Ph-Sensitive and Pluronic-Modified Pullulan Nanogels for Greatly Improved Antitumor in Vivo

It remains a crucial challenge to achieve efficient cellular uptake in tumor cells for nanoscale drug delivery systems. This work described that two multi-functional pullulan nanogels were prepared by co-polymerization between methacrylated pullulan (Pullulan-M) and different crosslink agents, an acid-labile ortho ester-modified pluronic (L61-MOE) or non-acid-sensitive methacrylated pluronic (L61-M). The prepared nanogels showed a regular spherical structure with the size about 200 nm measured by dynamic light scattering and transmission electron microscopy (TEM). Doxorubicin as a model drug was successfully encapsulated into nanogels. As expected, Pul-L61-MOE showed pH-dependent DOX release, and 25% of DOX was released at pH 7.4 while 84.48% of DOX was released at pH 5.0. In vitro cellular uptake and MTT results indicated that pH-sensitive nanogels (Pul-L61-MOE) displayed higher cellular internalization and cytotoxicity than acid-insensitive nanogels (Pul-L61-M) and free DOX. Flow cytometry assay suggested these nanogels remarkably increased intracellular reactive oxygen species (ROS) level and induced more cell apoptosis by the function of pluronic. Finally, in vivo antitumor results indicated that the multi-functional nanogels exhibit supreme antitumor efficiency, and the tumor growth inhibition (TGI) was 83.37%. Therefore, the pH-sensitive pullulan nanogels can be potential nano-carriers for drug delivery in tumor treatment.