What is claimed is:
1. A collector assembly for a linear beam device, the assembly comprising:
a heat sink comprised of a first material, the heat sink having a cavity therein configured to hold a vacuum;
an electrode comprised of a second material disposed inside the cavity; and
a segmented ceramic insulator disposed inside the cavity around the electrode and interposed between the electrode and the heat sink, configured to electrically insulate the electrode from the heat sink and to conduct heat from the electrode to the heat sink.
2. The collector assembly of claim 1, wherein the electrode is not attached to the ceramic insulator.
3. The collector assembly of claim 1, wherein the ceramic insulator further comprises a plurality of sectors separated from one another by a plurality of gaps.
4. The collector assembly of claim 1, wherein the ceramic insulator further comprises a plurality of longitudinal notches in an outer surface thereof, each of the plurality of longitudinal notches spanning a corresponding one of the plurality of gaps.
5. The collector assembly of claim 1, wherein the electrode further comprises a first stage and a second stage.
6. The collector assembly of claim 5, wherein the second stage does not have a probe and comprises a central conical recess.
7. The collector assembly of claim 5, further comprising an annular forward seal brazed to the ceramic insulator and to the heat sink adjacent to the first stage of the electrode at a front end of the assembly.
8. The collector assembly of claim 5, further comprising a rear seal brazed to the ceramic insulator and to the heat sink adjacent to the second stage of the electrode at a rear end of the assembly.
9. The collector assembly of claim 1, wherein the first material is molybdenum and the second material is molybdenum.
10. The collector assembly of claim 1, wherein the first material is copper and the second material is copper.
11. The collector assembly of claim 1, wherein the first material is molybdenum and the second material is selected from tungsten, carburized tungsten, an elconite material, or carbon.
12. The collector assembly of claim 11, wherein the elconite material is a sintered tungsten carbide material infiltrated with copper.
13. The collector assembly of claim 1, wherein the ceramic insulator is comprised of a material selected from beryllium oxide, aluminum nitride, or alumina.
14. The collector assembly of claim 1, wherein the first material is copper, the second material is copper, and the ceramic insulator is an aluminum nitride material.
15. The collector assembly of claim 1, further comprising a sleeve of a metallic material interposed between the ceramic insulator and the heat sink.
16. The collector assembly of claim 1, wherein an exterior surface of the heat sink is contoured to match an exterior surface of a device.
17. The collector assembly of claim 1, wherein an exterior surface of the heat sink is contoured to match an exterior surface of an airborne device.
18. The collector assembly of claim 1, wherein the ceramic insulator is compressed between the electrode and the heat sink at ambient temperature.
19. The collector assembly of claim 1, wherein the ceramic insulator is compressed between the electrode and the heat sink over a temperature range between not greater than 0 C. and not less than 250 C.
20. The collector assembly of claim 1, wherein the ceramic insulator directly contacts the electrode and the heat sink over a temperature range between not greater than 0 C. and not less than 250 C.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An insulin conjugate having the formula:
X1-X2
wherein X1 is insulin, an insulin analog, glucagon, GLP-1, or a GLP-1 agonist,
X2 is:
(i) \u2014CO\u2014(CH2)\u2014NH\u2014CO\u2014CR1R2,
wherein j is an integer from 3-25
R1 is \u2014NH\u2014R12 or \u2014NH\u2014CO\u2014CH2\u2014CH2\u2014CNR12\u2014R32, where R32 is glucamine, gluconic acid, glucosamine, fructosamine, galactosamine, mannosamine, or other hexosamines,
R12 is selected from the group consisting of hydrogen, \u2014SO2alkyl, \u2014SO2cycloalkyl, \u2014SO2heterocycloalkyl, \u2014SO2aryl, \u2014SO2heteroaryl, \u2014COalkyl, \u2014COcycloalkyl, \u2014COheterocycloalkyl, \u2014COaryl, \u2014COheteroaryl, \u2014CONHalkyl, \u2014CONHcycloalkyl, \u2014CONHheterocycloalkyl, \u2014CONHaryl, \u2014CONHheteroaryl,
wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are substituted or unsubstituted,
R2 is \u2014(CH2)n\u2014NH\u2014CO\u2014Rii or \u2014(CH2)n\u2014NH\u2014SO2R11,
n is an integer from 3-25, and
R11 is a phenylboronic acid group;
(ii) an oligomer comprising a plurality of monomers, wherein the monomers comprise a side chain, wherein the side chain comprises one or more phenylboronic acid groups, hydrophobic residues, hydrophilic neutral residues, hydrophilic charged residues, diol residues, fluorescent residues, and combinations thereof, wherein at least one of the side chains comprises a phenylboronic acid group;
(iii) \u2014CO\u2014R6\u2014R7,
wherein R6 is a linker or is not present,
wherein R7 is a diol-containing group complexed to a hydrophobic phenylboronic acid (PBA) group, wherein the diol-containing group comprises one or more diols, wherein the hydrophobic PBA group comprises one or more PBA groups covalently linked to a hydrophobic group, wherein at least on diol and one hydrophobic PBA group form a boronic ester; or
(iv) \u2014CO\u2014R8, wherein R8 is:
(a) -alkylene-R9 or -alkenyl-R9, wherein R9 is a phenylboronic acid group, wherein the alkylene or alkenyl group can be substituted or unsubstituted, wherein the number of carbons in the alkylene or alkenyl group is from 3 to 25,
(b) \u2014R13, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with a phenylboronic acid group, or
(c) \u2014(CH2)r\u2014NH\u2014CO\u2014CHR14\u2014NH\u2014CO\u2014(CH2)8, wherein r is an integer from 3-25, wherein s is an integer from 3-25, wherein R14 is an amine-containing group comprising a phenylboronic acid group.
2. The derivatized insulin of claim 1, wherein n is 4.
3. The derivatized insulin of claim 1, wherein each monomer residue of the oligomer is \u2014CO\u2014O\u2014R3\u2014, wherein R3 is:
\u2014CR4\u2014(CH2)m\u2014NH\u2014 or pyrrolidine substituted with R4,
wherein m is an integer from 0-25,
wherein R4 is \u2014CO\u2014NH\u2014R5 or \u2014CO\u2014NH\u2014C(CH\u2014CO\u2014NH\u2014R5)2,
wherein each R5 is independently:
(a) a phenylboronic acid group,
(b) C8-18 alkyl,
(c) \u2014CH2-phenyl,
(d) \u2014(CH2\u2014CH2\u2014O)p\u2014H or \u2014(CH2\u2014CH2\u2014O)p\u2014CH3,
wherein p is an integer from 1-500,
(e) \u2014CH2-dioxane,
(f) \u2014CH2\u2014CH2-oxazane,
(g) \u2014CH2\u2014CH2\u2014N(CH2\u2014CH3)2,
(h) \u2014CH2\u2014CH2-pyrazole,
(i) a fluorescent group,
(j) -piperidine-phenyl,
(k) -piperidine-oxazane,
(l) -piperidine-CH2\u2014CH2\u2014N(CH2\u2014CH3)2,
(m) -piperidine-CH2\u2014CH2-pyrazole,
(n) -dimethylaminobenzyl, or
(o) -pyridine,
wherein at least one R5 is a phenylboronic acid group.
4. The derivatized insulin of claim 1, wherein the diol-containing group is -(DOPA-Gly)i-NH2, wherein i is an integer from 1-5.
5. The derivatized insulin of claim 1, wherein the diol-containing group is 6-methyl-6-deoxy-D-galactose, 1-deoxy-\u03b2-D-lactopyranoside, \u03b1-D-Mannopyranosyl, or adenosine.
6. The derivatized insulin of claim 1, wherein R6 is \u2014CO\u2014(CH2)h\u2014R31\u2014, wherein h is an integer from 3-25, wherein R31 is O-triazole- or CO\u2014NH\u2014CH2\u2014CO-dibenzo-cyclocta-triazole-.
7. The derivatized insulin of claim 1, wherein the hydrophobic group is \u2014(CH2)k\u2014CH3, wherein k is an integer from 3-25.
8. The derivatized insulin of claim 7, wherein k is 11.
9. The derivatized insulin of claim 1, wherein the hydrophobic group is a bile acid.
10. The derivatized insulin of claim 1, wherein q is 11.
11. The derivatized insulin of claim 1, wherein the bile acid is cholic acid, lithocholic acid, hyocholic acid, deoxyxholic acid, hyodeoxycholic acid, or chenodeoxycholic acid.
12. The derivatized insulin of claim 1, wherein R14 is \u2014(CH2)t\u2014R30, wherein R30, is the phenylboronic acid group, wherein t is an integer from 3-25.
13. The derivatized insulin of claim 1, wherein r is 3 and s is 6, 8, 10, 12, or 14.
14. The derivatized insulin of claim 1, wherein r is 5 and s is 6, 8, 10, 12, or 14.
15. The derivatized insulin of claim 1, wherein r is 11 and s is 6, 8, 10, 12, or 14.
16. The derivatized insulin of claim 1, wherein r+s is an integer from 13 to 21.
17. The derivatized insulin of claim 1, wherein each phenylboronic acid group is:
wherein R16 is NH, NR29, or is not present,
wherein R17 is CH2, CO, SO2, or is not present,
wherein R18, R19, R20, R21, and R22 are each independently \u2014B(OH)2, \u2014F, \u2014NO2, \u2014CN, \u2014H, or not present, wherein one and only one of R18, R19, R20, R21, and R22 is \u2014B(OH)2,
wherein R23, R24, R25, R26, and R27 are each independently C or N, wherein at most only three of R23, R24, R25, R26, and R27 are N, and
wherein R29 is C1-4 alkyl.
18. A method of alleviating one or more symptoms of diabetes comprising administering to a diabetic subject an effective amount of the derivatized insulin of claim 1.
19. A method of making a derivatized insulin comprising:
(i) reacting a N-hydroxysuccinimide (NHS)-activated alkyne linker with insulin or an insulin analog to form an alkyne-derivatized insulin,
(ii) reacting a diol-containing compound comprising azide with the alkyne-derivatized insulin to form diol-derivatized insulin, and
(iii) reacting a hydrophobic phenylboronic acid (PBA) group with the diol-derivatized insulin to form the derivatized insulin.
20. A method of making a derivatized insulin comprising:
(i) reacting a first monomer with a second monomer, wherein the monomers each comprise an amine moiety, an alcohol moiety, and a modified sidechain, wherein the alcohol moiety of the first monomer and the amine moiety of the second monomer are linked via a carbamate reaction to produce a dimer;
(ii) reacting the dimer with a third monomer, wherein the third monomers comprises an amine moiety, an alcohol moiety, and a modified sidechain, wherein the alcohol moiety of the dimer and the amine moiety of the third monomer are linked via a carbamate reaction to produce a trimer;
(iii) reacting the trimer with a coupling group and an amine moiety, wherein the amine moiety of the coupling group and the alcohol moiety of the last monomer are linked via a carbamate reaction to produce a coupling group-trimer, wherein the coupling group is an azide-containing group, an acid-containing group, an ester-containing group, a thiol-containing group, an alcohol-containing group, or an amine-containing group, wherein the azide-containing group, acid-containing group, ester-containing group, thiol-containing group, alcohol-containing group, or amine-containing group comprises an azide, acid, ester, thiol, alcohol, or amine moiety, respectively; and
(iv) (a) if the coupling group is an azide-containing group, reacting the coupling group-trimer with an alkyne-dibenzocylcooctyne-, or other cyclooctyne-derivatized insulin, wherein the alkyne-, dibenzocylcooctyne-, or other cyclooctyne-derivatized insulin comprises insulin or an insulin analog, wherein the azide moiety and the alkyne, dibenzocylcooctyne, or other cyclooctyne moiety of the alkyne-, dibenzocylcooctyne-, or other cyclooctyne-derivatized insulin are linked to produce the derivatized insulin;
