Drug Delivery Systems Based on Trimethyl Lock Lactonization:  Poly(ethylene glycol) Prodrugs of Amino-Containing Compounds

Abstract

A novel methodology for the synthesis of poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed which is based on the trimethyl lock lactonization reaction. These PEG-modified double prodrugs are water soluble, and by selective modification of the specifier or trigger, plasma half-lives can be adjusted at will to result in a wide range of values. Facile syntheses of ester, carbonate, and carbamate functionalities were accomplished and combined with greater or lesser degrees of steric hindrance in the spacer group, or on the aromatic framework, to achieve predictable ranges of drug concentration in plasma. In vivo screening of PEG prodrugs was done using a M109 syngeneic solid mouse tumor model. One of the PEG-daunorubicin prodrugs, with a half-life of 2 h, was evaluated in an in vivo solid tumor panel and found to be more efficacious against ovarian tumors (SKOV3) than equivalent amounts of daunorubicin.

Mechanistic Studies of the Photoinduced Quinone Trimethyl Lock Decaging Process

“…As in the bulk photolysis, a significant KIE is seen for the transient lifetime for the benzyl compound (1e vs. 1e-d 2 ). However, a minimal KIE is seen for the methyl compound (1a vs. 1a-d 3 ). …”

“…For the benzyl system, 1e/1e-d 2 , a value of 7 is observed, which is relatively large for a reaction of this sort. Remarkably, the parent methyl system, 1a/1a-d 3 , gives a k H /k D of 70 (Table 1). This effect is not evident in transient lifetime data because the dominant decay path for the 1a/1a-d 3 triplet is return to S 0 .…”

“…Remarkably, the parent methyl system, 1a/1a-d 3 , gives a k H /k D of 70 (Table 1). This effect is not evident in transient lifetime data because the dominant decay path for the 1a/1a-d 3 triplet is return to S 0 . Such a large KIE strongly implies tunneling in the hydrogen shift for this system.…”

Cyclization-activated Prodrugs

“…Approaches to the design of two-step prodrugs based on concepts such as the "trimethyl lock", apart from being quite elegant, were proven to promote significant increase in the oral bioavailability of known antivirals such as gancyclovir [93] and to be useful in the conception of PEG-daunorubicin prodrugs for the therapy of solid tumors [94]. More recently, the "trimethyl lock" concept has been applied by Raines and co-workers to the design of latent fluorophores as labels/indicators for biochemical and biological research [95,96].…”

Polymers for Protein Conjugation

“…Other future directions in the development of PEGylation include: (i) releasable PEGs, which are polymers linked to the protein through cleavable linkers that allows the slow release of the conjugated protein in its full active form [17][18][19][20][21][22][23]; (ii) non-covalent PEGylation, which can be mediated through either hydrophobic interactions or the formation of coordination complexes [24][25][26]; and (iii) new PEG forms; in fact, the classic linear or branched structures of PEG can be further modified to obtain new copolymers with improved features, such as the comb shape PEGs [27][28][29].…”