Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release

Shaobo Ruan, Xi Cao, Xingli Cun, Guanlian Hu, Yi Zhou, Yijia Zhang, Libao Lu, Qin He, Huile Gao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

262 Citations (Scopus)

Abstract

Nanocarriers are widely used for delivering drugs to tumors and are progressing in a stable trend. The enhanced permeability and retention (EPR) effect has been a key rationale for the development of stimulus-responsive nanocarriers to solid tumor. In this study, we developed a kind of novel nanocarrier, G-AuNPs-DOX-PEG, which was constructed with shrinkable gelatin nanoparticles coated, doxorubicin (DOX) tethered gold nanoparticles and long chain polyethylene glycol (PEG). The particle size of G-AuNPs-DOX-PEG was 186.5nm with a zeta potential of-4.21mV and the DOX loading capacity was 9.22%. Invitro, the G-AuNPs-DOX-PEG could be degraded by MMP-2 proteins with a size shrink from 186.5nm to 59.3nm. The release of DOX from G-AuNPs-DOX-PEG was in a pH- and time-dependent manner. At pH 5.0, the release of DOX was much quicker than that at high pH value and the cumulative release rate of DOX from G-AuNPs-DOX-PEG was approach 90.9%. Cellular uptake demonstrated that G-AuNPs-DOX-PEG could be internalized via the endosome-mediated pathway. Tumor spheroid penetration and collagen gel diffusion showed G-AuNPs-DOX-PEG with pre-incubation with MMP-2 could significantly enhance its penetrating efficiency. Invivo and exvivo imaging exhibit that G-AuNPs-DOX-PEG could distribute into 4T1 and B16F10 tumor at a highest intensity. Correspondingly, 4T1 and B16F10 tumor bearing mice treated with G-AuNPs-DOX-PEG displayed the lowest tumor growth rate. In summary, the tumor microenvironment sensitive size-shrinkable G-AuNPs-DOX-PEG could deliver into deep tumor region and then release DOX, resulting in a best anti-tumor effect.

Original languageEnglish
Pages (from-to)100-110
Number of pages11
JournalBiomaterials
Volume60
DOIs
Publication statusPublished - 1 Aug 2015
Externally publishedYes

Keywords

  • Deep penetration
  • Gelatin nanoparticle
  • Gold nanoparticle
  • Matrix metalloproteinase
  • PH release
  • Size-shrinkable

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Ruan, S., Cao, X., Cun, X., Hu, G., Zhou, Y., Zhang, Y., Lu, L., He, Q., & Gao, H. (2015). Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release. Biomaterials, 60, 100-110. https://doi.org/10.1016/j.biomaterials.2015.05.006