Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

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.

Nuclear-cytoplasmic interaction QTL mapping of the lipoprotein and cholesterol traits in mice / 中国比较医学杂志

Objective To study the cholesterol nuclear-cytoplasmic interaction effect and position cholesterol traits QTL in mice.Methods Improving the nuclear-cytoplasmic interaction models and methods that have been constructed, and analyzing the public database of total cholesterol and lipoprotein data of F2 group that derived from DBA/2J ( D2) and CAST/EiJ ( CAST) mice.Results Six QTL that controlling total cholesterol, HDL and nonHDL were located in 4 linkage groups in the genome.In the models constructed in this study, we found a QTL has significant interaction with cytoplasmic background, which changes the previous results of data analysis, the genetic mouse cholesterol and lipoprotein components opened up new ideas.Conclusion Mouse cholesterol trait is the result of interaction of nuclear genes and cytoplasmic background.