Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells

Abstract

Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.

Combinatorial optimization of PEG architecture and hydrophobic content improves ternary siRNA polyplex stability, pharmacokinetics, and potency in vivo

“…Upon coating, cytotoxicity of the DB pre-NPs is entirely mitigated, further suggesting their successful coating and surface presentation of the biocompatible PEG molecules (Supplementary Figure S6). These results underscore the potential cytotoxicity of hemolytic materials which are not well-stabilized (such as DB-PD) and agree with previous reports of cell-type dependent cytotoxicity of nanomaterials[38, 51, 52]. …”

“…Library-based screens, such as those highlighted above, used high throughput synthesis methods to screen different compositions of cationic lipids[9, 29, 30, 34, 35] or polymers[25, 26, 31–33, 36–38]. This approach has proven powerful in elucidation of siRNA carrier structure-function relationships, especially for endpoints focused on in vitro activity and/or in vivo liver gene silencing.…”

“…In these studies, the authors did not utilize a PEGylation component[25, 26, 36, 37] or used a simple amphiphile ( i.e. , (mPEG2000-carbamoyl)-1,2-di-O-tetradecyl-sn-glyceride (PEG-DMG) lipid) to sterically stabilize the surface of the resultant nanoparticles[9, 29, 30, 32–35, 38]. Here, we sought to create a library for simultaneous investigation of the composition (cationic versus balanced hydrophobic/cationic) and the relative quantity of both core- and (PEG-containing) corona-forming polyplex components.…”

Non‐Viral CRISPR/Cas Gene Editing In Vitro and In Vivo Enabled by Synthetic Nanoparticle Co‐Delivery of Cas9 mRNA and sgRNA

“…Next, lead ZNPs were loaded with sgLuc and evaluated for delivery to HeLa-Luc-Cas9 cells. Luciferase and viability [13] were measured after 48 hours (h) relative to untreated cells. As anticipated from the chemical design combining cationic and zwitterionic functionalities, ZNPs do not require inclusion of helper phospholipids (Fig.…”

Molecular Imaging in Nanotechnology and Theranostics

“…Ultrasmall 64 Cu-PEG-melanin nanoparticles loaded with FDA-approved multikinase inhibitor sorafenib provide PET-PAI image-guided chemotherapy in liver xenograft models [106]. Recently, siRNA-loaded nanoparticles were employed in various settings, such as gene delivery into lung cancer cells – but not normal cells – without targeting ligands [107]; transdermal application for suppressing EGFR expression and downstream ERK signaling in mice and humans with no clinical or histological toxicity [108]; and increasing progression-free survival in murine acute kidney injury models and nonhuman primates [109]. …”