Programmable co-assembly of various drugs with temperature sensitive nanogels for optimizing combination chemotherapy

Combination chemotherapy, such as doxorubicin (Dox) plus cisplatin, based on co-assembling nanoparticles plays increasingly important role in the clinical treatment of cancer. But their synergistic antitumor effect is highly limited by unmatched release behavior of Dox and cisplatin. To enhance the synergistic antitumor effect of Dox and cisplatin, herein, an acidic triblock polymer (pAA100-b-pNIPAM200-b-pAA100, PNA) was developed as a temperature sensitive template for programmable fabrication of two antitumor drugs (Dox and cisplatin). In these co-assembly nanogels, Dox@PNA-Pt nanogels show compact 3D network cisplatin-shell surrounding Doxloading core, enabling parallel release of Dox and cisplatin, which is beneficial to maximizing the synergistic effect of Dox and cisplatin. Moreover, Dox@PNA-Pt nanogels could be efficiently internalized into tumor cells mainly by caveolin-mediated pathway. In in vivo evaluation on 4T1-bearing BALB/c mice, after single injection, Dox@PNA-Pt nanogels exhibited much stronger suppression of tumor growth, proliferation and metastasis, and induction of apoptosis and necrosis of tumor tissue/cells than Pt@PNA + Dox@PNA and Pt@PNA-Dox groups thanks to the parallel release of Dox and cisplatin. In addition, Dox@PNA-Pt nanogels showed a distinct transition from free-flowing sol to free-standing gel at critical gellating temperature (CGT), facilitating the long-term tumor retention and the optimally synergistic antitumor effect of Dox and cisplatin. The programmable fabrication with PNA was promising to be developed as an efficient approach for improving the antitumor efficacy of combination chemotherapy.