AUTHOR=Li Weinan , Zhang Xiaoyu , Nan Yang , Jia Li , Sun Jialin , Zhang Lina , Wang Yanhong 

TITLE=Hyaluronidase and pH Dual-Responsive Nanoparticles for Targeted Breast Cancer Stem Cells

JOURNAL=Frontiers in Oncology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.760423

DOI=10.3389/fonc.2021.760423

ISSN=2234-943X

ABSTRACT=A pH-responsive and CD44 receptor mediated targeted nanoparticles for eliminating cancer stem cells (CSCs) were developed based on complexes (HPPMc) of PEG-poly (β-amino ester) (PEG-PBAE) micelles (PPM) coated by hyaluronic acid (HA). The thioridazine (Thz) was loaded into the HPPMc with a decent drug loading content. The release results of drug in vitro showed that the Thz was released from the HPPMc, which was stimulated by both acidic pH and specific enzymes. Cytotoxicity studies on mammospheres (MS) revealed that the toxicity potential of Thz-loaded HPPMc (Thz-HPPMc) at pH 5.5 was prior to drug solutions. Compared with that at pH 7.4, higher cellular uptake of Coumarin-6 (C6)-labeled complex at pH 5.5 was observed, which demonstrated that complexes were efficiently taken up in MS. Meanwhile, free HA competitively inhibited cellular uptake of HPPMc which revealed that the uptake mechanism was CD44 receptor-mediated endocytosis. Within the acidic endolysosomal environment, the protonation of PBAE facilitated the escape of the complex from the lysosome and releases the drug. The results of in vivo distribution studies and tumor suppression experiments showed that HPMMc could stay in the tumor site of nude mice for a longer period of time, and Thz-HPPMc could significantly improve the tumor suppressing effect. All these results demonstrated the great potential of the multifunctional nanoparticles system for eliminating the CSCs.