Receptor and Microenvironment Dual-Recognizable Nanogel for Targeted Chemotherapy of Highly Metastatic Malignancy.

Targeted delivery of chemotherapeutic drugs to the desired lesion sites is the main objective in malignancy treatment, especially in highly metastatic malignancies. However, extensive studies around the world on traditional targeting strategies of recognizing either overexpressed receptors or microenvironments in tumors show great limitations, owing to the off-target effect and tumor homogeneity. Integration of both receptor-mediated targeting (RMT) and environment-mediated targeting (EMT) enhances the tumor accumulation and subsequent cell uptake at the same time, which may avoid these limitations. Herein, a dual targeting nanogel of PMNG engineered with both phenylboronic acid (PBA) and morpholine (MP) was reported for not only RMT via specific recognition of sialyl (SA) epitopes but also EMT toward extracellular acidity. Further engineering the nanoparticles via loading doxorubicin (DOX) brought a novel dual targeting system, that is, PMNG/DOX. PMNG/DOX demonstrated a greater targeting effect to both primary and metastatic B16F10 melanoma than the single PBA-modified nanogel (PNG) with only RMT in vitro and in vivo. Moreover, PMNG/DOX was also proved to be highly potent on inhibiting primary tumor growth as well as tumor metastasis on B16F10 melanoma-grafted mouse model. The results demonstrated the dual targeting design as a translational approach for drug delivery to highly metastatic tumor.