Leveraging nanochannels for universal, zero-order drug delivery in vivo
2013
Ferrati, Silvia | Fine, Daniel | You, Junping | De Rosa, Enrica | Hudson, Lee | Zabre, Erika | Hosali, Sharath | Zhang, Li | Hickman, Catherine | Sunder Bansal, Shyam | Cordero-Reyes, Andrea M. | Geninatti, Thomas | Sih, Juliana | Goodall, Randy | Palapattu, Ganesh | Kloc, Malgorzata | Ghobrial, Rafik M. | Ferrari, Mauro | Grattoni, Alessandro
Drug delivery is essential to achieve effective therapy. Herein we report on the only implantable nanochannel membrane with geometrically defined channels as small as 2.5nm that achieves constant drug delivery in vivo. Nanochannels passively control the release of molecules by physico-electrostatic confinement, thereby leading to constant drug diffusion. We utilize a novel design algorithm to select the optimal nanochannel size for each therapeutic agent. Using nanochannels as small as 3.6 and 20nm, we achieve sustained and constant plasma levels of leuprolide, interferon α-2b, letrozole, Y-27632, octreotide, and human growth hormone, all delivered at clinically-relevant doses. The device was demonstrated in dogs, rats, and mice and was capable of sustaining target doses for up to 70days. To provide evidence of therapeutic efficacy, we successfully combined nanochannel delivery with a RhoA pathway inhibitor to prevent chronic rejection of cardiac allografts in a rat model. Our results provide evidence that the nanochannel platform has the potential to dramatically improve long-term therapies for chronic conditions.
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