Nature Sub-Journal | Chen Jun and other teams from Fudan University develop new nanomaterials to target tumors that have metastasized throughout the body

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The main reason for the failure of conventional clinical treatments such as iNature tumor resection and chemotherapy is poor control of tumor metastasis.

Metastasis involves three steps: (i) tumor cells infiltrate the circulatory system from the primary site through epithelial-mesenchymal transition (EMT), (ii) circulating tumor cells (CTC) and platelets form "microthrombi" to avoid immune surveillance in the circulation , And (iii) CTC is colonized in the niche before the transfer.

On May 27, 2021, Chen Jun of Fudan University and Gao Xiaoling of Shanghai Jiaotong University jointly published a research paper entitled "Systemic metastasis-targeted nanotherapeutic reinforces tumor surgical resection and chemotherapy" in Nature Communications.
The research designed a whole body Metastasis-targeted nano-therapeutic drugs (H@CaPP), composed of anti-inflammatory agent piceatannol and anti-thrombotic agent low molecular weight heparin, to prevent multiple steps of tumor metastasis.

It was found that H@CaPP effectively blocked EMT, inhibited the formation of "microthrombus", and prevented the development of the niche before metastasis.

When combined with surgical resection or chemotherapy, H@CaPP can effectively inhibit tumor metastasis and prolong the overall survival of tumor-bearing mice.

In general, this study provides a simple and effective systemic metastasis targeted nanotherapeutic agent for anti-tumor metastasis.

Metastasis is the leading cause of cancer-related deaths.

Current clinical treatments, including tumor resection, chemotherapy and radiotherapy, can effectively remove the primary tumor, but still cannot inhibit or even induce tumor metastasis.

Two main clinical therapies for tumors, surgical resection and chemotherapy can induce immunosuppression and inflammatory response, and ultimately promote tumor metastasis.

For example, surgical resection induces the acute release of angiogenic factors and immunosuppressive chemokines, and promotes cell invasion by increasing tumor angiogenesis and infiltration of regulatory T cells (Treg cells).

Chemotherapy may also lead to metastasis.
Once normal cells such as endothelial cells and cancer-related fibroblasts are exposed to chemotherapy drugs, these cells express high levels of pro-inflammatory molecules such as interleukin 6 (IL-6) and IL-8 to recruit Immunosuppressive cells, leading to suppression of anti-tumor immune response.

Therefore, the exploration of potential mechanisms based on tumor metastasis is essential for cancer treatment.

In the process of metastasis, malignant tumor cells act as "seeds", migrate from the original site and invade the distant site called "soil".

It consists of three main steps: invasion, circulation and colonization stages.

(i) During the invasion stage, tumor cells escape from the primary tumor tissue to surrounding tissues and infiltrate adjacent blood vessels.

At this stage, epithelial-mesenchymal transition (EMT) enhances the motility and aggressiveness of tumor cells.

During EMT, cell-cell junction proteins such as E-cadherin are down-regulated, while the expression of mesenchymal proteins such as vimentin is increased.

In addition, EMT occurs at the wound healing site and is an inflammatory response.

(ii) In the circulatory phase, tumor cells that enter and survive in the blood are called circulating tumor cells (CTC).

At this stage, platelets combine with CTC to form a special structure called "microthrombus", which can protect CTC from circulating natural killer cells (NK cells).

(iii) In the colonization stage, CTC infiltrates and colonizes in distant organs.

The distant organs that provide a suitable niche for CTC colonization are defined as the pre-metastasis niche.

Compared with normal tissues, the pre-metastasis niche showed higher expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).

In addition, increased expression of metalloproteinase 9 (MMP-9) will accelerate the degradation of extracellular matrix (ECM), leading to the colonization of CTCs.

In addition, it is an inflammatory site before metastasis that overexpresses S100 protein (such as S100A9), which recruits bone marrow-derived suppressor cells (MDSCs) such as macrophage antigen (Mac) 1+ bone marrow cells to the niche, and causes CTCs to be in the niche.
The site is colonized.

Due to the systematic process, there is currently no effective clinical treatment method for tumor metastasis.

Some treatment strategies have been proposed, such as N-cadherin antibody intervention in the EMT process, targeting CTC and preventing the formation of pre-metastasis niches to combat tumor metastasis.

However, the therapy for single-step metastasis failed to prevent multi-step metastasis.

When considering effective treatment strategies for the clinical field, systemic metastasis targeted therapy that hinders the entire metastasis process may provide a more powerful treatment method.

Here, the study designed a systemic metastasis targeted nano-therapeutic drug (H@CaPP) to co-deliver the anti-inflammatory agent piceatannol (PIC) and the antithrombotic low molecular weight heparin (LMWH) to fight tumors in the following ways Metastasis, the multiple steps that hinder tumor metastasis.

Piceatannol is expected to effectively inhibit metastasis by inhibiting the signal transduction and activator of STAT-3 and NF-κB.

LMWH is a class of anticoagulant drugs commonly used in clinical practice.
It has high affinity for P-selectin and is overexpressed on activated endothelial cells (EC) and activated platelets in the pre-metastasis niche.

Therefore, LMWH can be used not only as a targeting ligand for P-selectin, but also as an anti-microthrombus component.

Nanotechnology has many advantages in the collaborative delivery of drugs, including improved stability and circulation, especially the integration of different drugs on a platform.

Therefore, a calcium phosphate liposome (CaP)-based nanostructure was developed here to target and prevent multiple steps of tumor metastasis through the co-delivery of piceatannol and LMWH.

In order to effectively co-deliver and improve drug loading efficiency, piceatannol phosphate (PP) was synthesized by phosphorylation of the hydroxyl group of PIC.

Then the PP is precipitated with calcium to form calcium phosphate nanoparticles (CaPP), which is further modified with LMWH through electrostatic interactions on the surface to form a whole body transfer targeted nano-therapeutic agent (H@CaPP).

As expected, H@CaPP successfully prevented multiple steps of metastasis: inhibiting the EMT process during the invasion phase; preventing the formation of "microthrombi" during the colonization phase; inhibiting the pre-metastasis niche by binding to P-selectin and reducing endothelial cells The adhesion, reverse the remodeling of the extracellular matrix, and hinder the development of immunosuppressive inflammation sites.

When combined with chemotherapy or surgical resection, H@CaPP significantly reduced lung tumor metastasis and prolonged the overall survival of mice with breast tumors.

As a proof of concept, this study combines anti-inflammatory drugs and anticoagulants into targeted nano-therapeutics, providing a safe and potential strategy for adjuvant treatment of metastatic tumors.

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