Method for preparing nanoparticles based on functional amphiphilic molecules or macromolecules, and the use thereof
The invention relates to a method for preparing nanoparticles based on functional amphiphilic molecules or macromolecules, optionally in the presence of at least one colipide, enabling the encapsulation of therapeutic agents, especially anti-tumoral agents, and the use thereof for the transport and vectorization of therapeutic agents, especially anti-tumoral agents.
1. A process for encapsulating a therapeutic agent comprising the steps of:
a) preparing a mixture of a therapeutic agent and at least one functional amphiphilic compound of formula (I)
wherein
X is an oxygen atom,
B is a purine base or a pyrimidine base,
L 1 and L 2 , identical or different, are hydrogen or a hydroxyl group, provided that L 1 and L 2 are not simultaneously a hydroxyl group,
R 1 and R 2 do not exist, and
R 3 is a triazole group, wherein the triazole group is unsubstituted or substituted by C 2 -C 30 alkyl or (CH 2 ) m —O—(CH 2 ) p —R 9 , wherein m is from 1 to 6, p is from 0 to 10, and R 9 is a cyclic ketal group containing from 5 to 7 atoms, and wherein the cyclic ketal group is unsubstituted or substituted by a sterol radical or at least one selected from the group consisting of linear C 2 -C 30 alkyl and branched C 2 -C 30 alkyl;
b) subjecting said mixture to repeated heating and freezing cycles to obtain nanoparticles containing said therapeutic agent; and
c) recovering the nanoparticles containing said therapeutic agent.
2. The process according to claim 1 , wherein B is thymine or adenine.
3. The process according to claim 1 , wherein in formula (I):
L 1 is a hydroxyl group, L 2 is hydrogen, and R 3 is a triazole group substituted by a C 2 -C 30 alkyl chain optionally substituted by a hydroxyl group; or
L 1 is a hydroxyl group, L 2 is hydrogen, and R 3 is a triazole group substituted by (CH 2 ) m —O—(CH 2 ) p —R 9 , wherein m is from 1 to 6, p is from 0 to 10, and R 9 is a cyclic ketal group containing from 5 to 7 atoms, and wherein the cyclic ketal group is unsubstituted or substituted by a sterol radical or at least one selected from the group consisting of linear C 2 -C 30 alkyl and branched C 2 -C 30 alkyl.
4. The process according to claim 1 , comprising the steps of:
putting the compound of formula (I) in solution in an organic solvent to form a lipid mixture,
evaporating the organic solvent from the lipid mixture to form a lipid film,
putting the therapeutic agent in distilled water at a concentration of 0.1 ng/mL to 10 mg/mL to form a therapeutic agent solution,
combining the lipid film with the therapeutic agent solution to form a rehydrated lipid film, and
subjecting the rehydrated lipid film to 1 to 10 cycles of heating and cooling.
5. The process according to claim 1 , further comprising the step of putting the compound of formula (I) in solution in an organic solvent in the presence of a co-lipid.
6. The process according to claim 1 , further comprising the step of putting the compound of formula (I) in solution in an organic solvent in the presence of a co-lipid, wherein the co-lipid is chosen from dioleylphosphatidylcholine (DOPC) and dioleyl phosphatidyluridinephosphatidylcholine (DOUPC).
7. The process according to claim 1 , wherein B is uracil, adenine, guanine, cytosine, thymine, or hypoxanthine.
8. The process according to claim 1 , wherein in formula (I):
X is an oxygen atom,
B is thymine,
L 1 is a hydroxyl group,
L 2 is hydrogen, and
R 3 is a triazole group substituted by C 6 alkyl, C 7 alkyl, or (CH 2 ) m —O—(CH 2 ) p —R 9 ,
wherein in (CH 2 ) m —O—(CH 2 ) p —R 9
m is 1, p is 1, and R 9 is a ketal group disubstituted by a C 13 H 27 group;
m is 1, p is 4, and R 9 is a ketal group disubstituted by a C 13 H 27 group; or
m is 1, p is 0, and R 9 is a sterol radical.
9. The process of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
5′-(4-(1-hydroxy-hexyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-(hexyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-(heptyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-(2,2-ditridecyl-[1,3]dioxolan-4-ylmethoxymethyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-(2,2-ditridecyl-[1,3]dioxolan-4-ylbutoxymethyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-((O-cholesteryl)-methyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-(1(R)-hydroxy-hexyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine,
5′-(4-(1(S)-hydroxy-hexyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxythymidine, and
5′-(4-(1-hydroxy-hexyl)-[1,2,3]triazol-1-yl)-5′,2′dideoxyadenosine.