Polymeric nanoparticles and cancer: Lessons learnt from CRLX101

Ismael Gritli, Edward Garmey, Scott Eliasof, Andres Tellez, Mark E. Davis, Yen Yun

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

Abstract

CRLX101 (formerly IT-101) is a novel cyclodextrin-based polymer that self-assembles into nanoparticles. CRLX101 is covalently conjugated to the hydrophobic topoisomerase 1 (TOP1)-inhibitor camptothecin (CPT) resulting in stabilized structure and increased water solubility. Extensive preclinical studies of CRLX101 demonstrated delayed renal clearance and a prolonged plasma half-life. The nanoparticle passively accumulates in tumour tissue through the enhanced permeability and retention effect and slowly releases active CPT leading to enhanced TOP1 inhibition, potential hypoxia inducible factor-1a (HIF-1a) effect, cancer stem cell targeting, and increased antitumour activity against multiple human tumour xenografts. More than 200 human cancer patients have been treated with CRLX101 in phase I/IIa and phase II clinical trials. In this chapter we explore a wide range of anti-cancer nanotherapeutic strategies to inhibit TOP1, HIF-1a and cancer stem cells. Moreover, we discuss the therapeutic value of combining HIF-1a inhibition with antiangiogenics. Finally, we return to CRLX101 and cover in detail the latest preclinical and clinical evaluations and discuss future directions.

Original languageEnglish
Title of host publicationPrivileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation
PublisherRoyal Society of Chemistry
Pages199-232
Number of pages34
Volume2016-January
Edition51
DOIs
Publication statusPublished - 2016
Externally publishedYes

Publication series

NameRSC Drug Discovery Series
Number51
Volume2016-January
ISSN (Print)20413203
ISSN (Electronic)20413211

Fingerprint

Nanoparticles
Camptothecin
Neoplasms
Neoplastic Stem Cells
Topoisomerase I Inhibitors
Hypoxia-Inducible Factor 1
Phase II Clinical Trials
Heterografts
Solubility
Half-Life
IT-101
Permeability
Kidney
Water
Hypoxia

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Gritli, I., Garmey, E., Eliasof, S., Tellez, A., Davis, M. E., & Yun, Y. (2016). Polymeric nanoparticles and cancer: Lessons learnt from CRLX101. In Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation (51 ed., Vol. 2016-January, pp. 199-232). (RSC Drug Discovery Series; Vol. 2016-January, No. 51). Royal Society of Chemistry. https://doi.org/10.1039/9781782622536-00199

Polymeric nanoparticles and cancer : Lessons learnt from CRLX101. / Gritli, Ismael; Garmey, Edward; Eliasof, Scott; Tellez, Andres; Davis, Mark E.; Yun, Yen.

Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation. Vol. 2016-January 51. ed. Royal Society of Chemistry, 2016. p. 199-232 (RSC Drug Discovery Series; Vol. 2016-January, No. 51).

Research output: Chapter in Book/Report/Conference proceedingChapter

Gritli, I, Garmey, E, Eliasof, S, Tellez, A, Davis, ME & Yun, Y 2016, Polymeric nanoparticles and cancer: Lessons learnt from CRLX101. in Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation. 51 edn, vol. 2016-January, RSC Drug Discovery Series, no. 51, vol. 2016-January, Royal Society of Chemistry, pp. 199-232. https://doi.org/10.1039/9781782622536-00199
Gritli I, Garmey E, Eliasof S, Tellez A, Davis ME, Yun Y. Polymeric nanoparticles and cancer: Lessons learnt from CRLX101. In Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation. 51 ed. Vol. 2016-January. Royal Society of Chemistry. 2016. p. 199-232. (RSC Drug Discovery Series; 51). https://doi.org/10.1039/9781782622536-00199
Gritli, Ismael ; Garmey, Edward ; Eliasof, Scott ; Tellez, Andres ; Davis, Mark E. ; Yun, Yen. / Polymeric nanoparticles and cancer : Lessons learnt from CRLX101. Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation. Vol. 2016-January 51. ed. Royal Society of Chemistry, 2016. pp. 199-232 (RSC Drug Discovery Series; 51).
@inbook{c1813982894f47129d27780400c2ecb3,
title = "Polymeric nanoparticles and cancer: Lessons learnt from CRLX101",
abstract = "CRLX101 (formerly IT-101) is a novel cyclodextrin-based polymer that self-assembles into nanoparticles. CRLX101 is covalently conjugated to the hydrophobic topoisomerase 1 (TOP1)-inhibitor camptothecin (CPT) resulting in stabilized structure and increased water solubility. Extensive preclinical studies of CRLX101 demonstrated delayed renal clearance and a prolonged plasma half-life. The nanoparticle passively accumulates in tumour tissue through the enhanced permeability and retention effect and slowly releases active CPT leading to enhanced TOP1 inhibition, potential hypoxia inducible factor-1a (HIF-1a) effect, cancer stem cell targeting, and increased antitumour activity against multiple human tumour xenografts. More than 200 human cancer patients have been treated with CRLX101 in phase I/IIa and phase II clinical trials. In this chapter we explore a wide range of anti-cancer nanotherapeutic strategies to inhibit TOP1, HIF-1a and cancer stem cells. Moreover, we discuss the therapeutic value of combining HIF-1a inhibition with antiangiogenics. Finally, we return to CRLX101 and cover in detail the latest preclinical and clinical evaluations and discuss future directions.",
author = "Ismael Gritli and Edward Garmey and Scott Eliasof and Andres Tellez and Davis, {Mark E.} and Yen Yun",
year = "2016",
doi = "10.1039/9781782622536-00199",
language = "English",
volume = "2016-January",
series = "RSC Drug Discovery Series",
publisher = "Royal Society of Chemistry",
number = "51",
pages = "199--232",
booktitle = "Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation",
edition = "51",

