Abstract
BackgroundConventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue.MethodsA pH stimuli-sensitive conjugate based on polyethylene glycol (PEG) with covalently attachment doxorubicin via hydrazone bond (PEG-hyd-DOX) was prepared for tumor targeting delivery system. While PEG-DOX conjugates via amid bond (PEG-ami-DOX) was synthesized as control.ResultsThe synthetic conjugates were confirmed by proton nuclear magnetic resonance (NMR) spectroscopy, the release profile of DOX from PEG-hyd-DOX was acid-liable for the hydrazone linkage between DOX and PEG, led to different intracellular uptake route; intracellular accumulation of PEG-hyd-DOX was higher than PEG-ami-DOX due to its pH-triggered profile, and thereby more cytotoxicity against MCF-7, MDA-MB-231 (breast cancer models) and HepG2 (hepatocellular carcinoma model) cell lines. Following the in vitro results, we xenografted MDA-MB-231 cell onto SCID mice, PEG-hyd-DOX showed stronger antitumor efficacy than free DOX and was tumor-targeting.ConclusionsResults from these in vivo experiments were consistent with our in vitro results; suggested this pH-triggered PEG-hyd-DOX conjugate could target DOX to tumor tissues and release free drugs by acidic tumor environment, which would be potent in antitumor drug delivery.
Highlights
Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue
polyethylene glycol (PEG) has been widely used as a drug carrier in many drug design strategies for its low immunogenicity and long circulation time, antitumor agents conjugated to PEG are of great interest because of the passive tumor targeting by EPR effect and slow-released profile, led to a low toxicity, high efficacy and long-acting delivery vehicle [5,6]
Mice treated with free DOX showed an initial decrease in body weight until day 6 and a gradual weight gain; they did not achieve similar level of weight gain as compared with the DOX conjugates treatment groups (Fig. 5b). These results showed that PEG-hydDOX could make effect without weight loss, which is a common side-effect in chemotherapy, suggested that a higher dose of DOX conjugate could potentially be used to give greater therapeutic efficacy, without serious side effects
Summary
Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue This prevents the use of giving high but effective doses for cancer treatment [1,2,3]. Even extremely multidrug resistant (MDR) cells can be killed at high drug concentration, so this strategy is meaningful in MDR cells [13,14,15]
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