Efficacy of a Poly‐<scp>L</scp>‐Glutamic Acid‐Gemcitabine Conjugate in Tumor‐Bearing Mice

<jats:title>Abstract</jats:title><jats:p><jats:table-wrap position="anchor">

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<jats:th>Strategy, Management and Health Policy</jats:th>
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<jats:td>Enabling Technology, Genomics, Proteomics</jats:td>
<jats:td>Preclinical Research</jats:td>
<jats:td>Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics</jats:td>
<jats:td>Clinical Development Phases I‐III Regulatory, Quality, Manufacturing</jats:td>
<jats:td>Postmarketing Phase IV</jats:td>
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</jats:table-wrap></jats:p><jats:p>This study assessed the in vivo antitumor efficacy of a polypeptide‐based poly‐<jats:styled-content style="fixed-case">L</jats:styled-content>‐glutamic acid‐gemcitabine conjugate (<jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content>). <jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content> was synthesized by conjugating gemcitabine to poly‐L‐glutamic acid by a carbodiimide reaction. <jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content> was evaluated for its in vivo antitumor efficacy and toxicity using 4<jats:styled-content style="fixed-case">T</jats:styled-content>1 murine breast tumor‐bearing mice. The antitumor effects of <jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content> were superior to those of unconjugated gemcitabine in both single and four‐consecutive dosing studies. Tumor regression was observed within 1 day after <jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content> administration and continued for 4–5 days. Thereafter, tumors grew at a slower rate compared with the unconjugated gemcitabine treatment group and other control groups. The main toxicity observed from the <jats:styled-content style="fixed-case">B</jats:styled-content>erlin test was an apparent reversible weight loss of 10–12%. The unconjugated gemcitabine treatment group also demonstrated a similar, but reduced, weight loss trend. The present study demonstrates that the <jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content> formulation exhibits a significant antitumor activity in the aspects of tumor growth inhibition and shrinkage that is more robust than the parent drug and other control groups. Thus, the <jats:styled-content style="fixed-case">PG</jats:styled-content>‐<jats:styled-content style="fixed-case">G</jats:styled-content> dose regimen may be optimized to minimize side effects and render it a potential anticancer therapeutic.</jats:p>