Novel SN38 derivative-based liposome as anticancer prodrug: an in vitro and in vivo study

Abstract

BackgroundMany novel drug delivery systems have been extensively studied to exploit the full therapeutic potential of SN38, which is one of the most potent antitumor analogs of camptothecins (CPTs), whose clinical application is seriously hindered by poor water solubility, low plasmatic stability, and severe toxicity, but results are always unsatisfactory.MethodsIn this study, combining the advantages of prodrug and nanotechnology, a lipophilic prodrug of SN38, SN38-PA, was developed by conjugating palmitic acid to SN38 via ester bond at C10 position, and then the lipophilic prodrug was encapsulated into a long-circulating liposomal carrier by film dispersion method.ResultsThe SN38-PA liposomes were characterized as follows: an average particle size of 80.13 nm, an average zeta potential of −33.53 mv, and the entrapment efficiency of 99%. Compared with CPT-11, SN38-PA liposome was more stable in close lactone form, more efficient in conversion rate to SN38, and more potent in cytotoxicity against tumor cells. Pharmacokinetic study showed that SN38-PA liposome had significantly enhanced plasma half-life (t1/2) value of SN38 and increased area under the curve (AUC) of SN38, which was 7.5-fold higher than that of CPT-11. Biodistribution study showed that SN38-PA liposome had more active metabolite SN38 in each tissue. Finally, the pharmacodynamic study showed that SN38-PA liposome had higher antitumor effect with the antitumor inhibition rate of 1.61 times than that of CPT-11.ConclusionThese encouraging data merit further investigation on this novel SN38-PA liposome.

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

“…Liposomes are phospholipid bilayers equipped with inner aqueous pockets that are used as drug delivery enhancers of hydrophobic and hydrophilic agents [ 108 ]. Liposomes provide a protective layer that shelters encapsulated drug from the structural alterations or chemical degradation [ 109 ]. Furthermore, the covalent adherence of polyethylene glycol (PEG) molecules can be used to improve the systemic circulation of drugs [ 110 ].…”

BPRDP056, a novel small molecule drug conjugate specifically targeting phosphatidylserine for cancer therapy

“…In previous pharmacokinetic studies from literature and tumor-bearing mice PK study in the present study, the results showed that the plasma concentration of SN38 which is the major metabolite of CPT-11 gave a log-linear decrease [ 30 ]. CPT-11 has a large CL and theoretical V ss of pharmacokinetic parameter in vivo [ 31 , 32 ]. A large V ss may indicate rapid and extensive uptake into most tissues which may lead to an off-target toxicity for a cancer chemotherapeutics.…”

Current Landscape in Organic Nanosized Materials Advances for Improved Management of Colorectal Cancer Patients

“…For IRI delivery, several liposomal formulations have been developed and exhibited superior anticancer potential when compared with the free drug, and many of these formulations encapsulate directly IRI's active metabolite SN-38 [132,149,[156][157][158][159]. For example, Xing et al [149] developed, by the ethanol injection method, stable liposomal carriers of moeixitecan, a lipophilic SN38 prodrug. Their outcomes depicted a superior cytotoxic activity and a significantly increased proapoptotic potential than free IRI and moeixitecan in HT-29 tumor cell cultures.…”