Cyclodextrin-based PH-responsive Nanoparticles For Lung Metastasis Of Breast Cancer

Breast cancer is the major threat to women’s health, among which 90% of the patients died of the tumor metastasis. Although the clinical treatment of breast cancer achieved some positive consequent, metastasis remains the major obstacle for the successful therapy of metastatic breast cancer. Based on pH-responsive nanoparticles have attracted increasing attentions in cancer therapy, and have brought a new therapeutic strategies for cancer metastasis.In this paper, a cyclodextrin inclusion compound was prepared via the host-guest interactions, based on the synthesis of mPEG5K-Ad and β-CD-NPA, which were the guest and host molecular. Then based on this, a novel pH responsive nanoparticle was designed, and succinobucol as the model drug. The application value of the pH responsive nanoparticles as tumor-targeted drug delivery system and the potential to inhibit tumor metastasis was preliminarily evaluated.MPEG5K-Ad was synthesized by the reaction between the carboxyl of PEG and the hydroxyl of ADA, which was obtained by amide linkage reaction. The 1H NMR spectra of mPEG5k-Ad and β-CD-NPA was in accordance with the expected structures. The result of NOESY showed that the cyclodextrin inclusion compound was successfully prepared, based on which the pH responsive nanoparticle was prepared, then its physical and chemical properties such as particle size, appearance, encapsulation efficiency, drug-loading ratio and in vitro release were investigated. The results show that PHN were about 174 nm in diameter with a narrow size distribution. PHN exhibited a spherical morphology when the pH was 7.4, and in vitro release percentage was only 3.7%, when the pH was 5.8, the structure of PHN was damaged, and the in vitro release percentage was 84%; when the pH was 5.2, PHN had no fixed patterns, and in vitro release percentage was more than 90%; which showed that PHN showed a significant pH sensitivity. The encapsulation ratio and drug-loading efficient of PHN were 95.65%±0.02% and 15.40±0.01%, respectively. According to the detection method of SCB in vitro with HPLC, 1~500μ g/mL linear range was good.To evaluate the in vitro feature of PHN in cell level, the cytotoxicity, cell uptake, cell scratches, cell adhesion, anti-migration, anti-invasive abilities of PHN on 4T1 cells were investigated. The results showed that the safe concentration of SCB was 400ng/ml. At this concentration, the effect of anti-migrate and anti-invasive abilities of PHN were remarkable, and PHN could inhibit the expression of VCAM-1 significantly.Based on the construction of the model mice, the distribution of PHN in model mice and the ability to inhibit tumor metastasis were evaluated. The results show that: the distribution in lung tissue of PNI is 2 times of free ICG, PHN remarkably increased the distribution of drug in lung, compared with the blank control group, the inhibitory rate of PHN against lung metastasis was 70%, and the H & E sections had no pathological features, indicating that PHN can effectively inhibit metastasis of cancer cells.As a result, the novel pH responsive nanoparticles in this paper could be a very powerful approach to inhibit breast cancer growth and metastasis.