Tumor-targeted bioconjugate based delivery of camptothecin: design, synthesis and in vitro evaluation

J Control Release. 2004 Nov 24;100(2):275-92. doi: 10.1016/j.jconrel.2004.08.030.

Abstract

Camptothecin (CPT) presents numerous challenges associated with optimal transport and delivery including variability in clinically observed effects, low target tissue concentrations and severe and unpredictable toxicity. The objective of the present study was to optimize the delivery of CPT by targeting it to cancer cells using an endogenous receptor system. A novel CPT bioconjugate was synthesized using carbodiimide chemistry with a linear poly(ethylene glycol) (PEG) and amino acid glycine as the spacer and linker respectively. Folic acid was used as the targeting ligand to take advantage of folate receptor mediated endocytosis. The bioconjugate was extensively characterized using MALDI, proton NMR, FT-IR and amino acid analysis. Furthermore, the bioconjugate was evaluated in vitro for specific targeting to folate receptor-expressing KB cells, a human nasopharyngeal carcinoma. Finally, the delivery system was evaluated for cytotoxicity using a MTT based assay. The results indicate significantly higher efficacy of the bioconjugate in comparison to CPT. A control conjugate without PEG demonstrated no improvement in efficacy over untargeted CPT emphasizing the importance of spacer between the anticancer compounds and targeting moiety. This bioconjugate represents the 'first-in-series' of targeted bioconjugates and serves as prototype for improving tumor cell concentration and efficacy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / chemistry
  • CHO Cells
  • Camptothecin / administration & dosage*
  • Camptothecin / chemistry
  • Carboxylic Acids / chemistry
  • Carrier Proteins / biosynthesis
  • Cell Survival / drug effects
  • Chemistry, Pharmaceutical
  • Cricetinae
  • Drug Delivery Systems*
  • Drug Design
  • Drug Stability
  • Electrophoresis, Polyacrylamide Gel
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / metabolism
  • Folate Receptors, GPI-Anchored
  • Folic Acid / metabolism
  • Humans
  • KB Cells
  • Lactones / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Receptors, Cell Surface / biosynthesis
  • Spectroscopy, Fourier Transform Infrared

Substances

  • Antineoplastic Agents, Phytogenic
  • Carboxylic Acids
  • Carrier Proteins
  • Fluorescent Dyes
  • Folate Receptors, GPI-Anchored
  • Lactones
  • Receptors, Cell Surface
  • Folic Acid
  • Camptothecin