Poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin with enhanced cellular uptake

Surface modification of nanoparticles with poly (ethylene glycol) (PEG) shows poor cellular uptake, although it affords long circulation time and passive targeting potential to the tumor tissue. In this research, poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin (CPT) was developed, in order to enhance the cellular uptake ability, achieve the passive targeting potential to tumor tissue and long circulation time, and to improve the stability of CPT in aqueous media. Firstly, the five-member rings in poly (l-succinimide) (PSI) were successively opened by the amino terminated disulfide-linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH2) and 6-aminocaproic acid to produce the graft copolymer of mPEG-SS-NH-g-PHAsp. And then, the resultant prodrug of mPEG-SS-NH-g-PHAsp-CPT was obtained by the esterification between carboxylic groups of mPEG-SS-NH-g-PHAsp and 20-OH of CPT. The prodrug was able to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of about 100 nm measured by dynamic light scattering (DLS), suggesting its passive targeting potential to tumor tissue. Due to the detachment of PEG shell in the presence of dithiothreitol (DTT), the nanomicelle showed a tendency to aggregation, intense release of CPT, and enhanced cellular uptake ability. Also, the mPEG-SS-NH-g-PHAsp-CPT nanomicelle effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Compared with free CPT, mPEG-SS-NH-g-PHAsp-CPT nanomicelle showed essentially decreased cytotoxicity against L929 cell line in 24 h, especially at high dosage, indicating its great potential as tumor tissue targeted prodrug.

Figure optionsDownload as PowerPoint slideHighlights
► mPEG-SS-NH-g-PHAsp-CPT nanomicelles with sheddable PEG structure were fabricated.
► The detachment of PEG in reduction environment resulted in significantly improved cellular uptake of micells.
► The micelle effectively protected the active lactone ring of CPT from hydrolysis and showed a reduction-sensitive drug release profiles.
► The nanomicelles showed decreased cytotoxicity against L929 cell line compared with free CPT.