A dual strategy to improve the penetration and treatment of breast cancer by combining shrinking nanoparticles with collagen depletion by losartan

Although development of nanomedicines has been a promising direction in tumor treatment, the therapeutic outcome of current nanomedicines is unsatisfying, partly because of the poor retention and penetration in tumors. Recently, a kind of tumor microenvironment sensitive size shrinkable nanoparticles (DOX-AuNPs-GNPs) has been developed by our lab, which could enhance the tumor penetration and retention depending on the size shrinking. However, the further enhancement is still restricted by dense collagen network in tumors. Thus in this study, we combined DOX-AuNPs-GNPs with losartan to deplete tumor collagen (constituted up to 90% of extracellular matrix) to further improve tumor penetration. In vitro, DOX-AuNPs-GNPs can shrink from over 117.8 nm to less than 50.0 nm and release DOX-AuNPs under the triggering of tumor overexpressed matrix metalloproteinases-2 (MMP-2). In vivo, pretreatment with losartan significantly decrease the collagen level and improve the tumor penetration. In combination, losartan combined with DOX-AuNPs-GNPs showed the best drug delivery efficiency, striking penetration efficiency and best 4T1 breast tumor inhibition effect. In conclusion, this study provided a promising synergetic strategy to improve the tumor treatment efficiency of nanomedicines. Statement of significance We have developed a dual strategy for deep tumor penetration through combining size shrinkable DOX-AuNPs-GNPs with depleting tumor collagen by losartan. Additionally, we demonstrate therapeutic efficacy in breast tumor bearing mouse model. DOX-AuNPs-GNPs co-administration with losartan is a novel and highly attractive strategy for anti-tumor drug delivery with the potential for broad applications in clinic.