Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy with a five year survival rate of
Our novel sequentially triggered Apt/cell-penetrating peptide (CPP)-camptothecin prodrug (CPTD) NPs were prepared through a multistep approach as described in Scheme 1
To achieve the tumor intracellular redox responsiveness, we developed a redox-responsive dimeric CPTD prodrug based NPs according to our previous work.[18b]. Such NPs comprised of a redox-responsive dimeric CPTD prodrug and amphiphilic copolymer as a stabilizer
Summary
Our novel sequentially triggered Apt/CPP-CPTD NPs were prepared through a multistep approach as described in Scheme 1. By modulating weight ratio of CPTD and amphiphilic copolymer mPEG5k-pPhe(15), we prepared a series of CPTD prodrug NPs with different particle sizes and stability (Figure 1A). To validate the high drug loading ability, we measured the CPT loading rate in Apt/CPP-CPTD NPs by HPLC, which was 26.2% ± 1.6%, much higher than conventional polymeric micelles or inorganic NPs.[21] Such high drug loading was achieved due to the dimeric structure of CPTD prodrug, which included freely rotatable bonds and a phenol ring. Such structure was much less rigid comparing to prototype CPT, which could effectively prevent large aggregates/crystals during drug formulation, loading more prodrug into NPs with higher drug loading rate
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