CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels.

Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28 ± 10.42 nm and zeta potential of -15.7 ± 3.32 mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, in vitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by in vivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK-NP. The findings here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone.