Compact nanoparticles for biological applications
A water soluble nanoparticle can include a ligand of formula (I). The ligand can provide zwitterionic character and can provide water solubility, small hydrodynamic diameter, chemical stability, and the capability to modify the nanoparticle with additional functional moieties such as a small molecule, nucleic acid, or protein.
1. A water soluble nanoparticle comprising:
an inorganic nanoparticle; and
a ligand bound to a surface of the inorganic nanoparticle,
wherein the ligand is of formula (II):
wherein
R 1 is halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
n is 0, 1, 2, or 3;
each R a and each R b , independently, is hydrogen, hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each of w and y, independently, is 0 to 8; each of x and z, independently, is 0 to 4; provided that w and x are not simultaneously 0; and provided that y and z are not simultaneously 0;
R 2 is R c ; and R 3 is absent, or is R c ;
each R c , independently, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and
Z 2 is —OH, —SH, —CO 2 H, —OPO 3 H 2 , —PO 3 H, —OSO 3 H, —SO 3 H, or an ionized form thereof,
wherein the inorganic nanoparticle includes a superparamagnetic iron oxide nanoparticle.
2. The nanoparticle of claim 1 , wherein
w is 2, 3, 4, 5, or 6;
x is zero;
R 2 and R 3 are each, independently, hydrogen or alkyl;
y is 2, 3, 4, 5, or 6; and
z is 0.
3. The nanoparticle of claim 2 , wherein Z 2 is —SO 3 H, or an ionized form thereof.
4. The nanoparticle of claim 1 , wherein the nanoparticle has a hydrodynamic diameter of 100 nm or less.
5. The nanoparticle of claim 1 , wherein, for the ligand of formula (II),
A is
wherein R 1 is halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl, and n is 0, 1, 2, or 3;
L 1 is —(CR a R b ) w —(CR a ═CR b ) x —, wherein w is 0 to 8, x is 0 to 4, provided that w and x are not simultaneously 0;
L 2 is —C(O)—, —C(O)NR c —, —O—, —OC(O)—, —OC(O)O—, —OC(O)NR c —, —NR c —, —NR c C(O)—, —NR c C(O)O—, —NR c C(O)NR c —, or —S—;
H is —[(CR a R b ) a O] k —[(CR a R b ) b O] l —[(CR a R b ) c O] m —, wherein each of a, b, and c, independently, is 2, 3, or 4, and each of k, l, and m, independently, is 0 to 100;
each R a and each R b , independently, is hydrogen, hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each R c , independently, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and
R′ is CO 2 H, —NH 2 , —CH═CH 2 , —C≡CH, —N 3 , or —SH.
6. The nanoparticle of claim 1 , wherein, for the ligand of formula (II),
A is
wherein R 1 is halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl, and n is 0, 1, 2, or 3;
L 1 is —(CR a R b ) w —(CR a ═CR b ) x —, wherein w is 0 to 8, x is 0 to 4, provided that w and x are not simultaneously 0;
L 2 is —C(O)—, —C(O)NR c —, —O—, —OC(O)—, —OC(O)O—, —OC(O)NR c —, —NR c —, —NR c C(O)—, —NR c C(O)O—, —NR c C(O)NR c —, or —S—;
H is —[(CR a R b ) a O] k —[(CR a R b ) b O] l —[(CR a R b ) c O] m —, wherein each of a, b, and c, independently, is 2, 3, or 4, and each of k, l, and m, independently, is 0 to 100;
each R a and each R b , independently, is hydrogen, hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each R c , independently, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and
R is —C(O)NH—, —NHC(O)—, or —S—.
7. The nanoparticle of claim 6 , wherein B is a dye or a member of a binding pair.
8. The nanoparticle of claim 7 , further comprising a second, distinct ligand of formula (IV) bound to a surface of the inorganic nanoparticle.
9. A method of making a water-soluble nanoparticle, comprising:
providing an inorganic nanoparticle; and
contacting the inorganic nanoparticle with a ligand bound to a surface of the inorganic nanoparticle,
wherein the ligand is of formula (II):
wherein
R 1 is halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
n is 0, 1, 2, or 3;
each R a and each R b , independently, is hydrogen, hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, alkoxy, alkenyl, cycloalkyl, cycloalkoxy, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each of w and y, independently, is 0 to 8; each of x and z, independently, is 0 to 4; provided that w and x are not simultaneously 0; and provided that y and z are not simultaneously 0;
R 2 is R c ; and R 3 is absent, or is R c ;
each R c , independently, is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, wherein each of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, CN, OH, NO 2 , alkyl, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and
Z 2 is —OH, —SH, —CO 2 H, —OPO 3 H 2 , —PO 3 H, —OSO 3 H, —SO 3 H, or an ionized form thereof,
wherein the inorganic nanoparticle includes a superparamagnetic iron oxide nanoparticle.
10. The method of claim 9 , wherein
w is 2, 3, 4, 5, or 6;
x is zero;
R 2 and R 3 are each, independently, hydrogen or alkyl;
y is 2, 3, 4, 5, or 6; and
z is 0.
11. The method of claim 10 , wherein Z 2 is —SO 3 H, or an ionized form thereof.