Yun-Long Wu, Caisheng Wu | Chemical Engineering Journal: Engineered celastrol and plasmid co-delivery for in situ expression and targeted mitochondrial relocation of Nur77 protein towards effective drug resistance reversion

Highlights

Codelivery of celastrol to promote Nur77 gene expression.

Codelivery of celastrol to direct Nur77 protein’s mitochondria relocation.

Codelivery strategy to increase drug sensitivity in drug resistance cancer cells.

Activating mitochondrial dysfunction in Bcl-2 overexpression cancer cells.

A complementary strategy of combining chemotherapy and gene therapy.

Overexpression of Bcl-2 (B-cell lymphoma-2) is one of the important reasons for the drug resistance of tumor cells, which often leads to the failure of clinical cancer treatment. In recent years, studies have shown that the nuclear orphan receptor Nur77 can interact with Bcl-2 to change the Bcl-2 protein from an anti-apoptotic conformation to a pro-apoptotic conformation, thereby inducing apoptosis. However, since Nur77 needs to migrate from the nucleus to the mitochondria to reverse the anti-apoptotic effect of Bcl-2, it is difficult to effectively activate the Nur77-Bcl-2 apoptotic pathway by the existing system. Herein, we design an intelligent drug delivery system (PPP/Nur77/Cela) in which drug molecular-guided gene expression products actively act on Bcl-2 proteins, which consists of a mPEG-PCL-PEI (methoxy poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene imine), or PPP) polymer loaded with Nur77 gene and celastrol (Cela) via electrostatic and hydrophobic interactions. The system can effectively improve solubility and toxicity of Cela, and can express Nur77 efficiently in cells with a gene transfection efficiency comparable to that of PEI. Interestingly, besides being an anticancer drug, Cela can also promote Nur77 to transfer to mitochondria and convert Bcl-2 from anti-apoptotic protein to pro-apoptotic protein, thereby increasing the sensitivity of Bcl-2 overexpression cancer cells to drugs, which achieves efficient cancer treatment through complementary synergistic chemotherapy and gene therapy. To the best of our knowledge, this is a pioneering strategy to use drug molecules to guide gene expression products to actively act on target proteins, which is a truly successful realization of complementary intensive chemotherapy and gene therapy in the treatment of drug-resistant tumors.

Link: https://www.sciencedirect.com/science/article/pii/S1385894722053591