Toward targeted therapy in chemotherapy-resistant pancreatic cancer with a smart triptolide nanomedicine

Abstract

Chemoresistance is the major impediment for treating pancreatic cancer. Herb-derived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)–block–poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro. Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar® in vivo. Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer.

Meeting the needs of breast cancer: A nucleolin’s perspective

“…Therefore, the additional application of hyperthermia further unfolded a higher cytotoxic potential of these nanoparticles 327 . reverse drug resistance of pancreatic cancer 337 . Recently, the aptamer has been conjugated to gold nanospheres, presenting promising results in a mouse model of breast cancer 338 .…”

Evaluation of Intra-Arterial Chemotherapy Safety by Using of Gemcitabine and Oxaliplatin in Combined Treatment of Pancreatic Head Adenocarcinoma

“…Радикальное лечение ПАГПЖ является одной из наиболее сложных задач современной онкологии ввиду постоянного роста заболеваемости, поздней диагностики, а также высокой устойчивости опухоли к большинству химиопрепаратов [4]. Долгое время единственным способом радикального лечения заболевания являлось оперативное вмешательство.…”

“…ПАГПЖ обладает высокой устойчивостью ко многим цитостатическим препаратам [4]. Ответ опухоли на системную химиотерапию (СХТ) остается низким.…”

Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies

“…Many potential treatments are being tested in the preclinical stage. One in particular, a natural product called triptolide (TL), has shown promise as an anticancer drug for many different types of cancer, including PC (Wang et al, 2016 ). TL is an extract from the plant Tripterygium wilfordii Hook F (TwHF), also known as the thunder god vine or lei gong teng in Chinese (Kupchan et al, 1972 ).…”

“…TL is a diterpenoid triepoxide that was isolated from the roots of TwHF in 1972 (Figure 1 ; Kupchan et al, 1972 ; Wang et al, 2016 ). Although TL has not undergone extensive clinical testing, it shows broad spectrum anticancer effects, including proliferation inhibition, apoptosis induction and metastasis inhibition.…”