High molecular weight polymer-based prodrugs

DETAILED DESCRIPTION The present invention addresses the shortcomings described above.
In one aspect of the invention, compositions of formula (I) are provided: ##STR3## wherein: D is a biologically active moiety; M is X or Q; X is an electron withdrawing group; Q is a moiety containing a free electron pair positioned five or six atoms from Y'; Y and Y' are independently O or S; and R is a polyalkylene oxide.
In these aspects of the invention, the polyalkylene oxide, R, can be further substituted with a moiety Z, wherein: Z is a polymer capping group such as a C.
sub.
1-4 alkyl moiety, an additional biologically active moiety or ##STR4## where D' can be the same as D or a different biologically active moiety.
In some preferred embodiments of the invention, compositions of formula (II) and (III) are provided: ##STR5## The prodrugs include a water-soluble polyalkylene oxide polymer (designated R herein).
In particular, R is preferably a polyethylene glycol and has a molecular weight of at least about 20,000.
The prodrug compositions of the present invention can include one or more active compounds attached to the water-soluble polymer, each via a hydrolyzable linkage such as a suitably activated ester linkage.
Thus, mono- and bis-polymer-based prodrugs are contemplated.
In certain preferred aspects of the invention, the active or parent compound (designated D herein) attached to the polymer is a taxane such as taxol or taxotere.
In other aspects of the invention, the active or parent compound is camptothecin, etoposide or podophyllotoxin.
In still further embodiments, non-oncolytic agents such as anti-inflammatory agents, including steroidal compounds, as well as therapeutic low molecular weight peptides such as insulin are also contemplated.
One of the chief advantages of the compounds of the present invention is that the prodrugs achieve a proper balance between the rate of linkage hydrolysis and the rate of clearance of prodrug from the body.
The linkage between the polymer and the parent compound, also referred to herein as a biologically-active nucleophile, hydrolyzes at a rate which allows a sufficient amount of the parent molecule to be released in vivo before clearance of the prodrug from the plasma or body