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This paper reveals a new function of poly(ethylene glycol) (PEG) – a common polymer in pharmaceutics – enhancement of the active chemical form of the antitumor drugs of camptothecin (CPT) analogs. All of members in the CPT family confront the severe problem of hydrolysis of the active lactone ring to the inactive carboxylate, leading to not only less efficiency but also more toxicity. Herein, we report that the equilibrium fraction of the active lactone form could be enhanced significantly by simply mixing the drug solution with PEG. For instance, while the equilibrium lactone fraction of topotecan (TPT) was only a bit more than 10% under neutral pH at 37 °C, it was increased to nearly 50% in the presence of 40 wt.% PEG. Two CPT family members, TPT and 10-hydrocamptothecin, and six PEG agents with molecular weight from 200 to 5000, were tested, and the phenomenon was confirmed to be universal. The underlying reason was further discussed. The in vivo drug efficacy was also observed in a solid tumor model in mice.