4-Carboxyphenylboronic acid-decorated, redox-sensitive rod-shaped nano-micelles fabricated through co-assembling strategy for active targeting and synergistic co-delivery of camptothecin and gemcitabine

To achieve redox-controlled and tumor active targeting synergistic self-delivery of camptothecin and gemcitabine, redox-sensitive rod-shaped nano-micelles are fabricated through co-assembling between camptothecin-disulfide bond-PEG₂₀₀₀-4-carboxyphenylboronic acid and camptothecin-disulfide bond-gemcitabine conjugate. Most of all, for multidrug resistant cancer cell line MCF-7/ADR which is more resistant against CPT, increasing content of CPT in the formulation is favorable for synergistic effect of CPT and GEM drug combination. Benefiting from simple co-assembling strategy, it is easy and convenient to adjust drug ratio of CPT/GEM to optimize the synergism of drug combination. In addition, nano-micelles fabricated from co-assembling are endowed with both high absolute drug concentration and enhanced colloidal stability, which is helpful to in vivo studies. Transmission electron microscopy observation confirmed the rod-shaped morphology, which is beneficial to cellular internalization, of co-assembled nano-micelles resulting from π-π stacking interactions of CPT moieties and appropriate hydrophilic and hydrophobic interactions during co-assembling. Taking advantages of the specific interactions between 4-carboxyphenylboronic acid and sialic acid, co-assembled nano-micelles exerted enhanced cellular internalization. Noteworthy, compared with cocktail mixture of free CPT and GEM, nano-micelles greatly alleviated drug reflux against MCF-7/ADR and 4T1 cells. The nano-micelles realized redox-controlled ratio-metric and synchronous delivery of CPT and GEM, thereby pronounced in vitro synergistic antiproliferative effect against MCF-7/ADR and 4T1cells. Furthermore, in vivo bio-distribution analysis indicated the preferential accumulation of nano-micelles at tumor site, which could increase therapeutic efficacy and decrease side effects of non-selective anticancer drugs. Taken together, the redox-sensitive CPBA decorated co-assembled nano-micelles provided a promising strategy for tumor active targeting and redox-controlled intracellular synergistic combinational delivery of chemotherapeutics.