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Exploring new Horizons in overcoming P-glycoprotein-mediated multidrug-resistant breast cancer via nanoscale drug delivery platforms.

ABSTRACT: The high probability (13%) of women developing breast cancer in their lifetimes in America is exacerbated by the emergence of multidrug resistance after exposure to first-line chemotherapeutic agents. Permeation glycoprotein (P-gp)-mediated drug efflux is widely recognized as the major driver of this resistance. Initial in vitro and in vivo investigations of the co-delivery of chemotherapeutic agents and P-gp inhibitors have yielded satisfactory results; however, these results have not translated to clinical settings. The systemic delivery of multiple agents causes adverse effects and drug-drug interactions, and diminishes patient compliance. Nanocarrier-based site-specific delivery has recently gained substantial attention among researchers for its promise in circumventing the pitfalls associated with conventional therapy. In this review article, we focus on nanocarrier-based co-delivery approaches encompassing a wide range of P-gp inhibitors along with chemotherapeutic agents. We discuss the contributions of active targeting and stimuli responsive systems in imparting site-specific cytotoxicity and reducing both the dose and adverse effects.

SUBMITTER: Famta P

PROVIDER: S-EPMC8663938 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Smart Nanoscale Drug Delivery Platforms from Stimuli-Responsive Polymers and Liposomes.

Project description:Since the 1960's, stimuli-responsive polymers have been utilized as functional soft materials for biological applications such as the triggered-release delivery of biologically active cargos. Over the same period, liposomes have been explored as an alternative drug delivery system with potentials to decrease the toxic side effects often associated with conventional small-molecule drugs. However, the lack of drug-release triggers and the instability of bare liposomes often limit their practical applications, causing short circulation time and low therapeutic efficacy. This perspective article highlights recent work in integrating these two materials together to achieve a targetable, triggerable nanoscale platform that fulfills all the characteristics of a near-ideal drug delivery system. Through a drop-in, post-synthesis modification strategy, a network of stimuli-responsive polymers can be integrated onto the surface of liposomes to form polymer-caged nanobins, a multifunctional nanoscale delivery platform that allows for multi-drug loading, targeted delivery, triggered drug-release, and theranostic capabilities.

| S-EPMC5552073 | biostudies-other

?-casein nanovehicles for oral delivery of chemotherapeutic Drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells.

Project description:Multidrug resistance (MDR) is a primary obstacle to curative cancer therapy. We have previously demonstrated that ?-casein (?-CN) micelles (?-CM) can serve as nanovehicles for oral delivery and target-activated release of hydrophobic drugs in the stomach. Herein we introduce a novel nanosystem based on ?-CM, to orally deliver a synergistic combination of a chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific transport inhibitor (Tariquidar) individually encapsulated within ?-CM, for overcoming MDR in gastric cancer. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by ?-CN, suppressing drug crystallization. Spectrophotometry demonstrated high loading capacity and good encapsulation efficiency, whereas spectrofluorometry revealed high affinity of these drugs to ?-CN. In vitro cytotoxicity assays exhibited remarkable synergistic efficacy against human MDR gastric carcinoma cells with P-glycoprotein overexpression. Oral delivery of ?-CN - based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel efficacious therapeutic system that may overcome MDR in gastric cancer.

| S-EPMC5029629 | biostudies-literature

Overcoming ABCB1 mediated multidrug resistance in castration resistant prostate cancer

Project description:The few available therapies for mCRPC patients include taxanes docetaxel (DTX) and cabazitaxel (CBZ). However, development of resistance limits their clinical use. PCa that relapses after hormonal therapies, referred to as castration resistant prostate cancer (CRPC), often presents with metastases (mCRPC) that are the major cause of mortality. The few available therapies for mCRPC patients include taxanes docetaxel (DTX) and cabazitaxel (CBZ). However, development of resistance limits their clinical use. To study taxanes resistance, we produced CBZ resistant C4-2B cells (RC4-2B) and documented resistance to both CBZ and DTX in cell culture and in 3D prostaspheres settings. RNAseq identified increased expression of ABCB1 in RC4-2B, that was confirmed by immunoblotting and immunofluorescent analysis. ABCB1-specific inhibitor elacridar reversed CBZ and DTX resistance in RC4-2B cells, confirming ABCB1-mediated resistance mechanism.

