{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T20:12:30Z","timestamp":1793391150229,"version":"4.5.0"},"reference-count":24,"publisher":"National Academy of Sciences","issue":"16","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,4,17]]},"abstract":"<jats:p>\n                    Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic \u03b2-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of \u03b2-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to &gt;1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    and pharmacokinetic coordination of drug combinations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1117147109","type":"journal-article","created":{"date-parts":[[2012,4,3]],"date-time":"2012-04-03T01:11:02Z","timestamp":1333415462000},"page":"6211-6216","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":103,"title":["Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates"],"prefix":"10.1073","volume":"109","author":[{"given":"Daniel V.","family":"Santi","sequence":"first","affiliation":[{"name":"ProLynx, Hayward, CA 94545"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric L.","family":"Schneider","sequence":"additional","affiliation":[{"name":"ProLynx, Hayward, CA 94545"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Reid","sequence":"additional","affiliation":[{"name":"ProLynx, Hayward, CA 94545"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Robinson","sequence":"additional","affiliation":[{"name":"ProLynx, Hayward, CA 94545"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Ashley","sequence":"additional","affiliation":[{"name":"ProLynx, Hayward, CA 94545"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,4,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1039\/c1py00034a"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.21278"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2007.02.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(02)00180-1"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm8002558"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0497693"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0043-1354(78)90133-1"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.3891\/acta.chem.scand.18-0904"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1039\/p29770001914"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1039\/B917797C"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)51667-7"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja01094a025"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1758"},{"key":"e_1_3_3_14_2","doi-asserted-by":"crossref","unstructured":"MD Walsh et al. 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