Synthesis of a macromolecular camptothecin conjugate with dual phase drug release

Abstract

A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

Figures

Figure 1

Two stages of drug release from a succinamido ester linked conjugate.

Figure 2

The structure of PHF, copolymer (copolyacetal) of glycerol and glycol aldehyde.

Figure 3

Prodrug release from PHF–CPT in rat plasma at 37 °C. Inset: log linearization of PHF–CPT kinetics. Mean values from two independent experiments, for all points SD p < 0.05.

Figure 4

Biokinetics of PHF–CPT conjugate (111In-DTPA labeled PHF backbone and 3H labeled CPT).

Figure 5

Biodistribution of the carrier polymer (111In) and CPT (3H) 24 h post iv administration of double-labeled PHF–CPT. Xenograft: HT29, 0.1–0.15 mL tumors; n = 6 per group.

Figure 6

Microdistribution of CPT in tumor tissue 24 h post administration of PHF–CPT. CPT fluorescence (left) and phase contrast (right) images of the same region. Unstained unfixed 15 μm slice. Field: 80 × 130 μm.