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.
In this study, we describe the synthesis and aqueous
solution behavior
of temperature-sensitive N-(3-sulfopropyl)-N-methacroyloxyethyl-N,N-dimethylammonium betaine (SBMA) homopolymers and core cross-linked
micelles (CCMs) with an SBMA shell. Reversible addition–fragmentation
chain transfer polymerization has been utilized to synthesize sulfobetaine
homopolymers, followed by CCM formation during copolymerization in
the presence of an acid-degradable cross-linker. First, SBMA homopolymers
of varying chain lengths were synthesized, and it has been demonstrated
that an increase in the chain length and concentration of the homopolymer
resulted in an increase in the upper critical solution temperature
(UCST). Besides, micelles showed concentration-dependent dual temperature-sensitive
behavior with UCST and LCST transitions. Also, homopolymers and CCMs
were characterized by FTIR, 1H-NMR, GPC, and TEM. Micelle
formation and temperature sensitivity were also investigated by DLS.
As a result, stabilized micelles were successfully prepared with the
motivation of preventing premature drug release and achieving a pH-
and temperature-controlled system. Due to their dual-responsive characteristics,
the CCMs show promising potential to be used as smart drug carriers
for controlled delivery.
Gene therapy studies have been of great importance in the elimination of genetic diseases, and the capability of the CRISPR/Cas9 genome editing technique to correct genetic defects has shown great promise. As DNA-based Cas9 nuclease delivery is preferable because of its low cost and higher stability, effective vector-based CRISPR/Cas9 administration is urgently needed. Here, we used the multicellular organism Caenorhabditis elegans to optimize the polymer-mediated DNA delivery system to generate mutants with CRISPR/Cas9. Toward this end, the cationically quaternized polymer of POEGMA-b-P4VP (POEGMA-b-QP4VP) as a carrier of CRISPR/Cas9 components was first synthesized, followed by the formation of plasmid DNA-polymer complex called polyplexes. 1H NMR, Zeta-Sizer, Scanning Electron Microscopy (SEM) analysis, and gel retardation experiments confirmed the polyplexes formation, including pRF4 (Roller) and sgRNA dpy-10, which were then incubated with C. elegans. The polymer-mediated delivery system facilitated the generation of transgenic Roller animals and heritable Dumpy mutants with CRISPR/Cas9. Our study for the first time demonstrated optimized administration of CRISPR/Cas 9 components to C. elegans.
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