Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

Abstract

Using dithioester-capped 2-methacryloyloxyethyl phosphorylcholine (MPC) as a macro chain transfer agent, a diblock copolymer was synthesized with n-butyl methacrylate (BMA) as hydrophobic core-forming blocks. The MPC-BMA unit was copolymerized with an immobilizable unit, p-nitrophenylcarbonyloxyethyl methacrylate (NPMA). The NPMA moiety then was modified by the addition of preS1 domain of hepatitis B surface antigen (HBsAg). This micelle-forming nanoparticle, the poly (MPC-co-BMA-co-NPMA) (PMBN) conjugated with preS1 enables solubilization of paclitaxel (PTX) with increased hepatotropism. The 50% inhibitory concentration (IC 50 ) values of PTX and PTX/PMBN-preS1 against the human hepatocellular carcinoma cell line, HepG2, were 1,008 and 131 nM, respectively (p < 0.05). Conjugation of preS1 to PMBN enhanced strongly the synergistic inhibitory effect of paclitaxel on HepG2 cells in vitro, whereas such a change in IC 50 was not detected against the human squamous cell carcinoma cell line, A431. Tumor growth rates of a HepG2 xenograft in Balb/ c nude mice after intraperitoneal injection of PTX, PTX/PMBN and PTX/PMBN-preS1 were 197.9%, 274.3% and 296.2%*, respectively (*p < 0.05 versus PTX). The local paclitaxel levels after administration of the PMBN-preS1 conjugate were determined in the xenografts by high-performance liquid chromatography and were 8 times higher than that after administration of paclitaxel alone. No side effects attributable to PMBN-preS1 were observed histologically in vital organs, and body weight loss was significantly less in the PTX/PMBN-preS1 group. These studies demonstrate that PMBN-preS1 may be used as a human hepatocyte-specific drug delivery carrier without serious adverse effects.

Cell-penetrating macromolecules: Direct penetration of amphipathic phospholipid polymers across plasma membrane of living cells

“…The poly(MPC-co-BMA) (PMB), which forms nanoassemblies (polymeric aggregates) or nanoparticles in aqueous media depending on the degree of hydrophobicity and molecular weight of the polymers, has considerable potential for therapeutic nanomaterials [13]. Previously, a PMB carrying an antineoplastic drug was demonstrated to exhibit antitumor effects on cancer cells without cytotoxicity both in vitro and in vivo [14][15][16]; however, the mechanism whereby the drug in the PMB was delivered across the plasma membrane of cells remains poorly understood. In this study, we discovered direct penetration mechanism across the plasma membrane of living mammalian cells using fluorescence-tagged PMBs.…”

Effects of copolymer component on the properties of phosphorylcholine micelles

“…This might be related to both disulfide ratio and MPC content in the phosphorylcholine micelles, because high disulfide ratio in copolymer molecules could speed up the drug release under reduction condition ( Figure 4); at the same time, the intact shield of PC of PCL 20 -ss-PMPC 10 micelles could make the micelles easily pass through cell membranes and enter into tumor cells. 23 Both comprehensive effects lead to that PCL 20 -ss-PMPC 10 /DOX micelles showed higher cytotoxicity against HeLa cells than the other PCL-ss-PMPC/DOX micelles. cellular uptake and intracellular drug release It is known that DOX fluorescence is self-quenched inside micelles.…”

“…The phosphorylcholine micelles exhibit excellent properties, eg, good biocompatibility, high drug-loading ability, excellent prolonged circulation and prominent tumor therapy effect. 16,[19][20][21][22][23][24] Zhao et al 16 investigated in detail the drug loading, in vitro phagocytic uptake, blood clearance and biodistribution in vivo of random copolymer phosphorylcholine micelles with different compositions. However, investigations on the relation between the component of phosphorylcholine micelles and their properties are far from enough.…”

Zwitterionic drug nanocarriers: A biomimetic strategy for drug delivery

“…PreS1 conjugated PMBN (PMBN-preS1) strongly enhanced the synergistic inhibitory effect of PTX on HepG2 cells in vitro. Tumor growth of a HepG2 xenograft was strongly inhibited after intraperitoneal injection of PTX/PMBN-preS1 [34].…”