The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium

Hua Zhang, Ning Li, Padmini Sirish, Lisa Mahakian, Elizabeth Ingham, Fitz Roy Curry, Soichiro Yamada, Nipavan Chiamvimonvat, Katherine W. Ferrara

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Ligand-conjugated liposomes and other nano-sized constructs are attractive drug carriers due to their extended plasma circulation; however, limited data are available as to whether their cargo can traverse the endothelium of solid organs. To determine whether the cargo of endothelially targeted liposomes is internalized by endothelial cells and transported into tissue, and to evaluate whether such liposomes can accumulate in models of cardiovascular disease, we tracked the fate of the cargo (a hydrophilic fluorescent dye) and shell (conjugated with a radioisotope) of a heart-homing liposome (CRPPR-conjugated). The ex vivo heart was imaged with confocal microscopy and the in vivo heart with positron emission tomography in sham-treated mice and models of ischemia/reperfusion (I/R) and myocardial infarction (MI). Within 30 min of injection of 20 mg/kg CRPPR liposomes, fluorescence increased by 47 fold in the tissue surrounding the vascular lumen, as compared with non-targeted liposomes. Both the accumulation on the endothelium and the interstitial fluorescence saturated at an injected dose of 20 mg/kg. In both I/R and MI models, CRPPR liposomes accumulated in diseased sites, although less than in surrounding healthy tissue. The accumulation in the diseased sites increased with time post-injury: the ratio of accumulated radioactivity in the diseased and healthy cardiac tissue increased from 0.20 ± 0.04, to 0.58 ± 0.12 and 0.61 ± 0.19 for 1, 7, and 99 days post-MI, indicating the potential for adequate delivery and therapeutic efficacy if the targeted particles are injected at 7 or more days post-MI. In summary, CRPPR- liposomes accumulated in normal and diseased hearts, and the cargo accumulated in the tissue within minutes and remained detectable after 24 h.

Original languageEnglish (US)
Pages (from-to)10-17
Number of pages8
JournalJournal of Controlled Release
Volume163
Issue number1
DOIs
StatePublished - Oct 10 2012

Fingerprint

Liposomes
Endothelium
Myocardial Infarction
Reperfusion
Heart Diseases
Ischemia
Fluorescence
Drug Carriers
Fluorescent Dyes
Confocal Microscopy
Radioisotopes
Positron-Emission Tomography
Radioactivity
Blood Vessels
Cardiovascular Diseases
Endothelial Cells
Ligands
Injections
Wounds and Injuries

Keywords

  • Cardiovascular diseases
  • Cell penetrating peptides
  • Endothelium targeting
  • Targeted delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Zhang, H., Li, N., Sirish, P., Mahakian, L., Ingham, E., Curry, F. R., ... Ferrara, K. W. (2012). The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium. Journal of Controlled Release, 163(1), 10-17. https://doi.org/10.1016/j.jconrel.2012.06.038

The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium. / Zhang, Hua; Li, Ning; Sirish, Padmini; Mahakian, Lisa; Ingham, Elizabeth; Curry, Fitz Roy; Yamada, Soichiro; Chiamvimonvat, Nipavan; Ferrara, Katherine W.

In: Journal of Controlled Release, Vol. 163, No. 1, 10.10.2012, p. 10-17.

Research output: Contribution to journalArticle

Zhang, H, Li, N, Sirish, P, Mahakian, L, Ingham, E, Curry, FR, Yamada, S, Chiamvimonvat, N & Ferrara, KW 2012, 'The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium', Journal of Controlled Release, vol. 163, no. 1, pp. 10-17. https://doi.org/10.1016/j.jconrel.2012.06.038
Zhang, Hua ; Li, Ning ; Sirish, Padmini ; Mahakian, Lisa ; Ingham, Elizabeth ; Curry, Fitz Roy ; Yamada, Soichiro ; Chiamvimonvat, Nipavan ; Ferrara, Katherine W. / The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium. In: Journal of Controlled Release. 2012 ; Vol. 163, No. 1. pp. 10-17.
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AU - Sirish, Padmini

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AU - Curry, Fitz Roy

AU - Yamada, Soichiro

AU - Chiamvimonvat, Nipavan

AU - Ferrara, Katherine W.

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AB - Ligand-conjugated liposomes and other nano-sized constructs are attractive drug carriers due to their extended plasma circulation; however, limited data are available as to whether their cargo can traverse the endothelium of solid organs. To determine whether the cargo of endothelially targeted liposomes is internalized by endothelial cells and transported into tissue, and to evaluate whether such liposomes can accumulate in models of cardiovascular disease, we tracked the fate of the cargo (a hydrophilic fluorescent dye) and shell (conjugated with a radioisotope) of a heart-homing liposome (CRPPR-conjugated). The ex vivo heart was imaged with confocal microscopy and the in vivo heart with positron emission tomography in sham-treated mice and models of ischemia/reperfusion (I/R) and myocardial infarction (MI). Within 30 min of injection of 20 mg/kg CRPPR liposomes, fluorescence increased by 47 fold in the tissue surrounding the vascular lumen, as compared with non-targeted liposomes. Both the accumulation on the endothelium and the interstitial fluorescence saturated at an injected dose of 20 mg/kg. In both I/R and MI models, CRPPR liposomes accumulated in diseased sites, although less than in surrounding healthy tissue. The accumulation in the diseased sites increased with time post-injury: the ratio of accumulated radioactivity in the diseased and healthy cardiac tissue increased from 0.20 ± 0.04, to 0.58 ± 0.12 and 0.61 ± 0.19 for 1, 7, and 99 days post-MI, indicating the potential for adequate delivery and therapeutic efficacy if the targeted particles are injected at 7 or more days post-MI. In summary, CRPPR- liposomes accumulated in normal and diseased hearts, and the cargo accumulated in the tissue within minutes and remained detectable after 24 h.

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