Abstract
pH-responsive and CD44 receptor-mediated targeted nanoparticles for eliminating cancer stem cells (CSCs) were developed based on complexes of PEG-poly(β-amino ester) (PEG-PBAE) micelles (PPM) coated with hyaluronic acid (HA) (HA-coated PPM complex, or HPPMc). Thioridazine (Thz) was loaded into HPPMc with a decent drug loading content. The release results of the drug in vitro showed that Thz was released from the HPPMc, which was stimulated by both the 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 better than drug solutions. Compared with that at pH 7.4, a higher cellular uptake of a 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 the 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 BALB/c 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 nanoparticle system for eliminating CSCs.
Highlights
The cancer stem cells (CSCs) theory has received sustained and increased attention because it explains relapse and metastasis in a range of carcinomas, including breast cancer stem cells (BCSCs) [1]
BCSCs are marked as a CD44+/CD24− phenotype, which means that CD44 is expressed in BCSCs, but CD24 is not [4]
In terms of breast cancer, when CD44 was knocked down in a CD44+/CD24− breast cancer cell subpopulation, BCSCs differentiated into non-BCSCs with low tumor potential and altered the cell cycle and expression profiles of some stem cellrelated genes [7]
Summary
The cancer stem cells (CSCs) theory has received sustained and increased attention because it explains relapse and metastasis in a range of carcinomas, including breast cancer stem cells (BCSCs) [1]. How to kill CSCs that cause cancer recurrence and metastasis has become a new targeted strategy for antitumor therapy. In terms of breast cancer, when CD44 was knocked down in a CD44+/CD24− breast cancer cell subpopulation, BCSCs differentiated into non-BCSCs with low tumor potential and altered the cell cycle and expression profiles of some stem cellrelated genes [7]. Previous studies have shown that targeting the CD44 receptor of BCSCs is able to reduce the recurrence of breast cancer [10, 11]. CD44 plays a very important role in drug targeting therapy of BCSCs
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