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To compare the chemotherapeutic efficacy determined by extra- and intracellular drug release strategies, poly(ortho ester amide)-based drug carriers (POEAd-C) with well-defined main-chain lengths, are successfully constructed by a facile method. POEAd-C3-doxorubicin (DOX) can be rapidly dissolved to release drug at tumoral extracellular pH (6.5-7.2), while POEAd-C6-DOX can rapidly release drug following gradual swelling at intracellular pH (5.0-6.0). In vitro cytotoxicity shows that POEAd-C3-DOX exhibits more toxic effect on tumor cells than POEAd-C6-DOX at extracellular pH, but POEAd-C6-DOX has stronger tumor penetration and inhibition in vitro and in vivo tumor models. So, POEAd-C6-DOX with the intracellular drug release strategy has stronger overall chemotherapeutic efficacy than POEAd-C3-DOX with extracellular drug release strategy. It is envisioned that these poly(ortho ester amides) can have great potential as drug carriers for efficient chemotherapy with further optimization.

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To promote chemotherapeutic efficacy and easier clinical transformation, a series of pH-sensitive and dynamic drug delivery systems with facile two-step synthesis and simple structure have been successfully constructed by the tunable grafting reaction between pH-sensitive ortho ester and poly(vinyl alcohol). The amphipathic graft macromolecules (PVA- g-OE x, x represents the percentage of feed between ortho esters and hydroxyl groups of polyvinyl alcohol) could self-assemble into micelles and doxorubicin was embedded. These micelles exhibited pH-sensitivity to both extracellular and intracellular pH and demonstrated the following characteristics: (i) maintaining long-term storage and blood circulation stability at pH 7.4; (ii) responding to tumoral extracellular pH value following gradually larger nanoparticles for improved drug accumulation and retention; (iii) being sensitive to tumoral intracellular pH value following disintegration for rapid drug release to improve toxicity to tumor cells. Moreover, the doxorubicin-loaded micelle (PVA- g-OE30-DOX) showed similar cytotoxicity to free doxorubicin in vitro, but stronger tumor penetration and inhibition ability in vitro human liver carcinoma cell line multicellular tumor spheroids. In vivo biodistribution and tumor inhibition examinations demonstrated that PVA- g-OE30-DOX had more superior efficacy in significantly enhancing drug accumulation in tumor, restraining tumor growth while decreasing drug concentration in normal tissues. The pH-sensitive, dynamic graft polymer micelles via simple synthesis could be considered as a promising and effective drug carrier in tumor therapy.