Controlled synthesis of camptothecin-polylactide conjugates and nanoconjugates

Bioconjug Chem. 2010 Jan;21(1):111-21. doi: 10.1021/bc900356g.

Abstract

We report here a unique method of formulating camptothecin-polylactide (CPT-PLA) conjugate nanoparticles, termed nanoconjugates (NCs), through CPT/(BDI)ZnN(TMS)(2) [(BDI) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-bisalkyl)-imino)-2-pentene] mediated polymerization of lactide (LA) followed by nanoprecipitation. When CPT was used as the initiator to polymerize LA in the presence of (BDI)ZnN(TMS)(2), the polymerization was completed within hours with nearly 100% CPT loading efficiency and 100% LA conversion. CPT loading as high as 19.5% can be achieved for the CPT-polylactide (CPT-PLA) conjugate prepared at a LA/CPT ratio of 10. The steric bulk of the chelating ligands and the type of metals used had a dramatic effect on the initiation of the LA polymerization and the tendency of the ring-opening of the CPT lactone. The CPT/(BDI)ZnN(TMS)(2)-mediated LA polymerization yielded CPT-PLA conjugates with well-controlled molecular weights and narrow molecular weight distributions (1.02-1.18). The nanoprecipitation of CPT-PLA led to the formation of NCs around 100 nm in size with narrow particle size distributions. Sustained release of CPT from CPT-PLA NCs was achieved without burst release. CPT-PLA NCs were toxic to PC-3 cells with tunable IC(50) possible by adjusting the drug loading of the CPT-PLA NCs.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemical synthesis*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / toxicity
  • Biocompatible Materials / chemical synthesis*
  • Biocompatible Materials / chemistry
  • Biocompatible Materials / toxicity
  • Camptothecin / chemistry*
  • Cell Line, Tumor
  • Drug Stability
  • Humans
  • Inhibitory Concentration 50
  • Lactones / chemistry
  • Molecular Structure
  • Molecular Weight
  • Nanoparticles / chemistry*
  • Particle Size
  • Polyesters / chemistry*
  • Solubility
  • Succinic Anhydrides / chemistry

Substances

  • Antineoplastic Agents, Phytogenic
  • Biocompatible Materials
  • Lactones
  • Polyesters
  • Succinic Anhydrides
  • poly(lactide)
  • succinic anhydride
  • Camptothecin