pH-responsive high-density lipoprotein-like nanoparticles to release paclitaxel at acidic pH in cancer chemotherapy

Abstract

Background: Nanoparticles undergoing physicochemical changes to release enclosed drugs at acidic pH conditions are promising vehicles for antitumor drug delivery. Among the various drug carriers, high-density lipoprotein (HDL)-like nanoparticles have been shown to be beneficial for cancer chemotherapy, but have not yet been designed to be pH-responsive. Methods and results:In this study, we developed a pH-responsive HDL-like nanoparticle that selectively releases paclitaxel, a model antitumor drug, at acidic pH. While the well known HDL-like nanoparticle containing phospholipids, phosphatidylcholine, and apolipoprotein A-I, as well as paclitaxel (PTX-PL-NP) was structurally robust at a wide range of pH values (3.8-10.0), the paclitaxel nanoparticle that only contained paclitaxel and apoA-I selectively released paclitaxel into the medium at low pH. The paclitaxel nanoparticle was stable at physiological and basic pH values, and over a wide range of temperatures, which is a required feature for efficient cancer chemotherapy. The homogeneous assembly enabled high paclitaxel loading per nanoparticle, which was 62.2% (w/w). The molar ratio of apolipoprotein A-I and paclitaxel was 1:55, suggesting that a single nanoparticle contained approximately 110 paclitaxel particles in a spherical structure with a 9.2 nm diameter. Among the several reconstitution methods applied, simple dilution following sonication enhanced the reconstitution yield of soluble paclitaxel nanoparticles, which was 0.66. As a result of the pH responsiveness, the anticancer effect of paclitaxel nanoparticles was much more potent than free paclitaxel or PTX-PL-NP. Conclusion: The anticancer efficacy of both paclitaxel nanoparticles and PTX-PL-NP was dependent on the expression of scavenger receptor class B type I, while the killing efficacy of free paclitaxel was independent of this receptor. We speculate that the pH responsiveness of paclitaxel nanoparticles enabled efficient endosomal escape of paclitaxel before lysosomal break down. This is the first report on pH-responsive nanoparticles that do not contain any synthetic polymer.

Scavenger Receptors

“…RNAi-HDL nanoparticle targeting signal transducer and activator transcription 3 (STAT3) or FAK resulted in the suppression of ovarian and colorectal cancers (Shahzad et al, 2011). Recombinant HDL nanoparticles have also been used to deliver chemotherapeutic drugs, e.g., paclitaxel or α-tocopheryl-succinate, to SR-BI + cancers (Hrzenjak et al, 2004; Mooberry et al, 2010; Shin et al, 2012). It was recently reported that a highly biocompatible HDL-mimicking peptide-phospholipid scaffold nanocarrier not only can serve as a cargo to deliver therapeutic drugs to SR-BI + nasopharyngeal carcinoma but also can exert direct antitumor efficacy in vivo (Zheng et al, 2013).…”

Combined using of paclitaxel and salinomycin active targeting nanostructured lipid carriers against non-small cell lung cancer and cancer stem cells

“…To improve the cancer cell specificity and alleviate the side effects of small molecular chemotherapy drugs like PTX, numerous papers have been published in the field of nano drug delivery carriers, of which the superior antitumor effect has been validated (Shin et al., 2012 ; Werner et al., 2013 ; Chen et al., 2014 ; Pandey et al., 2015 ; Fu et al., 2016 ; Giordano et al., 2017 ; Zhang et al., 2018 ). Nevertheless, it has been mentioned that the drug resistance of cancer stem cells (CSCs) could cause the cancer recurrence and metastasis, which leads to the failure of the chemotherapy (Dallas et al., 2009 ; Heery et al., 2017 ).…”