(b) if the coupling group is an acid-, ester-, or alcohol-containing group, reacting the coupling group-trimer with an amine-containing insulin, wherein the amine-containing insulin is insulin, an insulin analog, or an amine-derivatized insulin, wherein the amine-derivatized insulin comprises insulin or an insulin analog, wherein the acid, ester, or alcohol moiety and the amine moiety of the amine-containing insulin are linked to produce the derivatized insulin;
(c) if the coupling group is an thiol-containing group, reacting the coupling group-trimer with a thiol-containing insulin, wherein the thiol-containing insulin is insulin, an insulin analog, or an thiol-derivatized insulin, wherein the thiol-derivatized insulin comprises insulin or an insulin analog, wherein the thiol moiety and the thiol moiety of the thiol-containing insulin are linked to produce the derivatized insulin; or
(d) if the coupling group is an amine-containing group, reacting the coupling group-trimer with an acid-derivatized, ester-derivatized, or amine-containing insulin, wherein the amine-containing insulin is insulin, an insulin analog, or an amine-derivatized insulin, wherein the acid-, ester-, or amine-derivatized insulin comprises insulin or an insulin analog, wherein the amine moiety and the acid, ester, or amine moiety of the acid-derivatized, ester-derivatized, or amine-containing insulin are linked to produce the derivatized insulin.
21. The method of claim 20, wherein step (i) is performed a plurality of times using the same or a different first monomer, the same or a different second monomer, or the same or different first and second monomers.
22. The method of claim 20, wherein step (ii) is performed a plurality of times using the same or a different dimer, the same or a different third monomer, or the same or a different dimer and a different third monomer.
23. The method of claim 20, wherein the monomers are prepared by reacting a monomer backbone with a sidechain modifying group, wherein the monomer backbone comprises a carboxylic acid moiety, an amine moiety, and an alcohol moiety, wherein the sidechain modifying group comprises an amine group, wherein the sidechain modifying group amidates the carboxylic acid moiety via the amine group.
24. The method of claim 20, wherein the sidechain modifying groups are independently a phenylboronic acid group, a hydrophobic residue, a hydrophilic residue, a neutral residue, an amine-containing residue, a charged residue, a diol residue, or a fluorescent residue.
25. The method of claim 20, wherein the sidechain modifying groups are independently a phenylboronic acid group, a nonpolar cyclic hydrocarbon residue, a nonpolar acyclic hydrocarbon residue, a tertiary amine residue, a cyclic amine residue, a cyclic neutral hydrophilic residue, or an acyclic neutral hydrophilic residue.
26. The method of claim 20, wherein each monomer residue of the oligomer is \u2014CO\u2014O\u2014R3\u2014, wherein R3 is:
\u2014CR4\u2014(CH2)m\u2014NH\u2014 or pyrrolidine substituted with R4, wherein m is an integer from 0-25,
wherein R4 is \u2014CO\u2014NH\u2014R5 or \u2014CO\u2014NH\u2014C(CH\u2014CO\u2014NH\u2014R5)2,
wherein each R5 is independently a phenylboronic acid group, a hydrophobic residue, a hydrophilic residue, a neutral residue, an amine-containing residue, a charged residue, a diol residue, a piperidine residue, or a fluorescent residue.
27. The method of claim 26, wherein each R5 is independently a phenylboronic acid group, a nonpolar cyclic hydrocarbon residue, a nonpolar acyclic hydrocarbon residue, a tertiary amine residue, a cyclic amine residue, a cyclic neutral hydrophilic residue, or a acyclic neutral hydrophilic residue.
