We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA).

We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA).

We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA).

We aimed to construct PDCs with linker controllable drug release rates simply by manipulating the linker unit. For a more rapid drug-release rate we developed GOXG1 and GOXG2. These conjugates bear a carboxylate ester linker directly attached to the primary and the secondary alcohol group of the drug respectively, followed by oxime and amide bond. The primary alcohol of gemcitabine has been used since it is involved in the phosphorylation process, through which gemcitabine exerts its cytotoxic effect. Therefore, we aimed to block the primary alcohol and examine its effect (GOXG1) and also take advantage of the secondary alcohol which could lead to a PDC with a completely different profile (GOXG2), although they share structural similarities. For a slower drug release rate, we designed and developed the PDC GN4OXG that contains an amide bond on the 4-N position of the parent drug followed by click oxime ligation and another amide bond. The stability of this molecule should be enhanced since it is devoid of rapidly hydrolyzable ester bonds. Furthermore, in this PDC since the 4-NH2 moiety of gemcitabine is capped it could further surmount the rapid gemcitabine metabolism that leads to the formation of dFdU, after the enzymatic 4-N deamination of gemcitabine by cytidine deaminase (CDA).