2024-08-08 | GSE271075 | GEO

Overcoming Multidrug-Resistant MRSA Using Conventional Aminoglycoside Antibiotics.

Project description:Global multidrug-resistant (MDR) bacteria are spreading rapidly and causing a great threat to human health due to the abuse of antibiotics. Determining how to resensitize MDR bacteria to conventional inefficient antibiotics is of extreme urgency. Here, a low-temperature photothermal treatment (PTT, 45 °C) is utilized with red phosphorus nanoparticles to resensitize methicillin-resistant Staphylococcus aureus (MRSA) to conventional aminoglycoside antibiotics. The antibacterial mechanism is studied by the proteomic technique and molecular dynamics (MD) simulation, which proves that the aminoglycoside antibiotics against MRSA can be selectively potentiated by low-temperature PTT. The catalytic activity of 2-aminoglycoside phosphotransferase (APH (2?))-a modifying enzyme-is demonstrated to be obviously inhibited via detecting the consumption of adenosine triphosphate (ATP) in the catalytic reaction. It is also found that the active site of aspartic acid (ASP) residues in APH (2?) is thermally unstable from the results of molecular dynamics simulation. Its catalytic ability is inhibited by preventing the deprotonating procedure for the target -OH of gentamycin. The combined therapy also exhibits great biocompatibility and successfully treats MRSA infections in vivo. This low-temperature PTT strategy has the potential to be an exogenous-modifying enzyme inhibitor for the treatment of MDR bacterial infection.

| S-EPMC7201259 | biostudies-literature

Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells.

Project description:Having unique architectural features, cationic polymeric nanocapsules (NCs) with well-defined covalently stabilized biodegradable structures were generated as potentially universal and safe therapeutic nanocarriers. These NCs were synthesized from allyl-functionalized cationic polylactide (CPLA) by highly efficient UV-induced thiol-ene interfacial cross-linking in transparent miniemulsions. With tunable nanoscopic sizes, negligible cytotoxicity and remarkable degradability, they are able to encapsulate doxorubicin (Dox) with inner cavities and bind interleukin-8 (IL-8) small interfering RNA (siRNA) with cationic shells. The Dox-encapsulated NCs can effectively bypass the P-glycoprotein (Pgp)-mediated multidrug resistance of MCF7/ADR cancer cells, thereby resulting in increased intracellular drug concentration and reduced cell viability. In vitro studies also showed that the NCs loaded with Dox, IL-8 siRNA and both agents can be readily taken up by PC3 prostate cancer cells, resulting in a significant chemotherapeutic effect and/or IL-8 gene silencing.

| S-EPMC4522154 | biostudies-literature

Overcoming ABCB1 mediated multidrug resistance in castration resistant prostate cancer.

