Synthesis and characterization of branched poly(L-glutamic acid) as a biodegradable drug carrier.
Polymeric drug delivery systems are used not only to improve aqueous solubility of drug molecules but also to achieve desirable pharmacokinetics and an enhanced therapeutic index. New biodegradable polymers are needed to improve the biodistribution and targeting-ability of polymeric carriers. In this study, the synthesis and characterization of branched poly(L-glutamic acid) (PG) containing multiple PG chains centered on a poly(amidoamine) (PAMAM) dendrimer or polyethyleneimine (PEI) cores were described. The branched PG polymers were obtained by ring-opening polymerization of benzyl ester of L-glutamic acid N-carboxyanhydride using PAMAM or PEI as the initiator. These polymers were degradable in the presence of the lysosomal enzyme cathepsin B, albeit more slowly than linear PG. Unlike conventional linear PG, each branched PG possessed multiple terminal amino groups. This made it possible to attach multiple targeting moieties selectively to the termini of branched PG. Conjugation of monofunctional or heterodifunctional polyethylene glycol to the chain ends of branched PG was demonstrated in the presence of side chain carboxyl groups. Furthermore, folic acid, a model targeting moiety, and the near-infrared dye indocyanine green, a model diagnostic agent, were successfully conjugated to the terminal amino groups and the side chain carboxyl groups of branched PG, respectively. The resulting conjugate had reduced nonspecific interaction and bound selectively to tumor cells expressing folate receptors. Thus, branched PG may be useful as a polymeric carrier for targeted drug delivery.
Tansey
W
W
Department of Experimental Diagnostic Imaging, Unit 59, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Ke
S
S
Cao
X-Y
XY
Pasuelo
Marites J
MJ
Wallace
Sidney
S
Li
Chun
C
D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000378:metabolism*; D006801:Humans; D011099:Polyglutamic Acid / Q000138:chemical synthesis* / Q000378:metabolism*
D004337:Drug Carriers; D011099:Polyglutamic Acid