Porous Silicon Nanocarriers with Stimulus-Cleavable Linkers for Effective Cancer Therapy

Porous silicon nanoparticles (pSiNPs) are widely utilized as drug carriers due to their excellent biocompatibility, large surface area, and versatile surface chemistry. However, the dispersion in pore size and biodegradability of pSiNPs arguably have hindered the application of pSiNPs for controlled drug release. Here, a step-changing solution to this problem is described involving the design, synthesis, and application of three different linker-drug conjugates comprising anticancer drug doxorubicin (DOX) and different stimulus-cleavable linkers (SCLs) including the photocleavable linker (ortho-nitrobenzyl), pH-cleavable linker (hydrazone), and enzyme-cleavable linker (β-glucuronide). These SCL-DOX conjugates are covalently attached to the surface of pSiNP via copper (I)-catalyzed alkyne-azide cycloaddition (CuAAC, i.e., click reaction) to afford pSiNP-SCL-DOXs. The mass loading of the covalent conjugation approach for pSiNP-SCL-DOX reaches over 250 µg of DOX per mg of pSiNPs, which is notably twice the mass loading achieved by noncovalent loading. Moreover, the covalent conjugation between SCL-DOX and pSiNPs endows the pSiNPs with excellent stability and highly controlled release behavior. When tested in both in vitro and in vivo tumor models, the pSiNP-SCL-DOXs induces excellent tumor growth inhibition.