Polyethylenimine-Dermatan Sulfate Complex, a Bioactive Biomaterial with Unique Toxicity to CD146-Positive Cancer Cells

Abstract

We report unique bioactivity of a polycation-polyanion complex with potential utility for cancer therapy. A complex of disulfide-crosslinked polyethyleneimine (CLPEI), a polycation used for gene complexation, and dermatan sulfate (DS), an anionic polysaccharide to shield excessive cationic charge of the former, has toxicity to a specific group of cancer cell lines, including B16-F10 murine melanoma, A375SM human melanoma, and PC-3 human prostate cancer cells. These CLPEI-DS-sensitive cells express CD146, which binds to the complex via interaction with DS. There is a positive correlation between toxicity and intracellular level of CLPEI, indicating that the CLPEI-DS-sensitivity is attributable to the increased cellular uptake of CLPEI mediated by the DS-CD146 interactions. In vitro studies show that CLPEI-DS complex causes G0/G1 phase arrest and apoptotic cell death. In syngeneic and allograft models of B16-F10 melanoma, CLPEI-DS complex administered with a sub-toxic level of doxorubicin potentiates the chemotherapeutic effect of the drug by loosening tumor tissues. Given the unique toxicity, CLPEI-DS complex may be a useful carrier of gene or chemotherapeutics for the therapy of CD146-positive cancers.

Programmed Cell Death Protein Ligand-1 Silencing with Polyethylenimine–Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth

“…14 To confirm the melanoma-specific uptake, the complex containing Cy5-labeled siRNA was incubated with B16F10 melanoma and NIH 3T3 fibroblasts. Both fluorescence microscopy and flow cytometry supported that siRNA/pd interacted with B16F10 cells (Figure 2a, b) but not with NIH 3T3 cells (Figure S1a, b).…”

“…However, the ternary complex prepared with the DS/CLPEI ratio of 2 showed greater toxicity than the binary complex (Figure 1f), consistent with our earlier observation. 14 As the toxicity of the ternary complex is specific to B16F10 cells and desirable for therapeutic purpose, a ternary complex with a weight ratio of 1:2:4 siRNA/ CLPEI/DS was chosen for this study. Transmission electron microscopy (TEM) found the siRNA/pd ternary complex to have a spherical shape with a diameter between 200 and 250 nm (Figure 1g,h), slightly smaller than the DLS measurement, likely due to dehydration of the particles during the sample preparation.…”

“…We used the CLPEI/DS (pd) complex as the carrier of siPD-L1 due to the safety and specific toxicity to CD146 + tumor cells observed in our previous study. 14 The in vitro PD-L1 silencing by siPD-L1/pd complex was examined with IFN-γ-treated B16F10 melanoma and NIH 3T3 fibroblast cells. As expected from the previous study, siPD-L1/pd complex transfected CD146 + B16F10 cells and decreased their expression of PD-L1 (Figure 2) but did not affect NIH 3T3 cells.…”

“…The CLPEI/DS (dubbed "pd") complex has specific toxicity to a group of cancer cells that express CD146, including B16F10 melanoma cells, which is an advantage compared to other polymeric gene carriers. 14 In this study, we hypothesize that siPD-L1 delivered by the pd complex can suppress melanoma growth via multiple mechanisms, including the melanoma-specific toxicity of pd complex and intrinsic and extrinsic antitumor effects of PD-1/ PD-L1 blockade. With B16F10 murine melanoma cells and tumor models in immune-competent and immune-compromised mice, we demonstrate that siPDL1/pd reduces the expression of PD-L1 in tumors and attenuates tumor growth by promoting cytotoxic T-cell immunity and suppressing the mTOR pathway.…”

“…The CLPEI/DS (dubbed “pd”) complex has specific toxicity to a group of cancer cells that express CD146, including B16F10 melanoma cells, which is an advantage compared to other polymeric gene carriers. 14 …”