Telodendrimers with enhanced drug delivery
View Patent ↗The present invention provides amphiphilic telodendrimers that aggregate to form nanocarriers characterized by a hydrophobic core and a hydrophilic exterior. The nanocarrier core may include amphiphilic functionality such as cholic acid or cholic acid derivatives, and the exterior may include branched or linear poly(ethylene glycol) segments. Nanocarrier cargo such as hydrophobic drugs and other materials may be sequester in the core via non-covalent means or may be covalently bound to the telodendrimer building blocks. Telodendrimer structure may be tailored to alter loading properties, interactions with materials such as biological membranes, and other characteristics.
1. A compound selected from the group consisting of:
wherein
each branched monomer unit X is lysine;
L is a bond;
PEG is a polyethyleneglycol (PEG) polymer, having a molecular weight of 1-100 kDa;
R′ is selected from the group consisting of cholic acid (CA), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(2,3-dihydroxy-1-propoxy)-cholic acid (CA-4OH), (3α, 5β, 7α, 12α)-7-hydroxy-3,12-di(2,3-dihydroxy-1-propoxy)-cholic acid (CA-5OH), (3α, 5β, 7α, 12α)-7,12-dihydroxy-3-(3-amino-2-hydroxy-1-propoxy)-cholic acid (CA-3OH—NH 2 ); and
R″ is selected from the group consisting of cholesterol formate (CF), doxorubicin (DOX), and rhein (Rh).
2. The compound of claim 1 , wherein the compound has the formula:
wherein
each X is lysine;
PEG is PEG5k; and
each R′ is CA-4OH, or
each R′ is CA-5OH, or
each R′ is CA-3OH—NH 2 .
3. The compound of claim 1 , wherein the compound has the formula:
wherein
each X is lysine having an α amino and an ε amino, wherein each R′ is linked to the α amino and each R″ is linked to the ε amino;
PEG is PEG5k; and
each R′ is CA, and each R″ is CF, or
each R′ is CA, and each R″ is Rh.
4. A nanocarrier having an interior and an exterior, the nanocarrier comprising a plurality of compounds of claim 1 , wherein each compound self-assembles in an aqueous solvent to form the nanocarrier such that a hydrophobic pocket is formed in the interior of the nanocarrier, and wherein the PEG of each compound self-assembles on the exterior of the nanocarrier.
5. A method of treating a disease, comprising administering to a subject in need of such treatment, a therapeutically effective amount of a nanocarrier of claim 4 , wherein the nanocarrier further comprises a drug.
6. A method of imaging, comprising administering to a subject to be imaged, an effective amount of a nanocarrier of claim 4 , wherein the nanocarrier further comprises an imaging agent.