November 30, 2023

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Trick cancer cells to take chemotherapy drugs to enhance treatment

Nature: Trick cancer cells to take chemotherapy drugs to enhance cancer treatment


Trick cancer cells to take chemotherapy drugs to enhance treatment.  It is usually difficult to bring enough anti-cancer drugs into tumors, and the strong demand of protein nutrition by cancer cells makes albumin the first nutrient of cancer cells, so attaching drugs to albumin is regarded as an excellent anti-tumor strategy Therefore, albumin preparations are used to improve the delivery of tumor drugs.

nab-paclitaxel (nab-PTX) is the first chemotherapeutic albumin preparation approved by the US FDA and the first-selling nanoprescription drug. It has been successfully used to treat advanced lung cancer and pancreatic cancer with high KRAS mutations. However, in clinical trials, not all patients respond to nab-PTX, and there is almost no direct evidence to prove how this albumin nanoprescription strategy affects drugs in the spatially heterogeneous tumor microenvironment (TME) in vivo The distribution, cellular uptake and activity of the payload.

Recently, a research team from Harvard Medical School/Massachusetts General Hospital published a research paper titled: Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer in the journal Nature Nanotechnology.

The study found that by reprogramming nutritional signals and enhancing the function of macrophages in tumors, the consumption of nanoparticle albumin-bound drugs by cancer cells can be increased, thereby killing cancer cells. This discovery will help to develop therapies that increase the intake of cancer drugs by cancer patients, thereby improving the effectiveness of chemotherapy.

First, the research team developed a dual-color imaging strategy based on AlexaFluor555-labeled albumin and fluorescent taxane payload (SiR-taxane) for single-cell resolution of KRAS-mutated non-small cell lung adenocarcinoma (NSCLC) and metastatic Imaging the transmission and cellular uptake of nab-PTX in a mouse model of pancreatic ductal adenocarcinoma (PDAC) revealed that unlike other nano-preparations, nab-PTX has obvious aggregation in cancer cells.

Trick cancer cells to take chemotherapy drugs to enhance treatment

Macrophage phagocytosis is related to the uptake of albumin by RAS mutant cancer cells, and punctate subcellular co-localization further supports the uptake by nab-PTX through pinocytosis. The use of transgenic kinase translocation reporter gene (ERK-KTR) to monitor ERK activation reveals the correlation between nab-PTX uptake and ERK activity at the cellular level. The use of clinical MEK1/2 inhibitor trametinib to inhibit ERK signaling can Blocking the uptake of nab-PTX indicates that ERK signal controls the uptake of nab-PTX by macrophages by cancer cells.

Trick cancer cells to take chemotherapy drugs to enhance treatment

Next, the research team examined whether inhibiting RAS/RAF/MEK/ERK signaling would affect the accumulation of nab-PTX in the body. Inhibition of RAS signal transduction through doxycycline withdrawal eliminates the selective accumulation of nab-PTX in tumor mouse models. In vitro doxycycline withdrawal can reduce nab-PTX uptake. A similar effect was also observed with trametinib. These results indicate that the signal transduction status of cancer cells will seriously affect the transmission of nab-PTX.

Finally, the research team tested whether the uptake of nab-PTX can be enhanced by treatment to improve the efficacy. Targeted screening showed that IGF1R kinase inhibitors promote macrophage phagocytosis by mimicking glucose deprivation and through the nutrient sensor AMPK in the cell, thereby enhancing nab-PTX Intake and efficacy.

Trick cancer cells to take chemotherapy drugs to enhance treatment

Overall, the study shows the potential impact of MAPK and nutritional signal status on the action of nab-PTX, and the uptake and efficacy of nab-PTX can be enhanced by reprogramming the nutritional signal. The image-based experimental technology developed in this research can be extended to other albumin-binding drugs, including nanotherapy of albumin components, albumin-binding prodrugs, albumin fusion biologics, and high intrinsic affinity for albumin and plasma protein binding The potential variety of drugs will help to understand the application of this mechanism in other cancer types and drug combinations.


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