Aerosol delivery of star polymer-siRNA nanoparticles as a therapeutic strategy to inhibit lung tumor growth

Z Ma; S W Wong; H Forgham; L Esser; M Lai; M N Leiske; K Kempe; G Sharbeen; J Youkhana; F Mansfeld; J F Quinn; P A Phillips; T P Davis; M Kavallaris; J A McCarroll

doi:10.1016/j.biomaterials.2022.121539

Aerosol delivery of star polymer-siRNA nanoparticles as a therapeutic strategy to inhibit lung tumor growth

Biomaterials. 2022 Jun:285:121539. doi: 10.1016/j.biomaterials.2022.121539. Epub 2022 Apr 23.

Authors

Z Ma¹, S W Wong², H Forgham¹, L Esser³, M Lai⁴, M N Leiske⁵, K Kempe⁶, G Sharbeen⁷, J Youkhana⁷, F Mansfeld⁸, J F Quinn⁹, P A Phillips¹⁰, T P Davis¹¹, M Kavallaris¹², J A McCarroll¹³

Affiliations

¹ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Australia; School of Women's and Children's Health, UNSW Sydney, Australia; Australian Centre for NanoMedicine, UNSW Sydney, Australia.
² Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Australia.
³ Commonwealth Scientific and Industrial Research Organisation, Melbourne, Australia.
⁴ Drug Delivery Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Australia.
⁵ Drug Delivery Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan, Belgium.
⁶ Drug Delivery Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; Materials Science and Engineering, Monash University, Australia.
⁷ Pancreatic Cancer Translational Research Group, Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Australia; School of Medical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Australia.
⁸ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Australia; Australian Centre for NanoMedicine, UNSW Sydney, Australia; Commonwealth Scientific and Industrial Research Organisation, Melbourne, Australia.
⁹ Drug Delivery Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; Department of Chemical Engineering, Faculty of Engineering, Monash University, Australia.
¹⁰ Australian Centre for NanoMedicine, UNSW Sydney, Australia; Pancreatic Cancer Translational Research Group, Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Australia; School of Medical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Australia.
¹¹ Drug Delivery Disposition and Dynamics Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Australia.
¹² Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Australia; School of Women's and Children's Health, UNSW Sydney, Australia; Australian Centre for NanoMedicine, UNSW Sydney, Australia; UNSW RNA Institute, Sydney, UNSW Sydney, Australia. Electronic address: mkavallaris@ccia.org.au.
¹³ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Australia; School of Women's and Children's Health, UNSW Sydney, Australia; Australian Centre for NanoMedicine, UNSW Sydney, Australia; UNSW RNA Institute, Sydney, UNSW Sydney, Australia. Electronic address: jmccarroll@ccia.org.au.

PMID: 35500393
DOI: 10.1016/j.biomaterials.2022.121539

Abstract

Lung cancer is a major contributor to cancer-related death worldwide. siRNA nanomedicines are powerful tools for cancer therapeutics. However, there are challenges to overcome to increase siRNA delivery to solid tumors, including penetration of nanoparticles into a complex microenvironment following systemic delivery while avoiding rapid clearance by the reticuloendothelial system, and limited siRNA release from endosomes once inside the cell. Here we characterized cell uptake, intracellular trafficking, and gene silencing activity of miktoarm star polymer (PDMAEMA-POEGMA) nanoparticles (star nanoparticles) complexed to siRNA in lung cancer cells. We investigated the potential of nebulized star-siRNA nanoparticles to accumulate into orthotopic mouse lung tumors to inhibit expression of two genes [βIII-tubulin, Polo-Like Kinase 1 (PLK1)] which: 1) are upregulated in lung cancer cells; 2) promote tumor growth; and 3) are difficult to inhibit using chemical drugs. Star-siRNA nanoparticles internalized into lung cancer cells and escaped the endo-lysosomal pathway to inhibit target gene expression in lung cancer cells in vitro. Nebulized star-siRNA nanoparticles accumulated into lungs and silenced the expression of βIII-tubulin and PLK1 in mouse lung tumors, delaying aggressive tumor growth. These results demonstrate a proof-of-concept for aerosol delivery of star-siRNA nanoparticles as a novel therapeutic strategy to inhibit lung tumor growth.

Keywords: Aerosol drug delivery; Lung cancer; PLK1; Star polymers; siRNA; βIII-tubulin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aerosols
Animals
Cell Line, Tumor
Lung / pathology
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Mice
Nanoparticles* / chemistry
Polymers / chemistry
RNA, Small Interfering / genetics
Tubulin
Tumor Microenvironment

Substances

Aerosols
Polymers
RNA, Small Interfering
Tubulin