Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment.
10.1016/j.apsb.2020.10.015
- Author:
Naveed Ullah KHAN
1
;
Jiang NI
1
;
Xiufeng JU
1
;
Tongtong MIAO
1
;
Haiyan CHEN
1
;
Liang HAN
1
Author Information
1. Jiangsu Key Laboratory of Neuropsychiatric Diseases Research and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
- Publication Type:Journal Article
- Keywords:
231Br, MDA-MB-231Br-HER2;
A, angiopep-2;
AUC0‒t, area under the curve from zero to time t;
Abluminal LRP1;
Amyloid beta;
Aβ, amyloid beta;
BBB, blood‒brain barrier;
BCBMs, breast cancer brain metastases;
BMECs, brain microvascular endothelial cells;
Blood‒brain barrier;
Brain clearance;
Breast cancer brain metastases;
CI, combination index;
CL, clearance;
DMEM, Dulbecco's modified eagle medium;
DMSO, dimethyl sulfoxide;
DOX, doxorubicin;
FBS, fetal bovine serum;
Fa, the fraction of tumor cells affected;
Fusion peptide;
K, KAAYSL;
LAP, lapatinib;
LRP1, low density lipoprotein receptor-related protein 1;
MAL-PEG-SCM, maleimide polyethylene glycol succinimidyl carboxymethyl ester;
MCM, MDA-MB-231Br-HER2 conditioned medium;
MMP;
MMP1, matrix metalloproteinase-1;
MRT0‒t, mean residence time from zero to time t;
NPs, nanoparticles;
Nanoparticles;
PLGA, poly(lactic-co-glycolic acid);
PLGA-PLL, poly(lactic-co-glycolic acid)-poly(ε-carbobenzoxy-l-lysine);
PLL, poly(ε-carbobenzoxy-l-lysine);
PVA, polyvinyl alcohol;
SDS, sodium dodecyl sulfate;
i, insensitive GDQGIAGF;
s, sensitive VPMS-MRGG;
t1/2, half time;
tPA, tissue plasminogen activator
- From:
Acta Pharmaceutica Sinica B
2021;11(5):1341-1354
- CountryChina
- Language:English
-
Abstract:
Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.
