Abstract
BackgroundHydroxycamptothecin (HCPT) has been shown to have activity against a broad spectrum of cancers. In order to enhance its tissue-specific delivery and anticancer activity, we prepared HCPT-loaded nanoparticles made from poly(ethylene glycol)-poly(γ-benzyl-L-glutamate) (PEG-PBLG), and then studied their release characteristics, pharmacokinetic characteristics, and anticancer effects. PEG-PBLG nanoparticles incorporating HCPT were prepared by a dialysis method. Scanning electron microscopy (SEM) was used to observe the shape and diameter of the nanoparticles. The HCPT release characteristics in vitro were evaluated by ultraviolet spectrophotometry. A high-performance liquid chromatography (HPLC) detection method for determining HCPT in rabbit plasma was established. The pharmacokinetic parameters of HCPT/PEG-PBLG nanoparticles were compared with those of HCPT.ResultsThe HCPT-loaded nanoparticles had a core-shell spherical structure, with a core diameter of 200 nm and a shell thickness of 30 nm. Drug-loading capacity and drug encapsulation were 7.5 and 56.8%, respectively. The HCPT release profile was biphasic, with an initial abrupt release, followed by sustained release. The terminal elimination half-lives (t 1/2 β) of HCPT and HCPT-loaded nanoparticles were 4.5 and 10.1 h, respectively. Peak concentrations (Cmax) of HCPT and HCPT-loaded nanoparticles were 2627.8 and 1513.5 μg/L, respectively. The apparent volumes of distribution of the HCPT and HCPT-loaded nanoparticles were 7.3 and 20.0 L, respectively. Compared with a blank control group, Lovo cell xenografts or Tca8113 cell xenografts in HCPT or HCPT-loaded nanoparticle treated groups grew more slowly and the tumor doubling times were increased. The tumor inhibition effect in the HCPT-loaded nanosphere-treated group was significantly higher than that of the HCPT-treated group (p < 0.01). Tumor inhibition in the control group by PEG-PBLG nanoparticles was not observed (p > 0.05).ConclusionCompared to the HCPT- and control-treated groups, the HCPT-loaded nanoparticle-treated group showed a more sustained release, a longer circulation time, increased delivery to tissue, and an enhanced anticancer effect. HCPT-loaded nanoparticles appear to change the pharmacokinetic behavior of HCPT in vivo.
Highlights
Hydroxycamptothecin (HCPT) has been shown to have activity against a broad spectrum of cancers
The hydrophilic block forms the hydrated outer shell, which plays a role in preventing uptake by the reticuloendothelial system (RES) [2,4]
Nanoparticles made from poly(γ-benzyl L-glutamate) (PBLG) and poly(ethylene oxide) (PEG) are hydrophilichydrophobic diblock copolymers which have these predominant characteristics [6,7]
Summary
Hydroxycamptothecin (HCPT) has been shown to have activity against a broad spectrum of cancers. In order to enhance its tissue-specific delivery and anticancer activity, we prepared HCPT-loaded nanoparticles made from poly(ethylene glycol)-poly(γ-benzyl-L-glutamate) (PEG-PBLG), and studied their release characteristics, pharmacokinetic characteristics, and anticancer effects. PEG-PBLG nanoparticles incorporating HCPT were prepared by a dialysis method. The predominant characteristics of these copolymers that have been reported include solubilization of hydrophobic drugs, sustained release, selective targeting, and lower interactions with the RES [2,4,5]. Nanoparticles made from poly(γ-benzyl L-glutamate) (PBLG) and poly(ethylene oxide) (PEG) are hydrophilichydrophobic diblock copolymers which have these predominant characteristics [6,7]. This PEG-PBLG copolymeric carrier may serve as an appropriate vehicle for drug delivery [6,7]
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