The CPTs are a family of synthetic and semisynthetic analogues of 20(S)-CPT that exhibit a broad range of anti-cancer activity by inhibiting topoisomerase-1 activity. Two properties of CPT compounds limit their therapeutic efficacy in humans: instability of the lactone form because of preferential binding of the carboxylate to serum albumin and a lack of aqueous solubility. PG is an effective solubilizing carrier of CPT and serves to protect the E-ring lactone structure in CPT. The PG-CPT conjugate was prepared by directly coupling the hydroxy group at the C20(S)-position of CPT with the carboxylic acid of PG.54 When given intravenously in four doses every four days at an equivalent CPT dose of 40 mg/kg, PG-CPT delayed the growth of established H322 human lung tumors subcutaneously grown in nude mice. In mice that received intratracheal inoculation of H322 cells, the same treatment prolonged the median survival duration in mice by fourfold when compared with that in untreated control mice. These results showed that PG was as efficient carrier of CPT.

Studies have systematically investigated the structural effects of the anti-tumor efficacy of CPT, including linkers between PG and CPT, the point of attachment of PG on the CPT molecule, the polymer molecular weight, and drug loading.55-57 First, coupling through the 20(S)-hydroxy group of CPT with or without a glycine linker yielded the most active conjugates because this site is located in close proximity to the lactone ring; therefore, the E-ring lactone is better protected by the linked PG chains. Second, increasing the molecular weight of PG from 33 to 50 kDa improved the anti-tumor efficacy of PG-CPT, probably because of an increased plasma half-life and reduced renal clearance. Third, based on the CPT-equivalent dosing levels, the investigators compared various linkers and found that PG-Gly-CPT and PG-(4-O-butyryl)-CPT seemed had the highest anti-tumor activity. Moreover, the linkers also affected the maximum drug payload; for example, only 15% (by weight) of CPT loading could be achieved for direct conjugation of PG-CPT by the ester linkage because of steric hindrance. On the other hand, up to 50% CPT loading could be achieved for the case with a glycine as linker. Fourth, the researchers observed improved anti-tumor efficacy of PG-Gly-CPT against HT-29 colon cancer and NCI-H460 lung carcinoma with increased CPT loading. However, increasing the loading of CPT to 47% resulted in significantly reduced solubility. Therefore, they recommended further investigation of PG-Gly-CPT with loading of CPT at 30-35%.

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