Modulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies

Jiwei Cui, Yi Ju, Zachary H. Houston, Joshua J. Glass, Nicholas L. Fletcher, Sheilajen Alcantara, Qiong Dai, Christopher B. Howard, Stephen M. Mahler, Adam K. Wheatley, Robert De Rose, Paul T. Brannon, Brett M. Paterson, Paul S. Donnelly, Kristofer J. Thurecht, Frank Caruso, Stephen J. Kent

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

Low-fouling or “stealth” particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG–BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs—one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)—is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.

Original languageEnglish
Article number1801607
Number of pages10
JournalAdvanced Healthcare Materials
Volume8
Issue number9
DOIs
Publication statusPublished - 9 May 2019

Keywords

  • biodistribution
  • bispecific antibodies
  • cell targeting
  • mesoporous silica particles
  • PEG particles

Cite this

Cui, Jiwei ; Ju, Yi ; Houston, Zachary H. ; Glass, Joshua J. ; Fletcher, Nicholas L. ; Alcantara, Sheilajen ; Dai, Qiong ; Howard, Christopher B. ; Mahler, Stephen M. ; Wheatley, Adam K. ; De Rose, Robert ; Brannon, Paul T. ; Paterson, Brett M. ; Donnelly, Paul S. ; Thurecht, Kristofer J. ; Caruso, Frank ; Kent, Stephen J. / Modulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies. In: Advanced Healthcare Materials. 2019 ; Vol. 8, No. 9.
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abstract = "Low-fouling or “stealth” particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG–BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs—one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)—is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.",
keywords = "biodistribution, bispecific antibodies, cell targeting, mesoporous silica particles, PEG particles",
author = "Jiwei Cui and Yi Ju and Houston, {Zachary H.} and Glass, {Joshua J.} and Fletcher, {Nicholas L.} and Sheilajen Alcantara and Qiong Dai and Howard, {Christopher B.} and Mahler, {Stephen M.} and Wheatley, {Adam K.} and {De Rose}, Robert and Brannon, {Paul T.} and Paterson, {Brett M.} and Donnelly, {Paul S.} and Thurecht, {Kristofer J.} and Frank Caruso and Kent, {Stephen J.}",
year = "2019",
month = "5",
day = "9",
doi = "10.1002/adhm.201801607",
language = "English",
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Cui, J, Ju, Y, Houston, ZH, Glass, JJ, Fletcher, NL, Alcantara, S, Dai, Q, Howard, CB, Mahler, SM, Wheatley, AK, De Rose, R, Brannon, PT, Paterson, BM, Donnelly, PS, Thurecht, KJ, Caruso, F & Kent, SJ 2019, 'Modulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies', Advanced Healthcare Materials, vol. 8, no. 9, 1801607. https://doi.org/10.1002/adhm.201801607

Modulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies. / Cui, Jiwei; Ju, Yi; Houston, Zachary H.; Glass, Joshua J.; Fletcher, Nicholas L.; Alcantara, Sheilajen; Dai, Qiong; Howard, Christopher B.; Mahler, Stephen M.; Wheatley, Adam K.; De Rose, Robert; Brannon, Paul T.; Paterson, Brett M.; Donnelly, Paul S.; Thurecht, Kristofer J.; Caruso, Frank; Kent, Stephen J.

In: Advanced Healthcare Materials, Vol. 8, No. 9, 1801607, 09.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Cui, Jiwei

AU - Ju, Yi

AU - Houston, Zachary H.

AU - Glass, Joshua J.

AU - Fletcher, Nicholas L.

AU - Alcantara, Sheilajen

AU - Dai, Qiong

AU - Howard, Christopher B.

AU - Mahler, Stephen M.

AU - Wheatley, Adam K.

AU - De Rose, Robert

AU - Brannon, Paul T.

AU - Paterson, Brett M.

AU - Donnelly, Paul S.

AU - Thurecht, Kristofer J.

AU - Caruso, Frank

AU - Kent, Stephen J.

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AB - Low-fouling or “stealth” particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG–BsAb particles via a one-step binding strategy for cell and tumor targeting. The dual specificity of the BsAbs—one arm binds to the PEG particles while the other targets a cell antigen (epidermal growth factor receptor, EGFR)—is exploited to modulate the number of targeting ligands per particle. Increasing the BsAb incubation concentration increases the amount of BsAb tethered to the PEG particles and enhances targeting and internalization into breast cancer cells overexpressing EGFR. The degree of BsAb functionalization does not significantly reduce the stealth properties of the PEG particles ex vivo, as assessed by their interactions with primary human blood granulocytes and monocytes. Although increasing the BsAb amount on PEG particles does not lead to the expected improvement in tumor accumulation in vivo, BsAb functionalization facilitates tumor cell uptake of PEG particles. This work highlights strategies to balance evading nonspecific clearance pathways, while improving tumor targeting and accumulation.

KW - biodistribution

KW - bispecific antibodies

KW - cell targeting

KW - mesoporous silica particles

KW - PEG particles

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