Construction of Dimeric Drug-Loaded Polymeric Micelles with High Loading Efficiency for Cancer Therapy

Abstract

Polymeric micelles (PMs) have been applied widely to transport hydrophobic drugs to tumor sites for cancer treatment. However, the low load efficiency of the drug in the PMs significantly reduces the therapeutic efficiency. We report here that disulfide-linked camptothecin (CPT) as a kind of dimeric drug can be effectively embedded in the core of poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) PMs for improving drug-loading efficiency, and PEG can be used as a hydrophilic shell. Moreover, the dimeric CPT-loaded PCL-PEG-PCL PMs exhibited excellent solubility in phosphate-buffered saline (PBS) media and significant cytotoxicity to cancer cells.

Keywords: camptothecin; cancer therapy; dimeric drug; micelles.

Figure 1

Synthesis route of a dimeric camptothecin derivative (CPT–SS–CPT) and poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone) (PCL–PEG–PCL) triblock copolymer (a) and process of the self-assembly of the PCL–PEG–PCL and CPT–SS–CPT (b).

Figure 2

Calibration curve of CPT concentrations (a) and the liquid chromatogram of CPT-loaded PCL–PEG–PCL PMs and CPT–SS–CPT/PMs (b).

Figure 3

Transmission electron microscope (TEM) images (a) and size distribution (b) of CPT–SS–CPT/PMs.

Figure 4

Ultraviolet-visible (UV-vis) absorption spectrum of CPT–SS–CPT in solvent and the CPT–SS–CPT/PMs in aqueous solution.

Figure 5

Photograph of CPT-loaded PCL–PEG–PCL PMs (a) and CPT–SS–CPT-loaded PCL–PEG–PCL PMs (b).

Figure 6

X-ray diffraction (XRD) spectra of CPT and CPT–SS–CPT.

Figure 7

(a) Cell viability of the HepG2 and NIH3T3 cell lines treated with various concentration of CPT, CPT–SS–CPT, and CPT–SS–CPT/PMs (mean ± standard deviation (SD), n = 6,). Each data point in the graph consists of the mean and standard deviation, repeated 6 times. (b) fluorescein diacetate–propidium iodinate (FDA–PI) staining mediated by CPT, and CPT–SS–CPT/PMs at 0.5 μL/mL (CPT concentration; Live cells: green; dead cells: red; scale bar: 100 μm).