Date Published: February 26, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Xi He, Xinli Chen, Lisha Liu, Yu Zhang, Yifei Lu, Yujie Zhang, Qinjun Chen, Chunhui Ruan, Qin Guo, Chao Li, Tao Sun, Chen Jiang.
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy with a five year survival rate of <5%. The aberrant expression of extracellular matrix (ECM) in the tumor stroma forms a compact physical barrier, which that leads to insufficient extravasation and penetration of nanosized therapies. To overcome the severe resistance of PDAC to conventional therapies, a sequentially triggered nanoparticle (aptamer/cell‐penetrating peptide‐camptothecin prodrug, i.e., Apt/CPP‐CPTD NPs) with tumor penetration and intelligent drug release profile is designed. An ECM component (tenescin‐C) targeting aptamer (GBI‐10) is modified onto stroma‐permeable cell‐penetrating peptide (CPP) for the in vivo CPP camouflage and PDAC‐homing. In PDAC stroma, tenascin‐C can detach GBI‐10 from CPP and exposed CPP can facilitate further PDAC penetration and tumor cell endocytosis. After being endocytosed into PDAC cells, intracellular high redox potential can further trigger controlled chemodrug release. Apt/CPP‐CPTD NPs show both deep penetration in vitro 3D PDAC spheroids and in vivo tumor sections. The relatively mild in vitro cytotoxicity and excellent in vivo antitumor efficacy proves the improved PDAC targeting drug delivery and decreased systemic toxicity. The design of ECM‐redox sequentially triggered stroma permeable NPs may provide a practical approach for deep penetration of PDAC and enhanced drug delivery efficacy.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5‐year survival rate below 5%.1 Its aggressive nature resides in the abnormally high expression of extracellular matrix in the tumor stroma, which forms a compact physical barrier for the delivery of cytotoxic chemotherapeutics into the tumor cells.2 Nanomedicines such as liposomes, polymeric nanopraticles, and micelles have been developed to optimize the drug delivery of anticancer agents by accumulation in most tumor site via the enhanced permeability and retention (EPR) effect.3 However, the abnormally high dense tumor stroma and hypovascularity in PDAC extracellular matrix (ECM), greatly compromising the tumor‐penetrating performance, and leading to the treatment failure for pancreatic cancer treatment.[[qv: 2a,4]] To address these problems, tremendous efforts have been devoted to the development of advanced drug delivery systems, which are capable of orchestrating several specific interactions in a coordinated pattern and successively overcoming the biological barriers to maximize the therapeutic potency.5 Recent years, there is an increasing interest in targeting different component of PDAC stroma and several preclinical studies in modulating ECM density for PDAC treatment.6 Coadministration of Nab‐paclitaxel and gemcitabine was one of the most famous strategies hypothesized to target the stroma, which specially collapsed the PDAC stroma accompanied by a marked distortion of the collagen and tumor vascularization.[[qv: 6b,c]] However, by removal of stroma in PDAC, there still remains a concern that this therapy method might provide new space for tumor proliferation and increase the probability of metastasis.7 Therefore, there is an urgent need to develop novel strategies to improve therapeutics’ stroma penetrating ability without damaging the ECM tumor barrier.
In summary, we have developed a sequentially responsive nanoparticle with ECM‐triggered tumor penetration and redox responsive drug release profile. The novel Apt/CPP‐CPTD NPs selectively accumulated in tumor site via EPR effect and performed increased tumor penetration ability by the exposed CPP, which was activated in the PDAC‐related ECM component tenascin C. After endocytosis, CPTD prodrug could be sequentially triggered by intravenous redox potential and provide controlled drug release. Enhanced drug distribution in tumor site and good antitumor efficacy were observed both in vitro and in vivo. In the light of these results, the unique sequentially triggered nanoparticle with tumor penetration and intelligent drug release could serve well as a promising strategy for PDAC treatment.
Amphiphilic Copolymer Synthesis and CPTD Prodrug Synthesis: Phe‐NCA was synthesized according to Fuchs‐Farthing method by triphosgene in anhydrous THF solution for 4 h at 50 °C under nitrogen atmosphere. The product was precipitated by slowly added into the anhydrous hexane and purified by washing with cold anhydrous hexane for three times. The solution was recrystallized at −20 °C overnight. The NCA monomer was then filtered and dried under vacuum for the following use.
The authors declare no conflict of interest.