pH-Responsive therapeutic solid lipid nanoparticles for reducing P-glycoprotein-mediated drug efflux of multidrug resistant cancer cells

Abstract

In this study, a novel pH-responsive cholesterol-PEG adduct-coated solid lipid nanoparticles (C-PEG-SLNs) carrying doxorubicin (DOX) capable of overcoming multidrug resistance (MDR) breast cancer cells is presented. The DOX-loaded SLNs have a mean hydrodynamic diameter of ~100 nm and a low polydispersity index (under 0.20) with a high drug-loading efficiency ranging from 80.8% to 90.6%. The in vitro drug release profiles show that the DOX-loaded SLNs exhibit a pH-controlled drug release behavior with the maximum and minimum unloading percentages of 63.4% at pH 4.7 and 25.2% at pH 7.4, respectively. The DOX-loaded C-PEG-SLNs displayed a superior ability in inhibiting the proliferation of MCF-7/MDR cells. At a DOX concentration of 80 μM, the cell viabilities treated with C-PEG-SLNs were approximately one-third of the group treated with free DOX. The inhibition activity of C-PEG-SLNs could be attributed to the transport of C-PEG to cell membrane, leading to the change of the composition of the cell membrane and thus the inhibition of permeability glycoprotein activity. This hypothesis is supported by the confocal images showing the accumulation of DOX in the nuclei of cancer cells and the localization of C-PEG on the cell membranes. The results of in vivo study further demonstrated that the DOX delivered by the SLNs accumulates predominantly in tumor via enhanced permeability and retention effect, the enhanced passive tumor accumulation due to the loose intercellular junctions of endothelial cells lining inside blood vessels at tumor site, and the lack of lymphatic drainage. The growth of MCF-7/MDR xenografted tumor on Balb/c nude mice was inhibited to ~400 mm 3 in volume as compared with the free DOX treatment group, 1,140 mm 3 , and the group treated with 1,2 distearoyl-sn-glycero-3-phosphoethanolamine- N -[methoxy(polyethylene glycol)] solid lipid nanoparticles, 820 mm 3 . Analysis of the body weight of nude mice and the histology of organs and tumor after the administration of DOX-loaded SLNs show that the SLNs have no observable side effects. These results indicate that the C-PEG-SLN is a promising platform for the delivery of therapeutic agents for MDR cancer chemotherapy.

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

“…Through this strategy, DOX forms an ion pair with a lipophilic anion, improving its lipophilicity and the affinity for the lipid matrix. This strategy is well described in the literature and has been used in several studies that utilized different counter ions to improve the DOX lipophilicity and its affinity for different lipid-based systems [33,41,[43][44][45][46][47][48][49][50][51][52][53][54][55][56]. In the present study, OA was used as the counter ion.…”

Lipid Nanoparticles as Carriers for Bioactive Delivery

“…A fast release profile of doxorubicin was observed at pH 4.7 as compared to pH 7.4. The enhanced rate of drug release at low pH may be due to the decreased electrostatic attractions among the negatively charged lipid core and the positively charged doxorubicin (Chen et al, 2015 ; Mishra et al, 2018 ).…”

“…Curcumin has very low bioavailability and high metabolism. Curcumin-loaded NLCs have shown 6.4 times higher plasma concentration and improved brain targeting (Chen et al, 2015 ). Lim et al reported 2-fold increase in brain concentration of itraconazole from the synthesized NLCs (Lim et al, 2014 ).…”

Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy

“…The ever-growing number of studies confirmed that this strategy might lead to the development of new class of drug delivery systems [ 97 ]. To date, a number of stimulus factors, including light, radiofrequency (RF) energy, magnetic field, enzymes or alternation in pH value, have been explored [ 9 , 31 , 98 – 101 ]. Recently, Yingyuad et al described new PEGylated siRNA-nanoparticles activated by human leukocyte elastase (HLE) or matrix metalloproteinase-2 (MMP-2), both present in the extracellular spaces of tumor in order to promote invasion and metastasis of cancerous cells via degradation of basement membrane and extracellular matrix barrier.…”

“…Such were designed for treatment of DOX-resistant breast cancers. Importantly, the solubility of DOX increased in acidic environment, which improves the release rate of drug [ 31 ]. Moreover, mild acidic conditions, characteristic for tumor environment facilitate release of DOX from polymer-conjugated MSNs due to hydrolysis of the acid-sensitive acetal linkage and dissociation of polymer coating layer, protecting payload drug from release in physiological pH [ 108 ].…”