Injectable thermo-responsive nano-hydrogel loading triptolide for the anti-breast cancer enhancement via localized treatment based on “two strikes” effects

Abstract

The clinical application of triptolide (TPL) in tumor therapy has been greatly limited by its toxicity and inefficient delivery. Herein, a localized and sustained-release thermo-sensitive hydrogel was developed for the intra-tumor administration of TPL. Based on the amphiphilic structure of poly ( N -isopropylacrylamide -co- acrylic acid)- g -F68 copolymer, it was able to form nano-micelles to efficiently encapsulate TPL, and then turn into a hydrogel at 37 °C. TPL@nano-gel exhibited a sustained drug release profile in vitro and a stronger anticancer effect caused by “two strikes”. The “first strike” was its enhanced cytotoxicity compared to free TPL, due to the enhanced pro-apoptosis effect observed in both MDA-MB-231 and MCF-7 cells caused by the regulation of endogenous mitochondrial pathways. Furthermore, TPL@nano-gel exhibited a “second-strike” through its anti-angiogenesis capabilities mediated through VEGFR-2 signaling inhibition. As expected, after intra-tumoral injection at a 0.45 mg/kg TPL-equivalent dose three times over 14 days in 4T1 tumor-bearing mice, TPL@nano-gel led to lower systemic toxicity and higher antitumor efficacy compared to multiple injections of TPL. In this regard, these findings indicate that this injectable thermo-responsive hydrogel carries great potential for TPL as a safe and effective cancer therapy.

Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis

“…MDA-MB-231 and MCF-7 human breast cells were seeded into 96-well plates at a density of 3 × 10 3 cells/well for 24 h [ 38 , 39 ]. MDA-MB-231 and MCF-7 cells were then given free TPL, blank NPs and TPL/NPs at various concentrations (0–160 nmol/L) in different culture media (pH 7.4; pH 7.4 + 10 mM GSH; pH 5.8; and pH 5.8 + 10 mM GSH) for 48 h. Cells treated with 0.1% DMSO served as the negative control.…”

Redox-sensitive carrier-free nanoparticles self-assembled by disulfide-linked paclitaxel-tetramethylpyrazine conjugate for combination cancer chemotherapy

“…On day 12, the animals were sacrificed and their tumors were dissected, photographed, and weighed to evaluate therapeutic efficacy. Then, tumor tissues from each group were fixed in formalin, embedded in paraffin, and stained with hematoxylin and eosin (H&E), In Situ Cell Death Detection Kit (Roche Applied Science, USA) for TUNEL assay, and anti-VEGF and anti-CD31 antibodies for immunohistochemistry 31 . Major organs including heart, liver, spleen, lung, and kidney were also harvested for H&E staining to evaluate tissue toxicity by histopathological analysis.…”

Tanshinone I exerts cardiovascular protective effects in vivo and in vitro through inhibiting necroptosis via Akt/Nrf2 signaling pathway

“…Based on our anterior study [ 24 , 25 ], cells were cultured in 96-well plates (4.0 × 10 3 cells in each well) overnight. After that, the cells were exposed to TI (1 μM) for 2 h and cultured with t-BHP (150 μM) up to 4 h. For measuring the MMP, JC-1 (5 µg/mL) was co-cultured for 30 min and relevant images were captured by a fluorescence microscope.…”

“…TI (0.25, 0.5, and 1 μM) was pretreated for 2 h and co-cultured with t-BHP induction for 4 h. The study employed RIPA (1% PMSF and 1% cocktail) to extract total proteins of cells as well as the heart tissue. As per the manufacturer’s instruction, the concentration of the protein was measured by the BCA protein kit [ 25 ]. Through 10% or 12% SDS-PAGE gels, the denatured protein was separated, which was transferred to polyvinylidene fluoride (PVDF) membrane (Millipore, Billerica, MA, USA).…”