PMID- 23063368
OWN - NLM
STAT- MEDLINE
DCOM- 20130326
LR  - 20240321
IS  - 1878-5905 (Electronic)
IS  - 0142-9612 (Print)
IS  - 0142-9612 (Linking)
VI  - 34
IP  - 1
DP  - 2013 Jan
TI  - Distinct mechanisms of membrane permeation induced by two polymalic acid 
      copolymers.
PG  - 217-25
LID - S0142-9612(12)00905-2 [pii]
LID - 10.1016/j.biomaterials.2012.08.016 [doi]
AB  - Anionic polymers are valuable components used in cosmetics and health sciences, 
      especially in drug delivery, because of their chemical versatility and low 
      toxicity. However, because of their highly negative charge they pose problems for 
      penetration through hydrophobic barriers such as membranes. We have engineered 
      anionic polymalic acid (PMLA) to penetrate biological membranes. PMLA copolymers 
      of leucine ethyl ester (P/LOEt) or trileucine (P/LLL) show either pH-independent 
      or pH-dependent activity for membrane penetration. We report here for the first 
      time on the mechanisms which are different for those two copolymers. Formation of 
      hydrophobic patches in either copolymer is detected by fluorescence techniques. 
      The copolymers display distinctly different properties in solution and during 
      membranolysis. P/LOEt copolymer binds to membrane as single molecules with high 
      affinity, and induces leakage cooperatively through a mechanism known as "carpet" 
      model, in which the polymer aligns at the surface throughout the entire process 
      of membrane permeation. In contrast, P/LLL self-assembles to form an oligomer of 
      105 nm in a pH-dependent manner (pKa 5.5) and induces membrane leakage through a 
      two-phase process: the concentration dependent first-phase of insertion of the 
      oligomer into membrane followed by a concentration independent second-phase of 
      rearrangement of the membrane-oligomer complex. The insertion of P/LLL is 
      facilitated by hydrophobic interactions between trileucine side chains and lipids 
      in the membrane core, resulting in transmembrane pores, through mechanism known 
      as "barrel-stave" model. The understanding of the mechanism paves the way for 
      future engineering of polymeric delivery systems with optimal cytoplasmic 
      delivery efficiency and reduced systemic toxicity.
CI  - Published by Elsevier Ltd.
FAU - Ding, Hui
AU  - Ding H
AD  - Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, 
      USA. Hui.Ding@cshs.org
FAU - Portilla-Arias, Jose
AU  - Portilla-Arias J
FAU - Patil, Rameshwar
AU  - Patil R
FAU - Black, Keith L
AU  - Black KL
FAU - Ljubimova, Julia Y
AU  - Ljubimova JY
FAU - Holler, Eggehard
AU  - Holler E
LA  - eng
GR  - R01 CA123495/CA/NCI NIH HHS/United States
GR  - R01 CA136841/CA/NCI NIH HHS/United States
GR  - U01 CA151815/CA/NCI NIH HHS/United States
GR  - R01 CA 136841/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121009
PL  - Netherlands
TA  - Biomaterials
JT  - Biomaterials
JID - 8100316
RN  - 0 (Esters)
RN  - 0 (Liposomes)
RN  - 0 (Malates)
RN  - 0 (Oligopeptides)
RN  - 0 (Polymers)
RN  - 0 (Rhodamines)
RN  - 0 (Solutions)
RN  - 0 (poly(malic acid))
RN  - L6HEL5ZI2V (leucyl-leucyl-leucine)
SB  - IM
MH  - Esters/chemistry
MH  - Fluorescence Resonance Energy Transfer
MH  - Hydrodynamics
MH  - Hydrogen-Ion Concentration/drug effects
MH  - Hydrophobic and Hydrophilic Interactions/drug effects
MH  - Kinetics
MH  - Liposomes/chemistry
MH  - Malates/chemical synthesis/chemistry/*pharmacology
MH  - Membranes/abnormalities
MH  - Microscopy, Confocal
MH  - Oligopeptides/chemistry
MH  - Particle Size
MH  - Permeability/drug effects
MH  - Polymers/chemical synthesis/chemistry/*pharmacology
MH  - Rhodamines/metabolism
MH  - Solutions
MH  - Temperature
PMC - PMC3487713
MID - NIHMS410447
EDAT- 2012/10/16 06:00
MHDA- 2013/03/27 06:00
PMCR- 2014/01/01
CRDT- 2012/10/16 06:00
PHST- 2012/07/24 00:00 [received]
PHST- 2012/08/09 00:00 [accepted]
PHST- 2012/10/16 06:00 [entrez]
PHST- 2012/10/16 06:00 [pubmed]
PHST- 2013/03/27 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - S0142-9612(12)00905-2 [pii]
AID - 10.1016/j.biomaterials.2012.08.016 [doi]
PST - ppublish
SO  - Biomaterials. 2013 Jan;34(1):217-25. doi: 10.1016/j.biomaterials.2012.08.016. 
      Epub 2012 Oct 9.