Preparation, characterization and application of star-shaped PCL/PEG micelles for the delivery of doxorubicin in the treatment of colon cancer

Abstract

Star-shaped polymer micelles have good stability against dilution with water, showing promising application in drug delivery. In this work, biodegradable micelles made from star-shaped poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymer were prepared and used to deliver doxorubicin (Dox) in vitro and in vivo. First, an acrylated monomethoxy poly (ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) diblock copolymer was synthesized, which then self-assembled into micelles, with a core-shell structure, in water. Then, the double bonds at the end of the PCL blocks were conjugated together by radical polymerization, forming star-shaped MPEG-PCL (SSMPEG-PCL) micelles. These SSMPEG-PCL micelles were monodispersed (polydispersity index = 0.11), with mean diameter of ≈25 nm, in water. Blank SSMPEG-PCL micelles had little cytotoxicity and did not induce obvious hemolysis in vitro. The critical micelle concentration of the SSMPEG-PCL micelles was five times lower than that of the MPEG-PCL micelles. Dox was directly loaded into SSMPEG-PCL micelles by a pH-induced self-assembly method. Dox loading did not significantly affect the particle size of SSMPEG-PCL micelles. Dox-loaded SSMPEG-PCL (Dox/SSMPEG-PCL) micelles slowly released Dox in vitro, and the Dox release at pH 5.5 was faster than that at pH 7.0. Also, encapsulation of Dox in SSMPEG-PCL micelles enhanced the anticancer activity of Dox in vitro. Furthermore, the therapeutic efficiency of Dox/SSMPEG-PCL on colon cancer mouse model was evaluated. Dox/SSMPEG-PCL caused a more significant inhibitory effect on tumor growth than did free Dox or controls (P , 0.05), which indicated that Dox/SSMPEG-PCL had enhanced anticolon cancer activity in vivo. Analysis with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed that Dox/SSMPEG-PCL induced more tumor cell apoptosis than free Dox or controls. These results suggested that SSMPEG-PCL micelles have promising application in doxorubicin delivery for the enhancement of anticancer effect.

Synthesis of three-arm block copolymer poly(lactic-<em>co</em>-glycolic acid)&ndash;poly(ethylene glycol) with oxalyl chloride and its application in hydrophobic drug delivery

“…All kinds of aliphatic polyesters, such as poly(l-lactic acid) (PLA), 14,15 poly(ε-caprolactone), 13,16 and poly(lacticco-glycolic acid) (PLGA), 17 have been linked with a hydrophilic polyethylene glycol (PEG) segment to yield the amphiphilic copolymer structure. 18 In 1994, the effect on pharmacokinetics of PLGA microparticles externally coated with PEG was first described.…”

Transferrin-modified nanostructured lipid carriers as multifunctional nanomedicine for codelivery of DNA and doxorubicin

“…Doxorubicin (DOX) is widely used as a single agent or in combination with other regimens for various kinds of solid tumors. [42][43][44] However, dose-limiting toxic side effects, such as cardiotoxicity, myelosuppression, mucositis, and alopecia, limit the clinical application of DOX, owing to its nonspecifc distribution to healthy normal tissues. 45,46 It is necessary to improve the anticancer activity and reduce the systemic toxicity of DOX with development of drug delivery systems.…”

Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy

“…Free DOX could pass through the filter, but FA-NPs/DOX could not pass through the filter. Unincorporated DOX in the solution was quantified by determining the absorbance at 485 nm using a spectrophotometer (Gao et al, 2013). DL and EE were calculated using the following equations:…”