Nanomicelles potentiate histone deacetylase inhibitor efficacy in vitro

Abstract

Background Amphiphilic block copolymers used as nanomicelle drug carriers can effectively overcome poor drug solubility and specificity issues. Hence, these platforms have a broad applicability in cancer treatment. In this study, Pluronic F127 was used to fabricate nanomicelles containing the histone deacetylase inhibitor SAHA, which has an epigenetic-driven anti-cancer effect in several tumor types. SAHA-loaded nanomicelles were prepared using a thin-film drying method and characterized for size, surface charge, drug content, and drug release properties. Loaded particles were tested for in vitro activity and their effect on cell cycle and markers of cancer progression. Results Following detailed particle characterization, cell proliferation experiments demonstrated that SAHA-loaded nanomicelles more effectively inhibited the growth of HeLa and MCF-7 cell lines compared with free drug formulations. The 30 nm SAHA containing nanoparticles were able to release up to 100% of the encapsulated drug over a 72 h time window. Moreover, gene and protein expression analyses suggested that their cytoreductive effect was achieved through the regulation of p21 and p53 expression. SAHA was also shown to up-regulate E-cadherin expression, potentially influencing tumor migration. Conclusions This study highlights the opportunity to exploit pluronic-based nanomicelles for the delivery of compounds that regulate epigenetic processes, thus inhibiting cancer development and progression.

Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models

“…Cells treated with NP-HA show an initial lag in uptake (mean RFU 2.9 ± 0.4, 4 h) in comparison to the NP treatment, however, by 48 h a much greater degree of internalization, 22.1 ± 1.6, was observed, (p < 0.0001). Example of each channel plus merge given in Figure S4b and z-stack of Ishikawa showed positive signal for NPs across entirety of cell, with an increased affinity for nuclear localization (Figure S4c) In Hec50 cells, NP uptake over time decreased from 22.0 ± 1.1 at 4 h to 13.2 ± 1.0 at 48 h, whereas NP-HA uptake improved over time from 3.9 ± 0.7 at 4 h to 10.3 ± 1.5 at 48 h. Distinct temporal cellular uptake patterns across different cell lines has previously been reported with F127 micelles [78]. Whilst the internalization level is lower for Hec50 treated with NP-HA than NP, the particle is significantly larger (an increase from 30 to 251 nm).…”

“…DLS measurements of empty NP gave sizes of 29.1 ± 2.1 nm, particle size increased to 35.7 ± 3.6 nm after drug incorporation (SAHA-NP) and the addition of HA to the surface of the particle (SAHA-NP-HA) gave a further increase to of 251.6 ± 22.0 nm (Table 1). High resolution analysis was undertaken by using AFM peak-force tapping mode imaging, giving more accurate size determination than is possible with DLS [74][75][76][77][78]. The spherical geometry of intact particles was clearly demonstrated, with diameters of 40 ± 3 nm and 75 ± 7 nm for SAHA-NP and SAHA-NP-HA, respectively (Figure 3a,b).…”