Acid–degradable carboxymethyl chitosan nanogels via an ortho ester linkage mediated improved penetration and growth inhibition of 3-D tumor spheroids in vitro

This work describes an acid–degradable and tumor–targeted nanogels prepared by the copolymerization between lactobionic acid-modified methacrylated carboxymethyl chitosan and acid–labile methacrylated orthoester–based monomers. The size distribution and micromorphology of the prepared nanogels were observed by dynamic light scattering, transmission electron microscopy and scanning electron microscopy. The stability of nanogels in various environments was then investigated. Doxorubicin as a model drug was successfully encapsulated into nanogels. In vitro cellular uptake and MTT results indicate that the tumor–targeting and pH–sensitive nanogels display higher cellular internalization and cytotoxicity than non–target nanogels and free DOX. The improved penetration and growth inhibition against 3–D multicellular spheroids further demonstrate that the dual–functional nanogels may be a potential nano-carrier for drug delivery in cancer therapy. - Highlights: • Carboxymethyl chitosan nanogels with pH-sensitive and tumor-targeting ability were prepared. • DOX-loaded nanogels show good stability in various physiological conditions. • The degradation and in vitro drug release of these nanogels are pH-dependent. • Nanogels show higher uptake and cytotoxicity in vitro. • Targeting antitumor effect is obtained in 3-D cell models.