Matrix metalloproteinase-cleavable nanocapsules for tumor-activated drug release

In the war against cancer, nanotechnology-based drug delivery systems may play a significant role by enhancing the efficacy of conventional therapies. Here, we tried to address some major limitations plaguing anticancer drugs, namely, poor water solubility and off-target toxicity. The systems we propose are cross-linked polyelectrolyte nanocapsules based on an oil-core and a matrix metalloproteinase-2 (MMP-2)-cleavable shell. They can load hydrophobic drugs, prevent their systemic leakage, and release their payload upon an endogenous stimulus. Both the stability enhancement and the stimuli-responsive drug release mechanisms were achieved by cross-linking the nanocapsule shell with an MMP-2-sensitive peptide. On the basis of this strategy, the system maintained its stability in PBS up to one month. Further, when tested on 3D tumor and healthy spheroid models, the nanocapsules were able to disrupt their integrity preferentially in the tumor-like microenvironment. The high level of MMP-2 enzymes expressed by tumor spheroids, indeed, catalyzed the disassembly of the nanocapsules, which ultimately leads to drug release. Therefore, this device holds great potential as a smart system that allows for the safe transport of hydrophobic drugs and for a spatially controlled release upon an endogenous stimulus coming from the very nature of the tumor itself. STATEMENT OF SIGNIFICANCE: The performance of nanoparticle-based therapeutic approaches is often hindered by some intrinsic limitations typically including laborious drug loading methods, synthetic routes of preparation and stability issues. In this work, we implemented for the first time a smart drug delivery strategy into oil-core multilayer nanocapsules, which represent an ideal family of nanocarriers. To this aim, we developed a robust method enabling the use of soft matters like oil-core nanocapsules combined with a microenvironmentally triggered release mechanism. The efficacy of nanocapsules was tested on tumor and healthy spheroids. Results clearly demonstrate their selective drug release, triggered by a stimulus intrinsically present in tumor microenvironment. We believe this study is of particular interest for cancer research and paves the way for the use of these robust stimuli-responsive nanocapsules in vivo.