Abstract
Anionic polymers with membrane permeation functionalities are highly desirable for secure cytoplasmic drug delivery. We have developed tritryptophan containing copolymer (P/WWW) of polymalic acid (PMLA) that permeates membranes by a mechanism different from previously described PMLA copolymers of trileucine (P/LLL) and leucine ethyl ester (P/LOEt) that use the "barrel stave" and "carpet" mechanism, respectively. The novel mechanism leads to solubilization of membranes by forming copolymer "belts" around planar membrane "packages." The formation of such packages is supported by results obtained from studies including size-exclusion chromatography, confocal microscopy, and fluorescence energy transfer. According to this "belt" mechanism, it is hypothesized that P/WWW first attaches to the membrane surface. Subsequently the hydrophobic tryptophan side chains translocate into the periphery and insert into the lipid bilayer thereby cutting the membrane into packages. The reaction is driven by the high affinity between the tryptophan residues and lipid side chains resulting in a stable configuration. The formation of the membrane packages requires physical agitation suggesting that the success of the translocation depends on the fluidity of the membrane. It is emphasized that the "belt" mechanism could specifically function in the recognition of abnormal cells with high membrane fluidity and in response to hyperthermia.
Highlights
Delivery of drugs through membrane barriers is an issue in modern nanomedicine comparably important with high water solubility, biodegradability, absence of toxicity, and immunogenicity
We studied the mode of action of membrane permeation and solubilization by P/WWW using model lipid membranes such as liposome and giant unilamellar vesicle
We identified the mechanisms for membrane permeation of PMLA copolymers of trileucine (P/LLL) and P/LOEt following two distinct mechanisms: “barrel stave” and “carpet” [15]
Summary
Delivery of drugs through membrane barriers is an issue in modern nanomedicine comparably important with high water solubility, biodegradability, absence of toxicity, and immunogenicity. We have explored poly(β-L-malic acid) (PMLA) as the molecular platform to deliver antisense oligonucleotides [8,9,10], chemotherapeutic drugs [11, 12], and cancer imaging agents [13]. When conjugated with certain hydrophobic amino acids, the natural hydrophilicity of PMLA was controlled and tuned to become lipophilic for cytoplasmic delivery through endosomal membranes [14]. The substituted PMLA acquired the properties for pH-responsive and constitutive permeation of lipid membranes [14]. These membrane permeating activities depending on the nature of the amino acid side chain were identified using an in vitro liposome leakage assay.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
