Targeting of Calcitriol to Inflammatory Breast Cancer Tumors and Metastasis In Vitro and In Vivo

Abstract

Inflammatory Breast Cancer (IBC) is arguably the most severe form of breast cancer with a very high mortality rate. IBC is distinct from other forms of breast cancer expressing unique cell surface markers such as hypoglycosylated MUC1. However, treatment options for IBC are limited. Calcitriol is a potential treatment for IBC due to its promising role as a therapeutic in other forms of cancer. Our previous research demonstrated that calcitriol inhibits the metastatic ability of the SUM149 IBC cell line. However, high concentration of calcitriol would be required for treatment. This may result in serious side effects such as hypercalcemia. Targeting calcitriol directly to the tumor site would allow for treatment without toxic levels of calcitriol. Here we developed SM3MUC1 antibody conjugated calcitriol bound QDs as a novel nanoparticles probe. We demonstrate that these particles can be used to target to MUC1 over-expressing IBC cells in vitro and in vivo. Therefore these particles can be used to determine the localization of IBC emboli in vivo and maybe used as a potential vehicle to deliver high doses of calcitriol to the IBC tumors and metastasis.

A Physiologically‐Based Pharmacokinetic Model for Targeting Calcitriol‐Conjugated Quantum Dots to Inflammatory Breast Cancer Cells

“…The antiproliferative effects are thought to be a result of calcitriol blocking the mitogenic effects of insulin‐like growth factor I through downregulation of its receptors, causing the G1 phase of the cell cycle to pause . In addition, it was found that SUM149 cells exposed to calcitriol exhibited a decreased ability to migrate, invade, and form tumor emboli, leading to decreased metastasis in vivo . However, previous studies have required toxic dosages of calcitriol (over 0.50 μg) to have a significant effect, which would lead to hypercalcemia .…”

“…In addition, it was found that SUM149 cells exposed to calcitriol exhibited a decreased ability to migrate, invade, and form tumor emboli, leading to decreased metastasis in vivo . However, previous studies have required toxic dosages of calcitriol (over 0.50 μg) to have a significant effect, which would lead to hypercalcemia . Therefore, targeting methods are required to reach desired levels of calcitriol at treatment sites without having an excess of calcitriol in the rest of the body.…”

“…Quantum dots (QDs) conjugated to calcitriol have previously been used to examine the distribution of calcitriol both in vitro and in vivo . QDs are semiconductor nanoparticles around 15 nm in diameter, which can be used for fluorescent imaging under UV light and have a variety of surface chemistries that are compatible with living systems.…”

“…QDs are semiconductor nanoparticles around 15 nm in diameter, which can be used for fluorescent imaging under UV light and have a variety of surface chemistries that are compatible with living systems. They localize in the liver, lymph nodes, kidneys, and spleen in mice, with some effects on distribution from the polymer surface chemistry (conjugated with carboxyl groups in this case) . To use calcitriol QDs for direct imaging of live cells, QDs are conjugated to calcitriol using an esterification reaction to produce calcitriol QDs (CalQDs) .…”

“…They localize in the liver, lymph nodes, kidneys, and spleen in mice, with some effects on distribution from the polymer surface chemistry (conjugated with carboxyl groups in this case) . To use calcitriol QDs for direct imaging of live cells, QDs are conjugated to calcitriol using an esterification reaction to produce calcitriol QDs (CalQDs) . To avoid hypercalcemia and potential toxicity, these CalQDs can be manipulated to target tumor sites.…”