Sequentially Triggered Nanoparticles with Tumor Penetration and Intelligent Drug Release for Pancreatic Cancer Therapy

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.

Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors

“…Next, we evaluated the homing ability of Nano-sapper. Tenascin-C is widely expressed in the stroma of PDAC and interacts with other ECM components (e.g., fibronectin, type I collagen), and is becoming an attractive target for PDAC therapy 41 . Therefore, the FHK peptide, which possess high binding affinity to tenascin C, was proposed as a suitable targeting ligand for Nano-sapper.…”

Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review

“…They were able to image U251 glioblastoma xenograft tissue in vivo with Technetium-99m-labeled TNC aptamers using radionuclide imaging [ 83 ]. He et al [ 84 ] developed a nanoparticle formulation of camptothecin prodrug conjugated with a cell penetrating peptide and TNC-targeted single-stranded DNA aptamer and evaluated this in a xenograft model of pancreatic ductal adenocarcinoma. They were able to demonstrate in vivo imaging of these particles and demonstrated therapeutic response in a xenograft model [ 84 ].…”

“…He et al [ 84 ] developed a nanoparticle formulation of camptothecin prodrug conjugated with a cell penetrating peptide and TNC-targeted single-stranded DNA aptamer and evaluated this in a xenograft model of pancreatic ductal adenocarcinoma. They were able to demonstrate in vivo imaging of these particles and demonstrated therapeutic response in a xenograft model [ 84 ]. These successful applications of TNC-targeted theranostics using aptamers is promising as antibody mimetics have several advantages over antibodies including their lower cost, scalability, and more ethical synthesis as they do not require an intact host immune system for their production [ 85 , 86 ].…”

Lipossomas De Longa-Circulação Como Estratégia Promissora Para O Transporte E Biodisponibilização De Fármacos No Tratamento Do Câncer

“…Outros ligantes incluem peptídeos (RGD, IL4RPep-1,NGR) com elevada afinidade e capazes de aumentar a permeabilidade dos fármacos através dos tumores sólidos (HAUBNER et al, 2005;GREGORC et al, 2009;SUGAHARA et al, 2010;CHI et al, 2015). Os aptâmeros (A-1411, GBI-10, a-Pegaptanib) constituem outra classe de compostos empregada, cujas principais vantagens são a biocompatibilidade, baixa imunogenicidade e seletividade controlável ( JO; BAN, 2016;STEIN;CASTANOTTO, 2017;HE et al, 2018). Por fim, moléculas de baixa massa molecular como ácido fólico, biotina, galactose dentre outras vêm sendo amplamente estudadas devido ao baixa custo de produção, e simplicidade de formulação e especificidade das interação ligante/receptor (DESHAYES et al, 2013;LEDERMANN;CANEVARI;THIGPEN, 2015;HUO et al, 2017;LV et al, 2017;PELLOSI et al, 2017;DE FREITAS et al, 2019).…”