ABSTRACT
The tumor microenvironment is different from that of normal tissue; therefore, the development of a prodrug that retains its efficacy in the tumor microenvironment can be useful in enhancing the anticancer properties of podophyllotoxin. An innovative podophyllotoxin prodrug (POD-PEG) was designed by linking podophyllotoxin to poly(ethylene glycol)(n) monomethacrylate with a H2O2-responsive oxalate ester bond. POD-PEG can self-assemble into stable nanoparticles (POD-PEG NPs). In vitro experiments demonstrated that the POD-PEG NPs can be activated by hydrogen peroxide resulting in podophyllotoxin release and are highly toxic against colon carcinoma CT26 cells. In vivo biodistribution studies demonstrate that PEGylated POD-PEG NPs are capable of prolonging blood circulation. Intravenous injection of POD-PEG NPs into CT26 tumor-bearing Balb/c mice resulted in a significantly enhanced therapeutic efficacy against tumors, with no significant systemic toxicity. Therefore, this H2O2-responsive prodrug delivery system exhibits good biosafety and provides a novel strategy for the development of drug delivery systems.
Subject(s)
Drug Carriers/chemistry , Drug Carriers/metabolism , Hydrogen Peroxide/metabolism , Nanoparticles/chemistry , Podophyllotoxin/chemistry , Prodrugs/chemistry , Prodrugs/metabolism , Animals , Biological Transport , Cell Line, Tumor , Cell Survival/drug effects , Drug Carriers/pharmacokinetics , Humans , Intracellular Space/metabolism , Male , Mice , Models, Molecular , Molecular Conformation , Permeability , Podophyllotoxin/metabolism , Podophyllotoxin/pharmacology , Polyethylene Glycols/chemistry , Prodrugs/pharmacokinetics , Reactive Oxygen Species/metabolism , Tissue DistributionABSTRACT
For the treatment of malignant tumors, drug nanocarriers with long blood circulation time and ability to target the tumor microenvironment are promising therapeutic abilities. In this work, to systematically investigate the roles and functions of polysaccharides as drug nanocarriers targeting the tumor microenvironment, different types of polysaccharides (alginic acid (Alg), hyaluronic acid (HA), and dextran (Dex)) were covalently bonded with doxorubicin (DOX) through a Schiff base reaction to form a pH-sensitive polysaccharide-DOX prodrug having an acid-sensitive imine bond. After screening, Dex-DOX exhibited high drug loading content and good stability, while Alg-DOX and HA-DOX may have disadvantages such as low degree of oxidation, limited drug loading capacity, or instability in physiological conditions. Dex-DOX prodrugs were able to self-assemble into stable nanoparticles in phosphate buffered saline (PBS). Then, Dex6k-DOX and Dex150k-DOX were selected for further comparisons since they had similar drug-binding rates and long circulation time. When compared with Dex6k-DOX, the longer main-chain Dex150k-DOX showed a higher drug release rate under simulated acidic conditions in vitro, which significantly inhibited cell proliferation. Further in vivo experiments showed that Dex150k-DOX could more effectively improve the antitumor efficiency and survival rate while reducing side-effects. Overall, the screening and comparisons provided detailed and systematical information about the polysaccharide-DOX prodrug platform as potential antitumor drugs.
