Prof.  Xiaoding  Xu
Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University,  China

Title: Bio-responsive nanoparticles for systemic siRNA delivery and effective cancer therapy

Abstract:

Nanomedicine has shown great promise for more effective and safer cancer therapy [1]. However, the successful clinical translation of cancer nanotherapeutics still faces considerable challenges due to the complexities and heterogeneity of tumors, therefore requiring the rational design of nanoparticle (NP) delivery systems and patient selection. To address the barriers involved in systemic NP delivery to solid tumors (e.g., blood circulation, tumor accumulation and penetration, cellular uptake, and intracellular release), bio-responsive NP-based delivery technique has recently emerged for effective cancer treatment [2]. These bio-responsive NP delivery systems can respond to tumor microenvironment (TME) (e.g., acidic pH, over-expressed enzymes and hypoxia) to change their physicochemical properties including size, zeta potential and hydrophilic-hydrophobic balance, thereby leading to enhanced diffusion, cellular uptake, and/or intracellular cargo release [3-5].

Herein, we reported a unique and robust TME pH-responsive multistaged NP platform for systemic targeted siRNA delivery and effective cancer therapy. This NP platform is composed of a sharp TME pH-responsive PEGylated polymer and a tumor cell-targeting and -penetrating peptide-amphiphile (TCPA). After encapsulating the siRNA/TCPA complexes, the resulting NP platform shows the following features for multistaged siRNA delivery: i) PEG outer shell prolongs blood circulation and thus enhances tumor accumulation; ii) sensitive response of the hydrophobic poly(2-(hexamethyleneimino) ethyl methacrylate) (PHMEMA) to TME pH induces the rapid disassembly of NPs and exposure of siRNA-TCPA complexes at tumor site; iii) tumor cell-targeting ability of TCPA attributable to its RGD ligand segment improves the cellular uptake of the siRNA-TCPA complexes; iv) cell-penetrating ability of TCPA attributable to its cationic polyarginine segment enhances the cytosolic siRNA transport to achieve efficient gene silencing; and v) facile synthesis of the PHMEMA polymer and TCPA as well as robust NP formulation enable the scale-up of this NP platform.

Key Words:Nanoparticle, Bio-responsive, siRNA Delivery, Cancer therapy

Reference

[1]    Farokhzad OC*, Langer R*. Impact of Nanotechnology on DrugDelivery.ACS Nano, 2009, 3:16-20

[2]    Shi J,Kantoff PW, Wooster R, Farokhzad OC*. Cancer Nanomedicine: Progress, Challenges and Opportunities. Nat Rev Cancer, 2017, 17:20-37.

[3]    Xu X, Wu J, Liu Y, Yu M, Zhao L, ZhuX,Bhasin S, Li Q, Ha E, Shi J*, Farokhzad OC*. Ultra-pH-Responsive and Tumor-Penetrating Nanoplatform forTargeted siRNA Delivery with Robust Anti-Cancer Efficacy. AngewChemInt Ed 2016, 55:7091-7094.

[4]    Xu X, Saw PE, Tao W, Li Y, Ji X, Bhasin S, LiuY,AyyashD, Rasmussen J,Huo M, Shi J*,Farokhzad OC*. ROS-Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy.Adv Mater 2017, 29:1700141.

[5]    Wang S, HuangP*, Chen X*. Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization. Adv Mater 2016, 28:7340-7364.

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