Abstract
The inherent instability of nucleic acids within serum and the tumor microenvironment necessitates a suitable vehicle for non-viral gene delivery to malignant lesions. A specificity-conferring mechanism is also often needed to mitigate off-target toxicity. In the present study, we report a stable and efficient redox-sensitive nanoparticle system with a unique core–shell structure as a DNA carrier for cancer theranostics. Thiolated polyethylenimine (PEI-SH) is complexed with DNA through electrostatic interactions to form the core, and glycol chitosan-modified with succinimidyl 3-(2-pyridyldithio)propionate (GCS-PDP) is grafted on the surface through a thiolate-disulfide interchange reaction to form the shell. The resulting nanoparticles, GCS-PDP/PEI-SH/DNA nanoparticles (GNPs), exhibit high colloid stability in a simulated physiological environment and redox-responsive DNA release. GNPs not only show a high and redox-responsive cellular uptake, high transfection efficiency, and low cytotoxicity in vitro, but also exhibit selective tumor targeting, with minimal toxicity, in vivo, upon systemic administration. Such a performance positions GNPs as viable candidates for molecular-genetic imaging and theranostic applications.
Highlights
IntroductionDespite recent advances in management, cancer remains the second leading cause of death globally and in the United States [1–3]
Succinimidyl-3-(2-pyridyldithio)propionate (SPDP) and trehalose were purchased from TCI America (Portland, OR, USA). (5,5-Dithiobis-(2-nitrobenzoic acid)) (DTNB) and nucleic acid dye YOYO-1 were obtained from Thermo
GCS was further conjugated with SPDP, and the readout from UV–VIS spectroscopy indicated that the degree of modification of glycol chitosan-modified with succinimidyl 3-(2pyridyldithio)propionate (GCS-PDP) was 68 ± 1.2 μmol SPDP groups per gram of GCS-PDP. 1HNMR of GCS-PDP showed pyridine proton chemical shifts at
Summary
Despite recent advances in management, cancer remains the second leading cause of death globally and in the United States [1–3]. Over 60% of patients with solid tumors die from metastases, suggesting that early detection coupled with new, advanced therapies would improve outcomes [4,5]. Imaging and therapy can be performed concurrently with theranostics, combining a therapeutic with a diagnostic (imaging) agent, an approach of increasing interest and visibility [6–9]. Conventional strategies to engage tumor cells with imaging or toxic warheads in vivo through cancer-specific markers, such as membrane receptors, metabolic enzymes, and structural protein targets, often provide a measure of undesired, off-target effects [7,10–13]. Molecular-genetic imaging and therapy using reporter–probe pairs have been pursued in various ways for over two decades [14–17]. An advantage of the molecular-genetic approach over other theranostics is the capacity to produce the imaging and/or therapeutic agent within the cancer cell, in situ, as the promoter activates production of these agents only when in contact with malignant tissues.
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