Poly-γ-l-glutamic acid (PGA) is an outstanding drug carrier candidate owning to its excellent biodegradability and biocompatibility. The PGA carrier may shield toxic drugs from the body and enable the delivery of poorly soluble or unstable drugs and thereby minimize the side effects and improve drug efficacy. However, the limitation of PGA as a drug carrier is low drug loading efficiency (DLE), which is usually below 30%. In this study, we reported a chemical modification method using l-phenylalanine ethyl ester (PAE). PGA-PAE construct was amphiphilic, which could form micelles in aqueous solution. Cisplatin (CDDP), a commonly used chemotherapy drug whose side effect is well-known, was used as a model molecule to test the drug-loading efficiency of PGA-PAE. In this paper, two sizes of CDDP-loaded PGA-PAE micelles (M(Pt)-1 and M(Pt)-2) were prepared, the average diameter of M(Pt)-1 was 106 ± 6 nm and M(Pt)-2 was 210 ± 9 nm. The DLE of M(Pt)-1 and M(Pt)-2 was 52.8 ± 2.2 and 55.8 ± 1.2%, respectively. Both exhibited excellent biocompatibility, stability, and drug-retaining capability in physiological condition. The in vitro accumulative drug-releasing profile, IC50 for different tumor cell lines HeLa, A549, and HCCC9810, and in vivo pharmacokinetics were similar between these two micelles; however, M(Pt)-1 showed higher tumor tissue retention and longer efficient cancer cell internalization time (up to 20 d). Our results suggested PGA-PAE micelle carriers reduced the toxicity of CDDP and its size at around 100 nm was the better for CDDP high-efficacy.
Keywords: EPR effect; cisplatin; drug-loading efficiency; micelles; poly-γ-l-glutamic acid (PGA).