}

TY - CHAP

T1 - Polymeric nanoparticles and cancer

T2 - Lessons learnt from CRLX101

AU - Gritli, Ismael

AU - Garmey, Edward

AU - Eliasof, Scott

AU - Tellez, Andres

AU - Davis, Mark E.

AU - Yun, Yen

PY - 2016

Y1 - 2016

N2 - CRLX101 (formerly IT-101) is a novel cyclodextrin-based polymer that self-assembles into nanoparticles. CRLX101 is covalently conjugated to the hydrophobic topoisomerase 1 (TOP1)-inhibitor camptothecin (CPT) resulting in stabilized structure and increased water solubility. Extensive preclinical studies of CRLX101 demonstrated delayed renal clearance and a prolonged plasma half-life. The nanoparticle passively accumulates in tumour tissue through the enhanced permeability and retention effect and slowly releases active CPT leading to enhanced TOP1 inhibition, potential hypoxia inducible factor-1a (HIF-1a) effect, cancer stem cell targeting, and increased antitumour activity against multiple human tumour xenografts. More than 200 human cancer patients have been treated with CRLX101 in phase I/IIa and phase II clinical trials. In this chapter we explore a wide range of anti-cancer nanotherapeutic strategies to inhibit TOP1, HIF-1a and cancer stem cells. Moreover, we discuss the therapeutic value of combining HIF-1a inhibition with antiangiogenics. Finally, we return to CRLX101 and cover in detail the latest preclinical and clinical evaluations and discuss future directions.

AB - CRLX101 (formerly IT-101) is a novel cyclodextrin-based polymer that self-assembles into nanoparticles. CRLX101 is covalently conjugated to the hydrophobic topoisomerase 1 (TOP1)-inhibitor camptothecin (CPT) resulting in stabilized structure and increased water solubility. Extensive preclinical studies of CRLX101 demonstrated delayed renal clearance and a prolonged plasma half-life. The nanoparticle passively accumulates in tumour tissue through the enhanced permeability and retention effect and slowly releases active CPT leading to enhanced TOP1 inhibition, potential hypoxia inducible factor-1a (HIF-1a) effect, cancer stem cell targeting, and increased antitumour activity against multiple human tumour xenografts. More than 200 human cancer patients have been treated with CRLX101 in phase I/IIa and phase II clinical trials. In this chapter we explore a wide range of anti-cancer nanotherapeutic strategies to inhibit TOP1, HIF-1a and cancer stem cells. Moreover, we discuss the therapeutic value of combining HIF-1a inhibition with antiangiogenics. Finally, we return to CRLX101 and cover in detail the latest preclinical and clinical evaluations and discuss future directions.

UR - http://www.scopus.com/inward/record.url?scp=84974846082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84974846082&partnerID=8YFLogxK

U2 - 10.1039/9781782622536-00199

DO - 10.1039/9781782622536-00199

M3 - Chapter

AN - SCOPUS:84974846082

VL - 2016-January

T3 - RSC Drug Discovery Series

SP - 199

EP - 232

BT - Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation

PB - Royal Society of Chemistry

ER -