28. The method of claim 26, wherein each R5 is independently:
(a) a phenylboronic acid group,
(b) C8-18 alkyl,
(c) \u2014CH2-phenyl,
(d) \u2014(CH2\u2014CH2\u2014O)p\u2014H or \u2014(CH2\u2014CH2\u2014O)p\u2014CH3, wherein p is an integer from 1-500,
(e) \u2014CH2-dioxane,
(f) \u2014CH2\u2014CH2-oxazane,
(g) \u2014CH2\u2014CH2\u2014N(CH2\u2014CH3)2,
(h) \u2014CH2\u2014CH2-pyrazole,
(i) a fluorescent group,
(j) -piperidine-phenyl,
(k) -piperidine-oxazane,
(l) -piperidine-CH2\u2014CH2\u2014N(CH2\u2014CH3)2,
(m) -piperidine-CH2\u2014CH2-pyrazole,
(n) -dimethylaminobenzyl, or
(o) -pyridine,
wherein at least one R5 is a phenylboronic acid group.
29. A method of making a derivatized insulin comprising:
(i) (a) reacting NH2-alkylene-CO\u2014O\u2014CH3 or NH2-alkenyl-CO\u2014O\u2014CH3 with a carboxyphenylboronic acid group to form R9-alkylene-CO\u2014O\u2014CH3 or R9-alkenyl-CO\u2014O\u2014CH3, wherein R9 is a phenylboronic acid group, or
(b) reacting NH2-alkylene-CO\u2014O\u2014CH3 or NH2-alkenyl-CO\u2014O\u2014CH3 with a bromo-chlorosulfonyl benzene group to form R15\u2014SO2\u2014NH-alkylene-CO\u2014O\u2014CH3R15\u2014SO2\u2014NH-alkenyl-CO\u2014O\u2014CH3, and reacting the R15\u2014SO2\u2014NH-alkylene-CO\u2014O\u2014CH3R15\u2014SO2\u2014NH-alkenyl-CO\u2014O\u2014CH3 with a diboron ester to form R9-alkylene-CO\u2014O\u2014CH3 or R9-alkenyl-CO\u2014O\u2014CH3, wherein R15 is a bromobenzene group, wherein R9 is a phenylboronic acid group;
(ii) reacting the R9-alkylene-CO\u2014O\u2014CH3 or R9-alkenyl-CO\u2014O\u2014CH3 to form R9-alkylene-COOH or R9-alkenyl-COOH, and
(iii) reacting the R9-alkylene-COOH or R9-alkenyl-COOH with insulin or an insulin analog to form the derivatized insulin.
30. A method of making a derivatized insulin comprising:
amidating insulin or an insulin analog at the B29 lysine with
\u2014R10-R13, wherein R10 is C1-6 alkyl, wherein R13 is a bile acid, wherein one or more hydroxyls on the bile acid are derivatized with a phenylboronic acid group.
31. A method of making a derivatized insulin comprising:
amidating insulin or an insulin analog at the B29 lysine with
\u2014(CH2)r\u2014 NH\u2014CO\u2014CHR14\u2014NH\u2014CO\u2014(CH2)s, wherein r is an integer from 3-25 and s is an integer from 3-25, wherein R14 is an amine-containing group comprising a phenylboronic acid.
32. The method of claim 19 further comprising:
(iv) testing an agglomerate of a plurality of the derivatized insulin molecules for glucose-responsive release of the derivatized insulin from the agglomerates, wherein glucose-responsive release of the derivatized insulin from the agglomerate identifies the derivatized insulin as useful for treating diabetes.
33. The method of claim 19, wherein each phenylboronic acid group is:
wherein R16 is NH, NR29, or is not present,
wherein R17 is CH2, CO, SO2, or is not present,
wherein R18, R19, R20, R21, and R22 are each independently \u2014B(OH)2, \u2014F, \u2014NO2, \u2014CN, \u2014H, or not present, wherein one and only one of R18, R19, R20, R21, and R22 is \u2014B(OH)2,
wherein R23, R24, R25, R26, and R27 are each independently C or N, wherein at most only three of R23, R24, R25, R26, and R27 are N, and
wherein R29 is C1-4 alkyl.
34. A derivatized insulin made by the method of claim 19.