MMP-2-Sensitive HA End-Conjugated Poly(amidoamine) Dendrimers via Click Reaction To Enhance Drug Penetration into Solid Tumor

Currently, the limited penetration of nano particles remains a major challenge for antitumor nano medicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of pOly(amidoamine) (PAMAM), using a matrix metalioproteinase-2,(MMP-2),cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of similar to 200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (i-10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusion and penetration. We have further conducted comparative studies of MMP-2sensitive macromolecules (HA-pep-PAMAM) and MMP-2-insensitive macromolecules (HA PAMAM) synthesized with a similar particle size, surface charge, and chemical composition and evaluated in both monolayer cells and multicellular spheroids. The results confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy. Meanwhile,, macromolecule-based nanoparticles with size-variable characteristics not only promote drug penetration, but they can also. be used as gene delivery systems, suggesting great potential as nano-delivery systems.