ABSTRACT
To increase the accumulation of nanocarriers at the tumor site and reduce premature drug leakage, we fabricated alginate modified superparamagnetic iron oxide nanoparticles (SPIONs) with magnetic targeting capability for pH-responsive release of the anticancer drug doxorubicin (DOX) in tumor-cell microenvironments. The drug loading content (DLC) of SPION-4 was as high as 48.98% with a stable size of 135 nm, whereas the DLC of SPION-2 (amine-functionalized SPIONs as the control) was 7.58%. The in vitro release studies revealed that the acidic environment (pH 6.5 and pH 5.0) triggered the effective release of DOX from DOX-loaded SPION-4 twice and thrice as much as the neutral condition (pH 7.4) after 10.7 h, respectively. These nanocarriers exhibited good cytocompatibility towards both normal cells (LO2) and cancer cells (HepG2), but higher cytotoxicity against HepG2 cells for DOX-loaded SPION-4 than that against LO2 cells could be observed due to the effects of an additional magnet and the acidic microenvironment of cancer cells, which greatly improved the cellular uptake of magnetic nanoparticles and released more DOX in the cytoplasm and nucleus. The in vivo biodistribution and anti-tumor efficacy demonstrated that DOX-loaded SPION-4 under an external magnetic field could obviously increase the DOX concentration in tumor tissues to remarkably inhibit tumor growth and significantly reduce side effects of free DOX. Therefore, this work suggested that these SPION-4 nanoparticles may be a potential carrier to deliver chemotherapeutic agents in anti-tumor treatment.
Subject(s)
Antineoplastic Agents/chemistry , Doxorubicin/chemistry , Drug Carriers/chemistry , Magnetite Nanoparticles/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Biological Transport , Cell Culture Techniques , Cell Line , Cell Nucleus/metabolism , Cell Survival , Cytoplasm/metabolism , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/pharmacokinetics , Drug Liberation , Humans , Hydrogen-Ion Concentration , Mice, Inbred BALB C , Particle Size , Surface Properties , Tissue DistributionABSTRACT
Water-soluble quaternized chitins (QCs) were homogeneously synthesized by reacting chitin with (3-chloro-2-hydroxypropyl) trimethylammonium chloride (CHPTAC) in 8wt% NaOH/4wt% urea aqueous solutions. The chemical structure and solution properties of the quaternized chitins were characterized by (1)H NMR, FT-IR, elemental analysis, dynamic light scattering (DLS) and zeta potential measurements. The results demonstrated that the water-soluble QCs, with a degree of substitution (DS) values of 0.27-0.54, could be obtained by varying the concentration of chitin, the molar ratio of CHPTAC to chitin unit, and the reaction time at room temperature (25°C). Two QCs (DS=0.36 and 0.54) were selected and studied as gene carriers. Agarose gel retardation assay revealed that both QCs could condense DNA efficiently when N/P ratio>3. The results of particle size and zeta potential indicated that both QCs had a good ability of condensing plasmid DNA into compact nanoparticles with the size of 100-200nm and zeta potential of +18 to +36mV. Compared to polyethylenimine (PEI, 25kDa), the QCs exhibited outstanding low cytotoxicity. Transfection efficiencies of the QCs/DNA complexes were measured using pGL-3 encoding luciferase as the foreign DNA, and the QCs/DNA complexes showed effective transfection efficiencies in 293T cells. These results revealed that the QCs prepared in NaOH/urea aqueous solutions could be used as promising non-viral gene carriers owing to their excellent characteristics.
