# 5′-NucA-SMCC-DM1 and 5′-NucA-SPDMV-DM1 are Potent Aptamer–Drug Conjugates against Pancreatic Cancer

## TL;DR

Researchers developed new drug conjugates that target pancreatic cancer cells more effectively and with less toxicity than existing treatments.

## Contribution

The design and synthesis of water-soluble aptamer–drug conjugates with improved targeting and reduced toxicity for pancreatic cancer.

## Key findings

- The conjugates showed significant accumulation in pancreatic tumor cells but not in normal cells.
- 5′-NucA-SMCC-DM1 and 5′-NucA-SPDMV-DM1 remained stable in human serum for up to 48 hours.
- The conjugates demonstrated potent antitumor efficacy in mice with reduced toxicity to the liver and heart.

## Abstract

Pancreatic cancer is one of the most lethal cancers,
characterized
by low survival rates due to a complex tumor microenvironment, late-stage
diagnosis and, notably, the limited effectiveness of current treatments.
First-line therapies, such as gemcitabine and nab-paclitaxel, often
lead to unexpected side effects. Mertansine, which is a more potent
cytotoxic agent, faces similar challenges. In response, we designed
and synthesized a highly water-soluble conjugate of an antinucleolin
aptamer (NucA) and mertansine (NucA-DM1) to enhance the delivery of
DM1 specifically to pancreatic tumor cells. Our in vitro studies demonstrated that the cytotoxic activity of this conjugate
could retain potency compared to DM1 alone, with significant accumulation
observed in pancreatic tumor cells rather than in normal cell lines.
Additionally, 5′-NucA-SMCC-DM1 and 5′-NucA-SPDMV-DM1
conjugates exhibited excellent stability in serum. Notably, 3′-Cy5-5′-NucA-SMCC-DM1
was primarily taken up by PANC-1 cells through macropinocytosis. Further
investigations into the antitumor activity and cell cycle dynamics
indicated that the conjugation of NucA and DM1 minimally impacted
the 5′-linked aptamer–drug conjugate (ApDC), whereas
the 3′-linked ApDC remained unaffected. Our findings also confirmed
that SMCC- and SPDMV-linked ApDCs retained stability in human serum
for up to 48 h. Flow cytometry and confocal microscopy analyses further
illustrated the excellent targeting capabilities of these conjugates
in pancreatic cancer cell lines PANC-1 and MIA PaCa-2, in contrast
to normal cells such as MIHA (normal human liver cells). Two candidates,
5′-NucA-SMCC-DM1 and 5′-NucA-SPDMV-DM1, were selected
based on in vitro evaluations and exhibited potent
antitumor efficacy with significantly decreased toxicity to the liver
and heart compared with DM1 alone in xenografted mice.