The limited penetration of nanoparticles and their poor accessibility to cancer cell fractions in tumor remain essential challenges for effective anticancer therapy. Herein, we designed a targeting peptide-decorated biomimetic lipoprotein (termed as BL-RD) to enable their deep penetration and efficient accessibility to cancer cell fractions in a tumor, thereby improving the combinational chemo-photodynamic therapy of triple negative breast cancer. BL-RD was composed of phospholipids, apolipoprotein A1 mimetic peptide (PK22), targeting peptide-conjugated cytotoxic mertansine (RM) and photodynamic agents of DiIC18(5) (DiD). The counterpart biomimetic lipoprotein system without RM (termed as BL-D) was fabricated as control. Both BL-D and BL-RD were nanometer-sized particles with a mean diameter of less than 30 nm and could be efficiently internalized by cancer cells. After intravenous injection, they can be specifically accumulated at tumor sites. When comparing to the counterpart BL-D, BL-RD displayed superior capability to permeate across the tumor mass, extravasate from tumor vasculature to distant regions and efficiently access the cancer cell fractions in a solid tumor, thus producing noticeable depression of the tumor growth. Taken together, BL-RD can be a promising delivery nanoplatform with prominent tumor-penetrating and cancer cells-accessing capability for effective tumor therapy.
Keywords: 4T1-GFP, 4T1 cancer cells with stable expression of green fluorescence protein; ApoA1, apolipoprotein A1; BL-D, biomimetic lipoprotein system without targeting peptide; BL-RD, targeting peptide decorated biomimetic lipoprotein system; CAF, cancer-associated fibroblasts; CLSM, confocal laser scanning microscopy; Cancer therapy; DAPI, 4′,6-diamidino-2-phenylindole; DCFH-DA, 2′,7′-dichlorodihydrofluorescein diacetate; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; DiD, DiIC18(5); Drug delivery; EC, endothelial cells; ECM, extracellular matrix; EE, encapsulation efficiency; FBS, fetal bovine serum; GSH, glutathione; H&E staining, hematoxylin-eosin staining; HDL, high density lipoprotein; HPLC, high performance liquid chromatography; IC50, half-inhibitory concentration; Lipo-D, liposome system without targeting peptide; Lipo-RD, targeting peptide decorated biomimetic lipoprotein system; Lipoprotein; MCS, multicellular spheroids; MTT, thiazolyl blue tetrazolium bromide; Nanoparticles; PBS, phosphate buffered solution; PDT, photodynamic therapy; RM, targeting peptide-conjugated cytotoxic mertansine; ROS, reactive oxygen species; SOSG, singlet oxygen sensor green; TAM, tumor-associated macrophage; TEM, transmission electronic microscope; TGI, tumor growth index; Tumor penetration; α-SMA, α-smooth muscle actin.
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