Fujiwara, Mitsuko (1993) Characterization of pH-dependent poly(acrylic acid)-vesicle interaction and its application in cellular drug delivery. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:11262012-114541543
Polymers can be used to control drug targeting and drug release from phospholipid vesicles through changes in pH. Understanding the effect of polymers on vesicle properties is important in obtaining a better control over drug delivery using phospholipid vesicles. The pH-dependent interaction of poly(acrylic acid) (PAA) with phosphatidylcholine (PC) vesicles (bilayers) and monolayers was investigated to elucidate the mechanism of P AA-induced vesicle destabilization. PAA induced aggregation of vesicles below pH 4.6 and lipid intermixing of vesicles below pH 4.1. Mixing of aqueous contents was not observed, indicating that the process is not a true membrane fusion. An increase in the membrane permeability accompanied lipid intermixing of vesicles. Both the hydrocarbon chain and phospholipid headgroup packing was more disordered from polymer association as evidenced by the increase in the CH_2 asymmetric stretching peakwidth and peak position and by the increase in the binding of potential-sensitive dye to the vesicle surface, respectively. Polymer binding to vesicles at pH 3.8 showed a negative cooperativity with a K_b of 1.5 x 10^6 M^(-1).The driving force for PAA adsorption on vesicles is the formation of hydrogen-bonds between the protonated carboxyl groups of the polymer and the phospholipid molecule. The polymer mobility was restricted upon complexation with vesicles as evidenced by the anisotropy measurements of polymerassociated fluorophore. The polymer-associated vesicles exhibited fused vesicles and tubular structures in freeze-fracture images. Formation of nonbihyer phases or phase separation was not detected in freeze-fracture images or ^(31)P-NMR powder spectra of PC vesicles. PAA induced expansion of PC monolayers at low pH, and the extent of expansion was dependent on the monolayer surface pressure and on the pH of the subphase. Polymer-induced expansion became more difficult at increasing monolayer packing density and increasing pH. Therefore PAA-induced destabilization of vesicles is believed to be initiated by partial penetration of PAA on vesicle surface. The stress on the membrane created by PAA association presumably resulted in the rupture of bilayer and lipid intermixing of vesicles.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Degree Grantor:||California Institute of Technology|
|Division:||Chemistry and Chemical Engineering|
|Thesis Availability:||Restricted to Caltech community only|
|Defense Date:||26 February 1993|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Dan Anguka|
|Deposited On:||26 Nov 2012 21:17|
|Last Modified:||24 Jan 2013 22:56|
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