| Title | Site-specific PEGylation endows a mammalian ribonuclease with antitumor activity |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Rutkoski, TJ, Kink, JA, Strong, LE, Raines, RT |
| Journal | Cancer Biology & Therapy |
| Volume | 12 |
| Pagination | 208-214 |
| Date Published | Aug |
| Keywords | Abel RL, 2002, V306, P100, Arnold U, 2006, V28, P1615, binding, Bioconjugation, biologic drug, Boix E, 1996, V257, P992, bovine seminal ribonuclease, Bretscher LE, 2000, V275, P9893, CALICETI P, 1990, V3, P89, cancer, catalytic-activity, cellular uptake, Chao TY, 2010, V49, P10666, Chapman AP, 2002, V54, P531, cytotoxic ribonucleases, Cytotoxin, enzymes, Fang EF, 2011, V1815, P65, Fishburn CS, 2008, V97, P4167, Fuchs SM, 2006, V63, P1819, Futami J, 2001, V40, P7518, Greenwald RB, 2003, V55, P217, Haigis MC, 2003, V31, P1024, Harris JM, 2003, V2, P214, HIAVON O, 1991, V46, P967, human pancreatic ribonuclease, inhibitor protein, Johnson RJ, 2007, V368, P434, Johnson RJ, 2007, V46, P10308, Kelemen BR, 1999, V27, P3696, KIM JS, 1995, V308, P547, Klink TA, 2000, V275, P17463, Kobe B, 1996, V264, P1028, Kothandaraman S, 1998, V251, P264, KURFURST MM, 1992, V200, P244, Lavis LD, 2007, V79, P6775, LCARDAYRE SB, 1994, V33, P6031, LEE FS, 1989, V28, P225, Lee JE, 2008, V22, P53, Leland PA, 1998, V95, P10407, Matousek J, 2002, V82, P29, Matousek J, 2003, V136, P343, Matousek J, 2004, V94, P401, MESSMORE JM, 1995, V117, P8057, modification, MONFARDINI C, 1995, V6, P62, MURDOCK AL, 1966, V114, P375, Oncology, Pasut G, 2008, V60, P69, pharmacokinetics, poly(ethylene glycol), RIBO M, 1994, V375, P357, ribonuclease, Ribonuclease inhibitor, rnase-a, Rutkoski TJ, 2005, V354, P41, Rutkoski TJ, 2008, V9, P185, Rutkoski TJ, 2010, V21, P1691, site-directed mutagenesis, Smith BD, 2003, V278, P20934, Soncin F, 1997, V272, P9818, surface, TARNOWSKI GS, 1976, V36, P4074, Turcotte RF, 2009, V276, P4270, VENKATACHALAM MA, 1978, V43, P337, VERONESE FM, 1985, V11, P141, xenograft, YAMAOKA T, 1994, V83, P601 |
| Abstract | Mammalian ribonucleases are emerging as cancer chemotherapeutic agents. Their cationicity engenders cell permeability, and their enzymatic activity destroys the biochemical information encoded by RNA. The pharmacologic potential of ribonucleases is, however, obviated by their high sensitivity to a cytosolic inhibitor protein (RI) and their small size, which limits their residence in serum. We reasoned that site-specific conjugation of a poly(ethylene glycol) (PEG) chain could both reduce sensitivity to RI and increase serum half-life. We found that appending a PEG moiety can enable bovine pancreatic ribonuclease (RNase A) to evade RI, depending on the site of conjugation and the length and branching of the chain. Although a pendant PEG moiety decreases antiproliferative activity in vitro, PEGylation discourages renal clearance in vivo and leads to nearly complete tumor growth inhibition in a mouse xenograft model. These data demonstrate that a pendant PEG moiety can be beneficial to the action of proteins that act within the cytosol, and that strategic site-specific PEGylation can endow a mammalian ribonuclease with potent antitumor activity.
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