Photoenzyme biresponsive biomimetic delivery nanoparticle integrated chemotherapy-photothermal therapy against triple-negative breast cancer

Triple-negative breast cancer is difficult to be treated with hormones and HER2 antibodies due to the lack of relevant receptors, and taxane-based chemotherapy is clinically the first-line treatment
.
In addition to poor tumor targeting, which leads to low response rate and large toxic side effects, taxane drugs can induce cancer cell metastasis
.
Calcitriol can regulate multiple tumor-related signaling pathways, and the combination with chemotherapy drugs can resist the metastasis caused by them, but the effective dose of ordinary calcitriol injection is easy to lead to severe hypercalcemia and other toxic side effects
.
Therefore, the combination of chemotherapy drugs and calcitriol urgently requires new drug delivery strategies to increase the concentration of drugs in the target site and reduce toxic side effects
.
The biomimetic nano-drug delivery system based on red blood cell membrane can prolong the blood circulation time of drugs and passively increase the distribution of drugs in tumors, but the insufficient release of drugs in the membrane and poor tumor permeability limit their efficacy
.

In response to the above problems, the team of researchers Li Yaping and Yin Qi of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, together with the team of Professor Xu Hua'e of Nanjing Medical University, designed a photo-enzyme biresponsive biomimetic nanoparticle (HDC-DM) for the co-delivery of taxane drugs docetaxel and calcitriol
.
The findings were published online in Advanced Functional Materials
on December 1, 2022.

docetaxel and calcitriol are coupled with heparan sulfate, respectively, to synthesize prodrugs and prepare mixed micelles; Nano-sized red blood cell membranes were prepared and modified with the photosensitizer DiR, and the modified red blood cell membranes were covered on the surface of the mixed micelles to make HDC-DM.

Due to the protection of the red blood cell membrane, HDC-DM is able to avoid the recognition and clearance of the mononuclear macrophage system in the body, remaining stable
in the blood circulation in the body.
After accumulating to the tumor site through enhanced penetration and retention effects, DiR is irradiated by near-infrared laser (808 nm), which produces a photothermal effect, destroys the red blood cell membrane, releases micelles, and under the action of tumor highly expressed heparanase, heparan sulfate is degraded, docetaxel and calcitriol are released
.
Photothermal therapy enhances tumor permeability, allowing drugs to enter cells deep in the tumor
.
In addition to directly killing cancer cells, chemotherapy drugs also induce immunogenic cell death and stimulate the body's tumor immune response
.

Studies have shown that in a mouse model of 4T1 breast cancer, HDC-DM increased the concentrations of docetaxel and calcitriol in tumors by 1.
7 and 2.
5 times
, respectively, compared with the free administration group.
After injection of HDC-DM and near-infrared laser irradiation with tumors, the tumor inhibition rate reached 77%.

In addition, calcitriol downregulated the levels of BCL-2 and matrix metalloproteinase-9 in tumors, upregulated the level of E-cadherin, and downregulated the level of CCL-2 in the lung, inhibiting the formation
of 82% of lung metastases.
The proportion of mature dendritic cells and intratumoral CD8+ T cells in the draining lymph nodes increased significantly, and the secretion of interferon-γ increased
.
The mice in the nanoparticle group did not experience side effects such as weight loss, hypercalcemia and leukocyte suppression, which prolonged the survival of
the mice.
The study provides new ideas
for the combination of multiple therapies for the treatment of triple-negative breast cancer and the delivery of drugs in vivo.

Professor Li Yaping and Yin Qi of Shanghai Institute of Materia Medica, Professor Xu Hua'e of Nanjing Medical University are co-corresponding authors of the paper, and Wu Ting, a doctoral student jointly trained by Shanghai Institute of Materia Medica-Nanjing Medical University, and Lang Tianqun, a postdoctoral fellow, are the first authors
of the paper.
The research was supported
by the National Natural Science Foundation of China and the High-level Talent Start-up Fund of Nanjing Medical University.

The preparation process of HDC-DM and the mechanism of anti-breast cancer tumor growth and lung metastasis in vivo

Original link: https://doi.
org/10.
1002/adfm.
202212109

(Contributing department: Li Yaping's research group; Contributor: Yin Qi)