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

Abstract

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.

Redox-Responsive Core-Cross-Linked Micelles of Miktoarm Poly(ethylene oxide)-b-poly(furfuryl methacrylate) for Anticancer Drug Delivery

“…For example, Savic et al reported the loss of PCL- b -PEO micelle integrity after 1 h of intramuscular or subcutaneous injection . Therefore, recent research have been focused on novel approaches to increase the stability of micelles, and the cross-linking approach has proven to be highly efficient for this purpose. , The cross-linking approaches reported so far include core-cross-linking, shell cross-linking, , and cross-linking at the shell–core interface . Together with improving the structural ability of micelles, cross-linking can also control the rate of drug release .…”

Sulfobetaine-Based Homo- and Copolymers by RAFT: Cross-Linked Micelles and Aqueous Solution Properties

“…10 Owing to the versatility of RAFT polymerization, it is possible to obtain cross-linked micelles during copolymerization and improve the functionality for further modifications. 8,9 The main concept to obtain a stable and multifunctional micelle-based nanocarriers relies on using a hydrophilic polymer in the shell part, while other components are used for the core part together with a specific cross-linker. Also, using polymers with the LCST or UCST behavior reveals temperature sensitivity that can be utilized for controlled delivery of the drugs.…”

“…Cross-linking in the micelle structure has been proposed in the last decade as a way to prevent early micelle dissociation and premature drug release. , They can be designed as environmentally degradable or hydrolyzable systems at low pH or reductive conditions, which can lead to time- or site-controlled release of bioactive agents . Owing to the versatility of RAFT polymerization, it is possible to obtain cross-linked micelles during copolymerization and improve the functionality for further modifications. , The main concept to obtain a stable and multifunctional micelle-based nanocarriers relies on using a hydrophilic polymer in the shell part, while other components are used for the core part together with a specific cross-linker.…”

“…Cross-linking in the micelle structure has been proposed in the last decade as a way to prevent early micelle dissociation and premature drug release. , They can be designed as environmentally degradable or hydrolyzable systems at low pH or reductive conditions, which can lead to time- or site-controlled release of bioactive agents . Owing to the versatility of RAFT polymerization, it is possible to obtain cross-linked micelles during copolymerization and improve the functionality for further modifications. , The main concept to obtain a stable and multifunctional micelle-based nanocarriers relies on using a hydrophilic polymer in the shell part, while other components are used for the core part together with a specific cross-linker. Also, using polymers with the LCST or UCST behavior reveals temperature sensitivity that can be utilized for controlled delivery of the drugs.…”

Near-Infrared Light-Responsive Shell-Crosslinked Micelles of Poly(d,l-lactide)-b-poly((furfuryl methacrylate)-co-(N-acryloylmorpholine)) Prepared by Diels–Alder Reaction for the Triggered Release of Doxorubicin

“…Polymeric self-assemblies such as vesicles and micelles prepared from amphiphilic copolymers have shown encouraging results as chemotherapeutic nanocarriers due to their distinct shell-core nanostructures [1,2]. The hydrophobic blocks of micellar cores can entrap and solubilize hydrophobic drugs [3,4]. In addition, hydrophilic coronas can efficiently protect the hydrophobic core and their entrapped therapeutics from the external biological environment during blood circulation to diminish the nonspecific adsorption by protein [5][6][7].…”