Editors' ChoiceCancer Nanotechnology

Efficacy by design

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Science Translational Medicine  23 Dec 2015:
Vol. 7, Issue 319, pp. 319ec219
DOI: 10.1126/scitranslmed.aad9011

Tumors in patients with triple-negative breast cancer (TNBC) are nonresponsive to the most common forms of chemotherapy. Researchers recently identified two small endogenous microRNA molecules (miRs) that differentially regulate tumor progression in TNBC. Delivery of antagonistic or complementary miRs to control these targets holds potential to treat TNBC, but a lack of stability in the body limits their therapeutic potential. Conde et al. set out to design a miR delivery strategy that uses the structure of the miRs themselves in combination with new biomaterials to enhance the stability and efficacy of the miRs.

The team combined a miR mimic to replace endogenous miR-205, which is reduced in TNBC, with another that antagonizes the function of miR-221, which is increased in TNBC, thus targeting two separate pathways involved in tumor progression. They carefully controlled processing conditions to ensure self-assembly of the miRs into a stable triple helix structure and incorporated fluorescent dyes to allow easy tracking in subsequent experiments. The structures of the miR complexes were further stabilized through combination with small, branched synthetic molecules called dendrimers to form nanoparticles. This enhanced stability led to increased uptake by cancer cells in vitro compared with double helix nanoparticles, resulting in reduced cell viability, migration, and proliferation. Then, to establish efficacy in a mouse model of TNBC, the nanoparticles were packaged into an adhesive hydrogel designed to coat tumors for enhanced penetration. Implanted adjacent to the tumors, the miR–triple helix–hydrogel constructs caused 90% tumor-size reduction over 13 days and significantly enhanced long-term survival, greatly outperforming chemotherapy drugs that represent the current standard of care for breast cancer. Remarkably, accumulation of the triplex nanoparticles was restricted exclusively to the tumor tissue, avoiding all major organs, a challenge in the therapeutic delivery of nanoparticles. Last, the team used a genetic expression screen to pinpoint the therapy’s main mechanisms of action, which will be critical to successful clinical translation.

Evaluation of this strategy to treat human breast cancer in mice required the use of immunodeficient animals, so future studies will require rigorous evaluation of the immune response to the miR–biomaterial constructs. Nonetheless, this report establishes an effective therapeutic-development platform for treating notoriously difficult forms of cancer.

J. Conde et al., Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment. Nat. Mater. 10.1038/nmat4497 (2015). [Abstract]

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