Dual phase drug release system

A method for preparing a conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure:

• wherein each occurrence of M is independently a modifier;
• denotes direct of indirect attachment of M to linker LM;
• and
• each occurrence of LM is independently an optionally substituted succinamide-containing linker, whereby the modifier M is directly or indirectly attached to the succinamide linker through an amide bond, and the carrier is linked directly or indirectly to each occurrence of the succinamide linker through an ester bond;
• said method comprising steps of:
• providing a carrier;
• providing one or more modifiers;
• reacting the carrier with an optionally substituted succinic anhydride having the structure:
• wherein q is an integer from 0-4;
• and each occurrence of R2 is independently hydrogen, halogen, —CN, NO2, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, aromatic, heteroaromatic moiety, or —GRG1 wherein G is —O—, —S—, —NRG2—, —C(═O)—, —S(═O)—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)—, —OC(═O)O—, —OC(═O)NRG2—, —NRG2C(═O)O—, —NRG2C(═O)NRG2—, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NRG2)—, —C(═NRG2)O—, —C(═NRG2)NRG3—, —OC(═NRG2)—, —NRG2C(═NRG3)—, —NRG2SO2—, —NRG2SO2NRG3—, or —SO2NRG2—, wherein each occurrence of RG1, RG2 and RG3 is independently hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl or heteroaryl moiety;
• under suitable conditions to form a succinylated carrier having the structure:
• or salt thereof;
• wherein s denotes the number of succinyl moieties on the carrier;
• and
• reacting the succinylated carrier with one or more modifier moieties (M), whereby at least one modifier moiety forms an amide bond, either directly or indirectly through a secondary linker, with a succinyl moiety present on the carrier;
• thereby generating the conjugate having the structure:
• wherein R2 and q are as defined above;
• denotes direct of indirect attachment of M to the succinamide linker;
• and t is an integer designating the number of modifier moieties conjugated to the carrier such that t≦s.

A method of treating a disease or disorder, comprising administering to a subject in need thereof an efficient amount of a conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure:

• wherein each occurrence of M is independently a modifier having a molecular weight≦10 kDa;
• denotes direct of indirect attachment of M to linker LM;
• each occurrence of LM is independently an optionally substituted succinamide-containing linker, whereby the modifier M is directly or indirectly attached to the succinamide linker through an amide bond, and the carrier is linked directly or indirectly to each occurrence of the succinamide linker through an ester bond;
• wherein said modifier is a suitable therapeutic agent for treatment of the disease or disorder;
• wherein said modifier is released from the conjugate by a dual phase process.