Abstract
A series of drug delivery systems based on a sodium alginate derivative were prepared by mixing glycyrrhetinic acid (GA) and doxorubicin (DOX) conjugates at different ratios. GA (a liver-targeting ligand) and DOX (an antitumor drug) were both conjugated to oligomeric glycol monomethyl ether-modified sodium alginate (ALG-mOEG) for prolonged duration of action. These NP-based delivery systems exhibited active cell uptake and cytotoxicity in vitro and liver-targeted distribution and anti-tumor activity in vivo. In addition, nanoparticles with a 1:1 (W:W) ratio of GA-ALG-mOEG and DOXALG-mOEG (NPs-3) showed the highest cellular uptake and cytotoxicity in vitro and liver-targeted distribution and antitumor activity in vivo. Specifically, when mixed nanoparticles defined as NPs-3 were injected in mice, liver DOX concentration reached 61.9 μg/g 3 h after injection, and AUC0-∞ and t 1/2 of DOX in liver reached 4744.9 μg·h/g and 49.5 h, respectively. In addition, mice receiving a single injection of NPs-3 exhibited much slower tumor growth (88.37% reduction in tumor weight) 16 days after injection compared with placebo. These results indicate that effective cancer treatment may be developed using mixed NP delivery systems with appropriate ratio of targeted ligand and drug.
Highlights
Nanometer-sized particles (NPs) display outstanding quantum size effect and have attracted significant attention as delivery systems for hydrophobic antitumor drugs[1−4]
We speculated that a balanced loading of drug and targeting ligand in NP-based delivery systems might be critical for optimal therapeutic efficacy with minimal adverse effects
We found that cellular uptake of DOX was higher in cells treated with NPs containing GAALG-monomethoxy polyethylene glycol (mOEG) (NPs-1, NPs-2, NPs-3, NPs-4, NPs-5) compared with NPs of DOX-ALG-mPEG alone (NPs-6)
Summary
Nanometer-sized particles (NPs) display outstanding quantum size effect and have attracted significant attention as delivery systems for hydrophobic antitumor drugs[1−4]. Kataoka et al.[16] reported a method to control folate concentration on surface of micelles by mixing folate-modified micelles and non-modified micelles at different ratios and demonstrated that cancer treatment efficacy was significantly increased by optimizing the number of folate molecules on surface of mixed micelles These results demonstrated the feasibility of using blending to create drug delivery systems with desired functions and properties. The NPs-3 was dispersed in 2.5 mL of buffer solution (pH = 4.0, 5.0, 6.0, 7.4) and placed in a dialysis bag with molecular weight cut-off of 7 kDa at a density of 2 mg/mL, it was immersed into another 10.0 mL PBS in the tube It was incubated at 37 °C with shaking at a constant speed of 100 r/min. The value of *p < 0.05 were considered statistically significant
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