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

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.

Fate of cisplatin and its main hydrolysed forms in the presence of thiolates: a comprehensive computational and experimental study.

Interaction of platinum-based drugs with proteins containing sulphur amino acids is usually argued as one of the major reasons for the observed resistance to these drugs, mainly due to the deactivation of the native compounds by very efficient thiolation processes in the organism. In this work, we have investigated the detailed thermodynamics and kinetics of reaction between cisplatin cis-[PtCl2(NH3)2] and its major hydrolysed forms (monohydroxocisplatin cis-[PtCl(OH)(NH3)2] and monoaquacisplatin cis-[PtCl(H2O)(NH3)2]+) with various thiolates (methanethiolate, cysteine and glutathione) and methionine. We have used a demanding quantum chemistry approach at the MP2 and DFT levels of theory to determine the Gibbs free energies and the barrier of reactions of the most possible reaction paths. The substitution of the four ligands of the complexes studied here (Cl-, OH-, H2O and NH3) can either proceed by direct thiolations or bidentations. Our Raman spectroscopy measurements show that only two thiolations actually occur, although four are possible in principle. The reason could lie in the bidentation reactions eventually taking place after each thiolation, which is backed up by our computational results. The observed lability scale of the ligands under thiolate exposure was found to be in the following order H2O > Cl- ≈ NH3(trans) > NH3(cis) > OH-, the difference between ammine ligands being induced by a significant trans-labilization by thiolates. Finally, the S,N bidentation is shown to be preferred with respect to the S,O one.