Polyoxazolines with inert terminating groups, polyoxazolines prepared from protected initiating groups and related compounds
The present disclosure provides novel functional polyoxazoline derivatives prepared by terminating polyoxazoline polymerization with inert chemical groups. In addition, the present disclosure demonstrates the synthesis of novel electrophilic initiators with protected functional groups capable of initiating oxazoline polymerization and capable of surviving the conditions of polymerization. These initiators are used to synthesize the above inert-terminal polyoxazoline derivatives as well as other polyoxazolines with active terminal groups. Furthermore, the present disclosure provides for polyoxazoline-lipid conjugates and liposomal compositions prepared using such polyoxazoline-lipid conjugates. Methods of using the foregoing to prepare conjugates with target molecules are also disclosed.
1. A heterofunctional polyoxazoline of the following general structure:
E-R 3 -{POZ I —POZ II } a —S—R*
wherein:
E is —OH, —CO 2 H or a group containing an active —OH group or an active —CO 2 H group;
POZ I is a polyoxazoline polymer of the structure [N(CO—R′—Z)CH 2 CH 2 ] m
POZ II is a polyoxazoline polymer of the structure [N(COR 2 )CH 2 CH 2 ] n
R′ is an optional linking group
R 3 is a linking group;
Z is an active functional group or a group capable of being converted to an active functional group, the active functional group capable of forming a linkage with a binding partner on a target molecule;
R 2 is independently selected for each repeating unit of the polyoxazoline polymer from an unsubstituted or substituted alkyl, alkenyl, aralkyl or heterocycylalkyl group;
R* is —(CH 2 ) q —C 6 H 5 and q is an integer from 1-25;
n is an integer from 0-1000, provided that when n=0, then m is >1;
m is an integer 1-1000; and
a is ran, which indicates a random copolymer, or block, which indicates a block copolymer.
2. The heterofunctional polyoxazoline derivative of claim 1 , wherein Z is an alkyne, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a hydrazide, an amine, a protected amine, a thiol, a vinyl sulfone, a maleimide or an orthopyridyl disulfide.
3. The heterofunctional polyoxazoline derivative of claim 1 , wherein R 3 is —(CH 2 ) p — where p is an integer from 1-25.
4. The heterofunctional polyoxazoline derivative of claim 1 , wherein R′ is —(CH 2 ) o — where o is an integer from 1-25.
5. The heterofunctional polyoxazoline derivative of claim 1 , wherein R 2 is a C 1 -C 12 alkyl or aralkyl group.
6. The heterofunctional polyoxazoline derivative of claim 1 , wherein R 2 is methyl, ethyl, isopropyl or n-propyl.
7. The heterofunctional polyoxazoline derivative of claim 1 , wherein at least one active functional group is protected.
8. The heterofunctional polyoxazoline derivative of claim 1 , wherein at least one of POZ I and POZ II has a polydispersity value of less than or equal to 1.2.
9. The heterofunctional polyoxazoline derivative of claim 1 , wherein each of the POZ I and POZ II has a polydispersity value of less than or equal to 1.2.
10. The heterofunctional polyoxazoline derivative of claim 1 , having the structure:
HO—(CH 2 ) p -{POZ I —POZ II } a —S—R*, wherein p is an integer selected from 1-25.
11. The heterofunctional polyoxazoline derivative of claim 1 , having the structure:
HO 2 C—(CH 2 ) p -{POZ I —POZ II } a —S—R*, wherein p is an integer selected from 1-25.
12. A target molecule-POZ conjugate of the general formula: A a -B-TM t wherein
A is a POZ derivative of any one of claims 1 - 6 and 7 - 11 , minus any leaving groups eliminated during the reaction of the active functional group on the POZ derivative with a binding partner on a target molecule;
TM is the target molecule containing the binding partner;
B is a linkage formed between the active functional group and the binding partner;
a is an integer ranging from 1 up to the number of active functional groups on TM; and
t is an integer ranging from 1 up to the number of active functional groups on A.
13. The target molecule-POZ conjugate of claim 12 , wherein A is a POZ derivative of claim 2 .
14. The target molecule-POZ conjugate of claim 12 , wherein A is a POZ derivative of claim 10 .
15. The target molecule-POZ conjugate of claim 12 , wherein A is a POZ derivative of claim 11 .
16. The target molecule-POZ conjugate of any one of claim 12 , 14 or 15 , wherein the target molecule is an organic small molecule, an oligonucleotide, a polypeptide, an antibody, an antibody fragment, a protein, a carbohydrate a lipid or a combination thereof.
17. The target molecule-POZ conjugate of claim 16 , wherein the lipid is a phospholipid.
18. The target molecule-POZ conjugate of any one of claim 12 , 14 or 15 , wherein the target molecule is a targeting agent, a diagnostic agent or a therapeutic agent or a combination thereof.