RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells

Bo Lou; Kate Connor; Kieron Sweeney; Ian S. Miller; Alice O’Farrell; Eduardo Ruiz-Hernandez; David M. Murray; Garry P. Duffy; Alan Wolfe; Enrico Mastrobattista; Annette T. Byrne; Wim E. Hennink

doi:10.1007/s13346-019-00637-y

RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells

Bo Lou
, Kate Connor
, Kieron Sweeney
, Ian S. Miller
, Alice O’Farrell
, Eduardo Ruiz-Hernandez
, David M. Murray
, Garry P. Duffy
, Alan Wolfe
, Enrico Mastrobattista
, Annette T. Byrne
, Wim E. Hennink^*

^*Corresponding author for this work

Royal College of Surgeons in Ireland
Beaumont Hospital, Dublin
National University of Ireland, Galway

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (~ 40 nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.

Original language	English
Pages (from-to)	679-693
Number of pages	15
Journal	Drug Delivery and Translational Research
Volume	9
Issue number	3
DOIs	https://doi.org/10.1007/s13346-019-00637-y
Publication status	Published - 15 Jun 2019

Funding

Funding information Bo Lou was funded by the China Scholarship Council (CSC). This work was supported in part by a Science Foundation Ireland Technology Innovation Award (15/TIDA/2963). ATB is further supported by the BGLIOTRAIN^ (http://www.gliotrain. eu) award, a Horizon 2020 Research and Innovation program funded under the Marie Skłodowska-Curie ETN initiative (Grant Agreement #766069).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer targeting
Cholesterol modification
cRGD peptide
Glioblastoma
siRNA delivery

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10.1007/s13346-019-00637-y

Lou2019_Article_RGD-decoratedCholesterolStabilFinal published version, 1.57 MB

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Lou, B., Connor, K., Sweeney, K., Miller, I. S., O’Farrell, A., Ruiz-Hernandez, E., Murray, D. M., Duffy, G. P., Wolfe, A., Mastrobattista, E., Byrne, A. T., & Hennink, W. E. (2019). RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells. Drug Delivery and Translational Research, 9(3), 679-693. https://doi.org/10.1007/s13346-019-00637-y

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title = "RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells",

abstract = "The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (\textasciitilde{} 40 nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.",

keywords = "Cancer targeting, Cholesterol modification, cRGD peptide, Glioblastoma, siRNA delivery",

author = "Bo Lou and Kate Connor and Kieron Sweeney and Miller, \{Ian S.\} and Alice O{\textquoteright}Farrell and Eduardo Ruiz-Hernandez and Murray, \{David M.\} and Duffy, \{Garry P.\} and Alan Wolfe and Enrico Mastrobattista and Byrne, \{Annette T.\} and Hennink, \{Wim E.\}",

year = "2019",

month = jun,

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doi = "10.1007/s13346-019-00637-y",

language = "English",

volume = "9",

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Lou, B, Connor, K, Sweeney, K, Miller, IS, O’Farrell, A, Ruiz-Hernandez, E, Murray, DM, Duffy, GP, Wolfe, A, Mastrobattista, E, Byrne, AT & Hennink, WE 2019, 'RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells', Drug Delivery and Translational Research, vol. 9, no. 3, pp. 679-693. https://doi.org/10.1007/s13346-019-00637-y

TY - JOUR

T1 - RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells

AU - Lou, Bo

AU - Connor, Kate

AU - Sweeney, Kieron

AU - Miller, Ian S.

AU - O’Farrell, Alice

AU - Ruiz-Hernandez, Eduardo

AU - Murray, David M.

AU - Duffy, Garry P.

AU - Wolfe, Alan

AU - Mastrobattista, Enrico

AU - Byrne, Annette T.

AU - Hennink, Wim E.

PY - 2019/6/15

Y1 - 2019/6/15

N2 - The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (~ 40 nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.

AB - The development of an effective and safe treatment for glioblastoma (GBM) represents a significant challenge in oncology today. Downregulation of key mediators of cell signal transduction by RNA interference is considered a promising treatment strategy but requires efficient, intracellular delivery of siRNA into GBM tumor cells. Here, we describe novel polymeric siRNA nanocarriers functionalized with cRGD peptide that mediates targeted and efficient reporter gene silencing in U87R invasive human GBM cells. The polymer was synthesized via RAFT copolymerization of N-(2-hydroxypropyl)-methacrylamide (HPMA) and N-acryloxysuccinimide (NAS), followed by post-polymerization modification with cholesterol for stabilization, cationic amines for siRNA complexation, and azides for copper-free click chemistry. The novel resultant cationic polymer harboring a terminal cholesterol group, self-assembled with siRNA to yield nanosized polyplexes (~ 40 nm) with good colloidal stability at physiological ionic strength. Post-modification of the preformed polyplexes with PEG-cRGD end-functionalized with bicyclo[6.1.0]nonyne (BCN) group resulted in enhanced cell uptake and increased luciferase gene silencing in U87R cells, compared to polyplexes lacking cRGD-targeting groups.

KW - Cancer targeting

KW - Cholesterol modification

KW - cRGD peptide

KW - Glioblastoma

KW - siRNA delivery

UR - https://www.scopus.com/pages/publications/85065639229

U2 - 10.1007/s13346-019-00637-y

DO - 10.1007/s13346-019-00637-y

M3 - Article

C2 - 30972664

AN - SCOPUS:85065639229

SN - 2190-393X

VL - 9

SP - 679

EP - 693

JO - Drug Delivery and Translational Research

JF - Drug Delivery and Translational Research

IS - 3

ER -

RGD-decorated cholesterol stabilized polyplexes for targeted siRNA delivery to glioblastoma cells

Abstract

Funding

UN SDGs

Keywords

Access to Document

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