Protective interactive noncondensing (PINC) polymers for enhanced plasmid distribution and expression in rat skeletal muscle

• Published in: Journal of controlled release Vol. 52; no. 1; pp. 191 - 203
• Main Authors: Mumper, Russell J, Wang, Jijun, L. Klakamp, Scott, Nitta, Hiro, Anwer, Khursheed, Tagliaferri, Frank, Rolland, Alain P
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 02.03.1998; Elsevier
• Subjects: Animals; beta-Galactosidase - metabolism; Biological and medical sciences; Ethidium; Gene delivery; Gene Expression; General pharmacology; Hydrogen bonding; Hydrogen-Ion Concentration; Immunohistochemistry; Interactive; Male; Medical sciences; Models, Molecular; Muscle; Muscle, Skeletal - metabolism; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Plasmid; Plasmids; Poly(N-vinyl pyrrolidone); Polyvinyl Alcohol - pharmacology; Povidone - pharmacology; Rats; Rats, Inbred F344; Plasmid; Gene delivery; Muscle; Poly(N-vinyl pyrrolidone); Hydrogen bonding; Interactive; Rat; Molecular interaction; Gene; Pyrrolidone(vinyl) polymer; Structure activity relation; Protection; Release; β-Galactosidase; Pharmaceutical technology; Enzyme; Control release polymer; Rodentia; Gene expression; Striated muscle; Polyvinylalcohol; In vivo; Vertebrata; Mammalia; Glycosidases; Animal; Distribution; Hydrolases; O-Glycosidases; Hydrogen bond
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(97)00215-0

We have developed protective interactive noncondensing (PINC) polymers, such as poly(N-vinyl pyrrolidone) (PVP) and poly(vinyl alcohol) (PVA), to protect plasmids from extracellular nuclease degradation while allowing the flexible complex to diffuse throughout the muscle tissue. Molecular modeling, zeta potential modulation, and ethidium bromide intercalation studies were performed to assess the mechanism of interaction between PVP and plasmid. The effect of salt concentration, pH, and polymer–plasmid ratios were investigated. We have correlated these variables with β-galactosidase (β-gal) expression after intramuscular administration to rats. PVP can form hydrogen bonds with the base pairs within the major groove of DNA at pH 4.0. The PVP–plasmid interaction results in a complex that is more hydrophobic (less negatively charged) than the uncomplexed plasmid due to the vinyl backbone of PVP. Up to a ten-fold enhancement in gene expression in rat muscle over the use of `naked' DNA has been demonstrated using these systems. A linear structure–activity relationship (SAR) was found between the percent vinyl pyrrolidone monomer content in poly(vinyl pyrrolidone-covinyl acetate) polymers and β-gal expression in muscle. Modulation of the interaction between PINC polymers and plasmid directly impacts the levels of gene expression in vivo. The linear SAR is being used to design novel PINC polymers with enhanced binding affinity to plasmids.