Lipoproteins LDL versus HDL as nanocarriers to target either cancer cells or macrophages
Tarik Hadi, … , Carmen Garrido, Frederic Lirussi
Tarik Hadi, … , Carmen Garrido, Frederic Lirussi
Published November 30, 2020
Citation Information: JCI Insight. 2020;5(24):e140280. https://doi.org/10.1172/jci.insight.140280.
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Research Article Oncology Therapeutics

Lipoproteins LDL versus HDL as nanocarriers to target either cancer cells or macrophages

Abstract

In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL, respectively) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupling of the drugs to lipoproteins and stability was assessed by mass spectometry and raman spectrometry analysis. Cisplatin vectorized in LDLs led to better tumor growth suppression with strongly reduced adverse effects such as renal or liver toxicity. AC1LINNC vectorized into HDLs induced a strong oxidative burst in macrophages and innate anticancer immune response. Cumulative antitumor effect was observed for both drug-loaded lipoproteins. Altogether, our data show that lipoproteins from patient blood can be used as natural nanocarriers allowing cell-specific targeting, paving the way toward more efficient, safer, and personalized use of chemotherapeutic and immunotherapeutic drugs in cancer.

Authors

Tarik Hadi, Christophe Ramseyer, Thomas Gautier, Pierre-Simon Bellaye, Tatiana Lopez, Antonin Schmitt, Sarah Foley, Semen Yesylevskyy, Thibault Minervini, Romain Douhard, Lucile Dondaine, Lil Proukhnitzky, Samir Messaoudi, Maeva Wendremaire, Mathieu Moreau, Fabrice Neiers, Bertrand Collin, Franck Denat, Laurent Lagrost, Carmen Garrido, Frederic Lirussi

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Figure 6

LDL vectorization of cisplatin diminishes cisplatin adverse effects.

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LDL vectorization of cisplatin diminishes cisplatin adverse effects. (A)...
(A) Balb/c mice were injected with CT-26 colorectal cancer cells (1 × 106 cells/mice, s.c.). When tumors reached approximately 300 mm3 (by day 10), mice were i.p. injected with either LDL-PBS (100 μM cholesterol, n = 4), cisplatin (20 mg/kg, n = 5), or LDL-Cis (100 μM cholesterol, 20 mg/kg cisplatin, n = 5). (B and C) Mice were euthanized 4 days later, and weight loss (B) and tumor volume (C) were determined. Data are represented as mean value ± SEM. **P < 0.01, ***P < 0.001; arrow indicates first injection. (D) To evaluate cisplatin nephrotoxicity, kidney samples were recovered for IHC H&E staining. Total magnification was 10 × 20. Images, taken in random fields, are representative of 5 pictures taken for each condition. n = 4–5 mice per group. (E) Quantification of the percentage of lesion area reported to total field area (black arrow) is represented as mean value ± SEM. **P < 0.01. (F) Apoptosis in organs was assessed by immunofluorescence in kidney and liver. Histological slides were labeled with a cleaved caspase-3 antibody (green) and with DAPI. Images are representative of 5 pictures taken for each condition. n = 4. Scale bar: 20 μm. (G and H) Quantifications of the immunofluorescence intensity of cleaved caspase-3 in kidneys (G) or tumor (H) sections. Data are represented as mean increase versus PBS ± SEM. n = 4–5 mice per group. **P < 0.01, ***P < 0.001. P values were calculated using 1-way ANOVA.