HER2-Targeted, Degradable Core Cross-Linked Micelles for Specific and Dual pH-Sensitive DOX Release

Bayram N. N., Ulu G. T., Topuzoğulları M., Baran Y., Dinçer İşoğlu S.

MACROMOLECULAR BIOSCIENCE, cilt.22, sa.1, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 22 Sayı: 1
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1002/mabi.202100375
  • Dergi Adı: MACROMOLECULAR BIOSCIENCE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Aerospace Database, BIOSIS, Chemical Abstracts Core, Communication Abstracts, Compendex, EMBASE, INSPEC, MEDLINE, Metadex, Civil Engineering Abstracts
  • Anahtar Kelimeler: breast cancer, cross-linked micelles, dual pH-responsiveness, HER2 targeting, micelle nanocarriers, RAFT polymerization, DRUG-DELIVERY SYSTEM, COPOLYMER MICELLES, POLYMERIC MICELLES, TARGETING PEPTIDES, BLOCK-COPOLYMERS, CANCER, DOXORUBICIN, ACID, NANOPARTICLES, NANOCARRIERS
  • Yıldız Teknik Üniversitesi Adresli: Evet

Özet

Here, a targeted, dual-pH responsive, and stable micelle nanocarrier is designed, which specifically selects an HER2 receptor on breast cancer cells. Intracellularly degradable and stabilized micelles are prepared by core cross-linking via reversible addition-fragmentation chain-transfer (RAFT) polymerization with an acid-sensitive cross-linker followed by the conjugation of maleimide-doxorubicin to the pyridyl disulfide-modified micelles. Multifunctional nanocarriers are obtained by coupling HER2-specific peptide. Formation of micelles, addition of peptide and doxorubicin (DOX) are confirmed structurally by spectroscopical techniques. Size and morphological characterization are performed by Zetasizer and transmission electron microscope (TEM). For the physicochemical verification of the synergistic acid-triggered degradation induced by acetal and hydrazone bond degradation, Infrared spectroscopy and particle size measurements are used. Drug release studies show that DOX release is accelerated at acidic pH. DOX-conjugated HER2-specific peptide-carrying nanocarriers significantly enhance cytotoxicity toward SKBR-3 cells. More importantly, no selectivity toward MCF-10A cells is observed compared to HER2(+) SKBR-3 cells. Formulations cause apoptosis depending on Bax and Caspase-3 and cell cycle arrest in G2 phase. This study shows a novel system for HER2-targeted therapy of breast cancer with a multifunctional nanocarrier, which has higher stability, dual pH-sensitivity, selectivity, and it can be an efficient way of targeted anticancer drug delivery.