Delivery Technology

Synthetic soluble polymer

Details

AP5346 is a diaminocyclohexane (DACH)-Pt complex coupled to a 25-kDa water-soluble, non toxic, biocompatible hydroxypropylmethacrylamide (HPMA) copolymer acting as a macromolecular carrier, increasing tumor delivery via enhanced vascular permeability and drug retention.

The polymer carrier is a substituted linear poly(methacrylamide) in which the amides are randomly substituted with 2-hydroxypropylamine (90%), resulting in a nonionic polymer with high water solubility. The remaining 10% of the amide groups are substituted with the tripeptide, Gly-Gly-Gly, terminated with an amidomalonic acid chelating group. 1,2-Diamino-cyclohexyl (DACH)-platinum(II) is complexed to the polymer. Use of the polymer carrier to deliver the active platinum entity potentially increases the circulating half-life of the platinum and is intended to capitalize on the Enhanced Permeability and Retention (EPR) effect of tumor vasculature, whereby macromolecules concentrate in tumors, but are excluded from normal tissue. Another advantage of polymeric delivery is the potential achievement of a therapeutic index superior to that of conventional therapy (enhanced activity with altered or less severe systemic toxicity) attributed to rapid renal elimination of the portion of the drug not retained in the tumor.

Its high molecular weight keeps the prodrug in circulation (t1/2 = 63hr) until it encounters permeable capillaries intumors. The drug is activated in low pH environments. In preclinical models, there is a 13-fold increase in delivery of DACH platinum to key intracellular target (DNA). The drug does not contain an oxalate group and thus may not be neurotoxic. ProLindac is excreted via the kidneys.

Also see record for AP5280.

Current as of

June 22, 2010

Delivery Technology

Polymer-based drug delivery

Details

Fleximers are modified purines with the imidazole and pyrimidine rings separated by a single carbon-carbon bond. Fleximer technology uniquely combines biodegradability with biological stealth properties, lacking interactions with biologic recognition elements including phagocytes and immune cells, making Fleximer materials and their conjugates long circulating and non-immunotoxic. Fleximer molecules are characterized by solubility in water, stability in common manufacturing procedures and in normal physiological conditions, and non-enzymatic biodegradability upon uptake by cells. Fleximer is non-toxic at large doses in rodents.

MER-1001 is a polymer-directed prodrug of camptothecin (CPT). MER-1001 is a macromolecular (60-70 kDa) conjugate of CPT with the hydrophilic polymer PHF [poly-(1-hydroxymethylethylene hydroxyl-methyl formal)]. Release of CPT from MER-1001 involves a dual-phase, non-enzymatic release mechanism, in which CPT is first released in plasma as lipophilic prodrugs CPT-SI (a succinimidoglycinate derivative) and CPT-SA (a succinamidoyl glycinate derivative), which are then hydrolyzed in tissues to release the lactone form of CPT (Schwertschlag U, AACR07, Abs. 4723).

MER-1001 is a polymeric prodrug derivative of camptothecin in which the drug is chemically tethered to a hydrophilic, biodegradable 60-70-kDa polymer, Fleximer (poly[1-hydroxymethylene hydroxymethyl formal], PHF). When administered IV, MER-1001 releases camptothecin-20-(N-succinimido-glycinate) (CPT-SI), CPT, and camptothecin-20-(N-succinamidoyl-glycinate) (CPT-SA) over an extended time period. Because of the biologically inert nature of Fleximer, MER-1001 distributes throughout the vascular space and slowly releases the prodrug CPT-SI, and to a lesser extent, CPT, over time. Initial PK measurements in animals confirm the release-limited PK of CPT and CPT-SI. Thus, in contrast to the known PK profile of CPT alone, MER-1001 (CPT+linker+PHF) releases CPT slowly and is not expected to be excreted at potentially toxic levels into the gallbladder, intestine, and urinary bladder. In addition, the dual-phase release mechanism affords a more sustained exposure to the active lactone form of CPT because the lactone ring is stabilized in prodrug CPT-SI. Both distribution and extended release are hypothesized to improve safety and efficacy over existing drugs of the same class (Yurkovetskiy A, etal, AACR07, Abs. 781).

Current as of

April 13, 2010