Hybrid pH-sensitive nanogels surface-functionalized with collagenase for enhanced tumor penetration.

Densely extracellular matrix (ECM) is one of the main barriers that hinder the penetration of drug into tumor parenchyma, compromising the therapeutic activity. In this work, alginic acid was copolymerized with an acid-labile monomer to give the acid-degradable nanogels (ALG NG), which was then immobilized with collagenase to obtain the surface-functionalized nanogels (Co@ALG NG). The introduction of collagenase would enhance the diffusion ability of nanogels in tumor parenchyma based on the hydrolytic activity to tumor ECM. The stability of these nanogels in various physiological environment and the pH-triggered degradation and drug release at different pH were then investigated. Monolayer cell and tumor-like spheroids were used to illustrate the penetration and drug delivery. In vivo drug distribution and antitumor efficiency of these nanogels were investigated using H22 tumor-bearing mice. The immobilization of collagenase significantly enhance the nanogels' penetration and diffusion ability in tumor area upon the digestion of tumor ECM, leading to higher drug concentration and superior antitumor effect.