More importantly, PMVDS stimulated both cytotoxic T cells and natural killer cells of cell-mediated immunity to provide tumor (B16-ova-Melanoma) protection in around 40% of vaccinated mice and significantly delayed tumor progression in rest of the mice. PMVDS is a unique bio-active vaccine delivery technology with broader applications for vaccines against cancer and several intracellular pathogens, where both humoral and cellular immune responses are desired.
The PMVDS is a pathogen-mimicking, immune-active (TLR-4 agonist) vaccine delivery system that provides strong antibody and cell-mediated immune responses against encapsulated antigens for efficient cancer immunotherapy. Display omitted
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Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate ‘core–shell’ delivery system for drug targeting. Recently, ...hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1® (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37±10.45nm with excellent drug encapsulation efficiency (95.66±2.25%) and loading (8.69±0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel.
Introduction: A major concern that limits the success of cancer chemotherapy is multidrug resistance (MDR). The drug resistance mechanisms are either host related or tumor related. The host tumor ...interacting factors also contribute to MDR. Multifunctional polymeric micelles offer several advantages in circumventing MDR due to their design, selectivity, and stability in cancer microenvironment.
Areas covered: The review is broadly divided into two parts: the first part covers MDR and its mechanisms; the second part covers multifunctional polymeric micelles in combating MDR through its state-of-the-art design. This part covers various strategies like use of P-gp transporter inhibitors, TPGS, pH & thermo-sensitive, and siRNA for selectivity of PMs against multidrug-resistant tumors.
Expert opinion: Numerous approaches have been tested using polymeric micelles to overcome MDR tumors. However, these are either limited to only in-vitro investigations and/or preliminary preclinical models and do not investigate the underlying biological mechanism. Hence, there exists an unmet need to perform fundamental research that focuses on studying the underlying mechanism and preclinical/clinical testing of the micellar formulations.
Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of ...flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit Cyclin Dependent Kinase (CDK) activity and cancer cell proliferation. Using in vitro kinase assays, we demonstrated that 2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and phloroglucinol, suggesting that orientation of the functional groups and specific amino acid interactions may play a role in inhibition. We showed that cellular uptake of 2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic acid transporter. Consistent with this, in cells expressing functional SLC5A8, 2,4,6-THBA induced CDK inhibitory proteins p21
and p27
and inhibited cell proliferation. These findings, for the first time, suggest that the flavonoid metabolite 2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC.
Approximately 40% of compounds in clinical drug development suffer from solubility and bioavailability challenges. Evidence from literature demonstrates the growing interest to utilize flavonoids as ...potential compounds owing to their widespread therapeutic utility in various ailments. Nobiletin (NOB), one such dietary polymethoxylated flavonoid found in citrus fruits, has multiple pharmacological effects such as antioxidant, anti-microbial, anti-cancer, and anti-inflammatory. It is useful in cancer, inflammatory bowel diseases, atherosclerosis, obesity, and Alzheimer’s disease. Although preclinical studies demonstrate the therapeutic utility of NOB, it suffers from serious biopharmaceutical limitations such as low aqueous solubility (below 1 μg/ml), poor permeability across biological barriers, and low bioavailability. To overcome these biopharmaceutical challenges associated with NOB, the use of advanced formulations and nanotechnology-based strategies appears to be a promising approach to potentiate its therapeutic action. Multiple reviews cover the various therapeutic benefits of NOB in various diseases; however, there is an absence of a comprehensive review that focuses on the formulation development strategies of NOB. The purpose of this review is to provide a concise perspective on NOB as a candidate molecule for formulation development. The manuscript covers various aspects related to NOB, such as its chemistry, physicochemical properties, and pharmacological effects. This is also a thorough review of various formulation development strategies with advances made in the past years to improve the solubility, bioavailability, and therapeutic efficacy of NOB. The review also contains information related to toxicity and patents involving NOB and its formulation.
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•This review addresses the major contributory factors responsible for chemoresistance and poor prognosis in TNBC.•Diverse TME, overexpression of transporters, genetic and epigenetic ...changes play a crucial role.•Alteration of the cell signaling pathways and cancer stem cells (CSCs) help in chemoresistance development.•Blockade of multiple cell signaling pathways and receptors are potential to inhibit TNBC progression.•Therapeutic modalities including reversal of chemoresistance are broadly discussed.
Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive phenotype of breast cancer with associated chemoresistance. The development of chemo- or radioresistance could be attributed to diverse tumor microenvironments, overexpression of membrane proteins (transporters), epigenetic changes, and alteration of the cell signaling pathways/genes associated with the development of cancer stem cells (CSCs).
Due to the diverse and heterogeneous nature of TNBC, therapeutic response to the existing modalities offers limited scope and thus results in reccurance after therapy. To establish landmark therapeutic efficacy, a number of novel therapeutic modalities have been proposed. In addition, reversal of the resistance that developed during treatment may be altered by employing appropriate therapeutic modalities. This review aims to discuss the plethora of investigations carried out, which will help readers understand and make an appropriate choice of therapy directed toward complete elimination of TNBC.
This manuscript addresses the major contributory factors from the tumor microenvironment that are responsible for the development of chemoresistance and poor prognosis. The associated cellular events and molecular mechanism-based therapeutic interventions have been explained in detail. Inhibition of ABC transporters, cell signaling pathways associated with CSCs, and epigenetic modification offers promising results in this regard. TNBC progression, invasion, metastasis and recurrence can also be inhibited by blocking multiple cell signaling pathways, targeting specific receptors/epigenetic targets, disrupting bioenergetics and generating reactive oxygen species (ROS).
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