New Detachable Poly(ethylene glycol) Conjugates:  Cysteine-Cleavable Lipopolymers Regenerating Natural Phospholipid, Diacyl Phosphatidylethanolamine

Abstract

A new strategy for the reversible attachment of methoxypoly(ethylene glycol) (mPEG) to an amino-containing substrate is described. The strategy is based on formation of a benzyl carbamate linkage substituted with a disulfide in the para or ortho position. While being stable under nonreducing conditions, the dithiobenzyl (DTB) urethane linkage is susceptible to cleavage by mild thiolysis with cysteine resulting in release of the parent amino component of the conjugate in its original form. The method is exemplified by preparation of mPEG-DTB-alcohol, its activation and attachment to distearoylphosphatidylethanolamine (DSPE). The resulting lipopolymer incorporates into liposomes, which are capable of losing their polymer coating under conditions approximating those existing in vivo. Implications for drug delivery are briefly discussed.

Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

“…Therefore, the rate-limiting step for bioavailability in such a system is actually the activation of prodrug rather than the release of drug from the liposome. In the current system, any thiol-containing agent can cleave the dithiobenzyl linker and generate free MMC (22,38). Although thiols are ubiquitously present in biological systems (39), these are mostly polar molecules (e.g., glutathione and cysteine) or macromolecules (e.g., albumin).…”

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

“…97) In addition to the pH gradient, an intracellular reducing environment and enzymes are considered alternative stimulating triggers. [103][104][105] Most of the current cleavable PEG devices were designed to be cleaved in response to some feature of the intracellular microenvironment. Therefore, a cleavable PEG-lipid triggered in a tumor-specific manner would be beneficial for tumor gene delivery.…”

Targeted pharmaceutical nanocarriers for cancer therapy and imaging

“…To solve these problems, for example, in the case of long-circulating liposomes, the chemistry was developed to detach PEG from the lipid anchor in the desired conditions. Labile linkage that would degrade only in the acidic conditions characteristic of the endocytic vacuole or the acidotic tumor mass can be based on the diortho esters, 132 vinyl esters, 133 cysteine-cleavable lipopolymers, 134 double esters, and hydrazones that are quite stable at pH around 7.5 but are hydrolyzed relatively fast at pH values of 6 and below. 132 , 135 , 136 Polymeric components with pH-sensitive (pH-cleavable) bonds are used to produce stimuli-responsive drug delivery systems that are stable in the circulation or in normal tissues but acquire the ability to degrade and release the entrapped drugs in body areas or cell compartments with lowered pH, such as tumors, or cell cytoplasm or endosomes.…”