A new tandem peptide modified liposomal doxorubicin for tumor “ecological therapy”
The tumor microenvironment (TME) acts as an ecosystem that includes not only tumor cells but also stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). In addition, the abnormal extracellular environment (ECM) of which the mechanical forces are regulated by fibronectin (Fn) and collagen I orchestrates tumorigenesis and progression by directly promoting invasion and cellular transformation of the ecosystem. Herein, we developed a novel peptide-modified liposome incorporated into doxorubicin (FnBPA5-AAN-Dox) as an ecological therapy system, which targets to not only cellular compartment but also non-cellular components for breast cancer. FnBPA5 is a Fn-binding peptide showing high affinity with relaxed Fn and collagen I in ECM as well as α-SMA-expressing CAFs. However, the fast clearance by Fn-excreting organs such as liver and spleen limits the accumulation of FnBPA5-Dox at TME. AAN peptide, which targets to legumain overexpressed in the TAMs, could extend the circulation time and improve therapeutic response as well as modulate tumor immune microenvironment (TMIE). Given twice at an equivalent dose of 5 mg/kg by i.v., the multi-in-one ‘ecological therapy’ applied in AAN-FnBPA5-Dox showed excellent antitumor efficacy in 4T1 breast cancer mice, and the tumor growth inhibition (TGI) is up to 98.20 % compared with saline. Immunofluorescence, flow cytometry and RT-PCR results revealed that the dramatic improvement in antitumor efficacy was attributed to the multifunctional targets of the drug delivery system.