Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting.

Masayori Hagimori,Marie Pierre Krafft,Estefanía E Mendoza-Ortega

doi:10.3762/bjoc.17.45

Abstract

Ligand-targeted microbubbles are focusing interest for molecular imaging and delivery of chemotherapeutics. Lipid–peptide conjugates (lipopeptides) that feature alternating serine–glycine (SG)n segments rather than classical poly(oxyethylene) linkers between the lipid polar head and a targeting ligand were proposed for the liposome-mediated, selective delivery of anticancer drugs. Here, we report the synthesis of perfluoroalkylated lipopeptides (F-lipopeptides) bearing two hydrophobic chains (CnF2n+1, n = 6, 7, 8, 1–3) grafted through a lysine moiety on a hydrophilic chain composed of a lysine–serine–serine (KSS) sequence followed by 5 SG sequences. These F-lipopeptides are precursors of targeting lipopeptide conjugates. A hydrocarbon counterpart with a C10H21 chain (4) was synthesized for comparison. The capacity for the F-lipopeptides to spontaneously adsorb at the air/water interface and form monolayers when combined with dipalmitoylphosphatidylcholine (DPPC) was investigated. The F-lipopeptides 1–3 demonstrated a markedly enhanced tendency to form monolayers at the air/water interface, with equilibrium surface pressures reaching ≈7–10 mN m−1 versus less than 1 mN m−1 only for their hydrocarbon analog 4. The F-lipopeptides penetrate in the DPPC monolayers in both liquid expanded (LE) and liquid condensed (LC) phases without interfacial film destabilization. By contrast, 4 provokes delipidation of the interfacial film. The incorporation of the F-lipopeptides 1–3 in microbubbles with a shell of DPPC and dipalmitoylphosphatidylethanolamine-PEG2000 decreased their mean diameter and increased their stability, the best results being obtained for the C8F17-bearing lipopeptide 3. By contrast, the hydrocarbon lipopeptide led to microbubbles with a larger mean diameter and a significantly lower stability.

Highlights

Various nano- and microsystems, including micelles, liposomes, and microbubbles, have been developed as imaging agents and to selectively deliver chemotherapeutics to tumor cells [1,2,3,4,5,6]
In order to investigate the capacity for F-lipopeptides 1–3 to spontaneously self-assemble into ordered monolayers at the air/water interface, we injected a solution of each peptide–lipid conjugate in DMSO into the aqueous subphase of an adsorption trough
The F-lipopeptide conjugates 1–3 and hydrocarbon analog 4 were obtained by a Fmoc solid-phase peptide synthesis method, in which the peptide sequence was stepwisely elongated, and eventually conjugated with theethyl acids

Summary

Introduction

Various nano- and microsystems, including micelles, liposomes, and microbubbles, have been developed as imaging agents and to selectively deliver chemotherapeutics to tumor cells [1,2,3,4,5,6]. One of our general objectives is to synthesize lipopeptides designed for the incorporation in the phospholipid shell of medical microbubbles (MBs) (Scheme 1a). Scheme 1: a) Schematic representation of a perfluorohexane-stabilized microbubble with a fluorinated lipopeptide anchored in its phospholipid shell and b) structures of the perfluoroalkylated lipopeptides 1–3 and of the hydrocarbon analog 4.

Results

Conclusion