Metastastic Cascade-targeted Nanodelivery System To Suppress Metastasis Of Breast Cancer

Metastasis is one of the main causes of death in breast cancer patients, responsible for over 90% of breast cancer-related death. Therefore, the efficient suppression of metastasis is of great importance for breast cancer therapy. Drug delivery systems based on nanotechnology demonstrate great potential for drug targeting and cancer treatment. However, metastases are small clusters of disseminated malignant cells that spread over the invaded organs in large numbers, significantly restricting the passive targeting effect of nanoparticles. Delivery of nanotherapeutics to metastatic foci remains a substantial challenge.In this work, three kinds of drug delivery systems were developed to suppress breast cancer metastasis in three different stages during metastasis:(1) pre-metastatic initiation;(2) metastasizing dissemination;(3) metastasized colonization.At first, amphiphilic polymer of poly(ethylene glycol)-block–poly(2-(diisopropylamino)ethyl methacrylate)(mPEG-PDPA10) was synthesized via atom-transfer radical polymerization. NIR fluorescent dye DiR and mPEG-PDPA10 were assembled into nanometer-sized photothermal therapeutics(DPN) with the mean diameter within 20–30 nm. The characteristics of DPN were investigated, such as heat-generating capability, photothermal cytotoxicity and photothermal effect on cell migration. The biodistribution of DPN was determined via NIR fluorescence imaging, and the tumor penetration capability of DPN was further evaluated through the multispectral optacoustic tomographic(MSOT) imaging system. Moreover, the photothermal effect of DPN on inhibiting tumor growth and lung metastasis of breast cancer was investigated. The experimental results showed that DPN presented superior production of thermal energy. The cell proliferation and migration activities of metastatic breast cancer cells were obviously inhibited by DPN photothermal effect. DPN could induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The growth and metastasis of breast cancer were entirely inhibited by a single treatment of DPN with NIR irradiation.Based on the synthesis of mPEG-PDPA10, mPEG-PDPA20 was synthesized by doubling the addition of monomer DPMA. Different from mPEG-PDPA10, mPEG-PDPA20 could be prepared into nanofibers and exhibited specific accumulation in lung. Therefore, vascular cell adhesion molecule-1(VCAM-1) inhibitor succinobucol was assembled with mPEG-PDPA20 to form pH-sensitive wormlike micelles(PWM). Drug loading capacity, encapsulation efficiency and release profile of PWM were determined. The efficiency of PWM in suppressing breast cancer metastasis was evaluated at the cellular and animal levels. The results showed that PWM significantly inhibited the migration and invasion abilities of metastatic breast cancer cells, and reduced the expression of VCAM-1. PWM could induce a higher specific accumulation in lung and be specifically delivered to the sites of metastases in lung, leading to an 86.6% inhibition on lung metastasis of breast cancer but no significant effect on primary tumor.To further enhance drug targeting to the metastatic nodules, monocytes were exploited as vehicles for nanotherapeutics. Legumain(LGMN)-sensitive polymeric micelles(SAD) were prepared by conjugating DM1 to poly(styrene-co-maleic anhydride)(SMA) derivative with alanine–alanine–asparagine peptide(AAN), the subtrate of LGMN. Then SAD was loaded into monocytes to form an active targeting tumor microenviroment-responsive drug delivery system(M-SAD). The characteristics of SAD, such as size distribution, drug release, cytotoxicity and cell uptake, were investigated. The phenotype and LGMN expression of monocytes were also discussed. The experimental results showed that SAD exhibited LGMN-sensitive drug release behavior. LGMN expression was low in monocytes, but in respond to the tumor microenvironment, monocytes could possibly differentiate into macrophages rapidly, leading to increase in LGMN expression which finally caused release of drug. Then,the efficiency of M-SAD in suppressing breast cancer metastasis was evaluated at the cellular and animal levels. M-SAD could obviously inhibite the migration and invasion abilities of metastatic breast cancer cells. Furthermore, M-SAD could deliver to lung and specifically to the sites of metastases in lung, inducing significant inhibition on lung metastasis.