Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 32, Pages E6490-E6497Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1621240114
Keywords
siRNA delivery; RNAi; albumin binding; pharmacokinetics; tumor delivery
Categories
Funding
- NIH [NIH NIBIB R01EB019409]
- National Science Foundation (NSF) [BMAT 1349604]
- NSF Graduate Research Fellowship Program [1445191, 1445197, 0909667]
- Div Atmospheric & Geospace Sciences
- Directorate For Geosciences [1445191] Funding Source: National Science Foundation
- Division Of Materials Research
- Direct For Mathematical & Physical Scien [1349604] Funding Source: National Science Foundation
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Clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA's comprehensively poor pharmacokinetic properties, which necessitate molecule modifications and complex delivery strategies. We sought an alternative approach to commonly used nanoparticle carriers by leveraging the long-lived endogenous serum protein albumin as an siRNA carrier. We synthesized siRNA conjugated to a diacyl lipid moiety (siRNA-L2), which rapidly binds albumin in situ. siRNA-L2, in comparison with unmodified siRNA, exhibited a 5.7-fold increase in circulation half-life, an 8.6-fold increase in bioavailability, and reduced renal accumulation. Benchmarked against leading commercial siRNA nanocarrier in vivo jetPEI, siRNA-L2 achieved 19-fold greater tumor accumulation and 46-fold increase in per-tumor-cell uptake in a mouse orthotopic model of human triple-negative breast cancer. siRNA-L2 penetrated tumor tissue rapidly and homogeneously; 30 min after i.v. injection, siRNA-L2 achieved uptake in 99% of tumor cells, compared with 60% for jetPEI. Remarkably, siRNA-L2 achieved a tumor: liver accumulation ratio >40:1 vs. <3:1 for jetPEI. The improved pharmacokinetic properties of siRNA-L2 facilitated significant tumor gene silencing for 7 d after two i. v. doses. Proof-ofconceptwas extended to a patient-derived xenograftmodel, in which jetPEI tumor accumulation was reduced fourfold relative to the same formulation in the orthotopic model. The siRNA-L2 tumor accumulation diminished only twofold, suggesting that the superior tumor distribution of the conjugate over nanoparticles will be accentuated in clinical situations. These data reveal the immense promise of in situ albumin targeting for development of translational, carrier-free RNAibased cancer therapies.
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