Project description:Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. PCa that relapses after hormonal therapies, referred to as castration resistant PCa (CRPC), often presents with metastases (mCRPC) that are the major cause of mortality. The few available therapies for mCRPC patients include taxanes docetaxel (DTX) and cabazitaxel (CBZ). However, development of resistance limits their clinical use. Mechanistically, resistance arises through upregulation of multidrug resistance (MDR) proteins such as MDR1/ABCB1, making ABCB1 an attractive therapeutic target. Yet, ABCB1 inhibitors failed to be clinically useful due to low specificity and toxicity issues. To study taxanes resistance, we produced CBZ resistant C4-2B cells (RC4-2B) and documented resistance to both CBZ and DTX in cell culture and in 3D prostaspheres settings. RNAseq identified increased expression of ABCB1 in RC4-2B, that was confirmed by immunoblotting and immunofluorescent analysis. ABCB1-specific inhibitor elacridar reversed CBZ and DTX resistance in RC4-2B cells, confirming ABCB1-mediated resistance mechanism. In a cell-based screen using a curated library of cytotoxic drugs, we found that DNA damaging compounds Camptothecin (CPT) and Cytarabine (Ara-C) overcame resistance as seen by similar cytotoxicity in parental C4-2B and resistant RC4-2B. Further, these compounds were cytotoxic to multiple PC cells resistant to taxanes with high ABCB1 expression and, therefore, can be used to conquer the acquired resistance to taxanes in PCa. Finally, inhibition of cyclin-dependent kinases 4/6 (CDK4/6) with small molecule inhibitors (CDK4/6i) potentiated cytotoxic effect of CPT or Ara-C in both parental and resistant cells. Overall, our findings indicate that DNA damaging agents CPT and Ara-C alone or in combination with CDK4/6i can be suggested as a new treatment regimen in CRPC patients, including those that are resistant to taxanes.

| S-EPMC11294535 | biostudies-literature

Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology.

Project description:Multidrug resistance (MDR), which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence, has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades. Several mechanisms of overcoming drug resistance have been postulated. Well known P-glycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure. Innovative theranostic (therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits. In this review, we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.

| S-EPMC3777470 | biostudies-literature

Multidrug Resistant and Extensively Drug Resistant Bacteria: A Study.

Project description:Background and Objective. Antimicrobial resistance is now a major challenge to clinicians for treating patients. Hence, this short term study was undertaken to detect the incidence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacterial isolates in a tertiary care hospital. Material and Methods. The clinical samples were cultured and bacterial strains were identified in the department of microbiology. The antibiotic susceptibility profile of different bacterial isolates was studied to detect MDR, XDR, and PDR bacteria. Results. The antibiotic susceptibility profile of 1060 bacterial strains was studied. 393 (37.1%) bacterial strains were MDR, 146 (13.8%) strains were XDR, and no PDR was isolated. All (100%) Gram negative bacterial strains were sensitive to colistin whereas all (100%) Gram positive bacterial strains were sensitive to vancomycin. Conclusion. Close monitoring of MDR, XDR, or even PDR must be done by all clinical microbiology laboratories to implement effective measures to reduce the menace of antimicrobial resistance.

| S-EPMC4749793 | biostudies-other

Nanoscale Drug Delivery Systems: From Medicine to Agriculture.

Project description:The main challenges in drug delivery systems are to protect, transport and release biologically active compounds at the right time in a safe and reproducible manner, usually at a specific target site. In the past, drug nano-carriers have contributed to the development of precision medicine and to a lesser extent have focused on its inroads in agriculture. The concept of engineered nano-carriers may be a promising route to address confounding challenges in agriculture that could perhaps lead to an increase in crop production while reducing the environmental impact associated with crop protection and food production. The main objective of this review is to contrast the advantages and disadvantages of different types of nanoparticles and nano-carriers currently used in the biomedical field along with their fabrication methods to discuss the potential use of these technologies at a larger scale in agriculture. Here we explain what is the problem that nano-delivery systems intent to solve as a technological platform and describe the benefits this technology has brought to medicine. Also here we highlight the potential drawbacks that this technology may face during its translation to agricultural applications, based on the lessons learned so far from its use for biomedical purposes. We discuss not only the characteristics of an ideal nano-delivery system, but also the potential constraints regarding the fabrication including technical, environmental, and legal aspects. A key motivation is to evaluate the potential use of these systems in agriculture, especially in the area of plant breeding, growth promotion, disease control, and post-harvest quality control. Further, we highlight the importance of a rational design of nano-carriers and identify current research gaps to enable scale-up relevant to applications in the treatment of plant diseases, controlled release of fertilizers, and plant breeding.

| S-EPMC7041307 | biostudies-literature

Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416.

Project description:MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

| S-EPMC3497725 | biostudies-literature

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