Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration

Aristides D Tagalakis, Stephanie M Grosse, Qing-Hai Meng, M Firouz Mohd Mustapa, Albert Kwok, Shahla E Salehi, Alethea B Tabor, Helen C Hailes, Stephen L Hart

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.

Original languageEnglish
Pages (from-to)1370-6
Number of pages7
JournalBiomaterials
Volume32
Issue number5
DOIs
Publication statusPublished - Feb 2011

Fingerprint

Integrins
Tumors
Neoplasms
Interleukin-2
Plasmids
Therapeutics
Interleukin-12
Luciferases
Infiltration
Peptides
Nanoparticles
Animals
DNA
Genes
T-cells
Liver
Lipids
Coculture Techniques
Neuroblastoma
Transfection

Keywords

  • Administration, Cutaneous
  • Animals
  • Cell Line, Tumor
  • Female
  • Gene Transfer Techniques
  • Genetic Therapy/methods
  • Integrins/genetics
  • Interleukin-12/genetics
  • Interleukin-2/genetics
  • Mice
  • Nanoparticles/administration & dosage
  • Neoplasms/therapy
  • Polymerase Chain Reaction
  • Transfection

Cite this

Tagalakis, Aristides D ; Grosse, Stephanie M ; Meng, Qing-Hai ; Mustapa, M Firouz Mohd ; Kwok, Albert ; Salehi, Shahla E ; Tabor, Alethea B ; Hailes, Helen C ; Hart, Stephen L. / Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration. In: Biomaterials. 2011 ; Vol. 32, No. 5. pp. 1370-6.
@article{83638ced411e472aa75a679ba8318acc,
title = "Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration",
abstract = "Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75{\%} smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.",
keywords = "Administration, Cutaneous, Animals, Cell Line, Tumor, Female, Gene Transfer Techniques, Genetic Therapy/methods, Integrins/genetics, Interleukin-12/genetics, Interleukin-2/genetics, Mice, Nanoparticles/administration & dosage, Neoplasms/therapy, Polymerase Chain Reaction, Transfection",
author = "Tagalakis, {Aristides D} and Grosse, {Stephanie M} and Qing-Hai Meng and Mustapa, {M Firouz Mohd} and Albert Kwok and Salehi, {Shahla E} and Tabor, {Alethea B} and Hailes, {Helen C} and Hart, {Stephen L}",
note = "Copyright {\circledC} 2010 Elsevier Ltd. All rights reserved.",
year = "2011",
month = "2",
doi = "10.1016/j.biomaterials.2010.10.037",
language = "English",
volume = "32",
pages = "1370--6",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier",
number = "5",

}

Tagalakis, AD, Grosse, SM, Meng, Q-H, Mustapa, MFM, Kwok, A, Salehi, SE, Tabor, AB, Hailes, HC & Hart, SL 2011, 'Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration', Biomaterials, vol. 32, no. 5, pp. 1370-6. https://doi.org/10.1016/j.biomaterials.2010.10.037

Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration. / Tagalakis, Aristides D; Grosse, Stephanie M; Meng, Qing-Hai; Mustapa, M Firouz Mohd; Kwok, Albert; Salehi, Shahla E; Tabor, Alethea B; Hailes, Helen C; Hart, Stephen L.

In: Biomaterials, Vol. 32, No. 5, 02.2011, p. 1370-6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration

AU - Tagalakis, Aristides D

AU - Grosse, Stephanie M

AU - Meng, Qing-Hai

AU - Mustapa, M Firouz Mohd

AU - Kwok, Albert

AU - Salehi, Shahla E

AU - Tabor, Alethea B

AU - Hailes, Helen C

AU - Hart, Stephen L

N1 - Copyright © 2010 Elsevier Ltd. All rights reserved.

PY - 2011/2

Y1 - 2011/2

N2 - Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.

AB - Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.

KW - Administration, Cutaneous

KW - Animals

KW - Cell Line, Tumor

KW - Female

KW - Gene Transfer Techniques

KW - Genetic Therapy/methods

KW - Integrins/genetics

KW - Interleukin-12/genetics

KW - Interleukin-2/genetics

KW - Mice

KW - Nanoparticles/administration & dosage

KW - Neoplasms/therapy

KW - Polymerase Chain Reaction

KW - Transfection

U2 - 10.1016/j.biomaterials.2010.10.037

DO - 10.1016/j.biomaterials.2010.10.037

M3 - Article

C2 - 21074847

VL - 32

SP - 1370

EP - 1376

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 5

ER -