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 language | English (US) |
|---|---|
| Pages (from-to) | 10-17 |
| Number of pages | 8 |
| Journal | Journal of Controlled Release |
| Volume | 163 |
| Issue number | 1 |
| DOIs | |
| State | Published - Oct 10 2012 |
Fingerprint
Keywords
- Cardiovascular diseases
- Cell penetrating peptides
- Endothelium targeting
- Targeted delivery
ASJC Scopus subject areas
- Pharmaceutical Science
Cite this
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 journal › Article
}
TY - JOUR
T1 - The cargo of CRPPR-conjugated liposomes crosses the intact murine cardiac endothelium
AU - Zhang, Hua
AU - Li, Ning
AU - Sirish, Padmini
AU - Mahakian, Lisa
AU - Ingham, Elizabeth
AU - Curry, Fitz Roy
AU - Yamada, Soichiro
AU - Chiamvimonvat, Nipavan
AU - Ferrara, Katherine W.
PY - 2012/10/10
Y1 - 2012/10/10
N2 - 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.
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.
KW - Cardiovascular diseases
KW - Cell penetrating peptides
KW - Endothelium targeting
KW - Targeted delivery
UR - http://www.scopus.com/inward/record.url?scp=84866737862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866737862&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2012.06.038
DO - 10.1016/j.jconrel.2012.06.038
M3 - Article
C2 - 22776291
AN - SCOPUS:84866737862
VL - 163
SP - 10
EP - 17
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 1
ER -