Nylon-3 co-polymers and synthetic lung surfactant compositions containing same
Non-natural oligomers have recently shown promise as functional analogs of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Presented herein an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of β-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers affords further improvements by reducing the percent surface area compression to reach low minimum surface tension.
1. An artificial lung surfactant composition comprising a nylon-3 homopolymer, a nylon-3 random copolymer, or a nylon-3 non-random copolymer, whose monomers are selected from the group consisting of:
wherein:
R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; or
one of R 3 and R 4 combined with one of R 5 and R 6 , together with the carbon atoms to which they are attached, define a cyclic moiety “A”
wherein “A” is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
provided that at least two of R 3 , R 4 , R 5 , or R 6 are not hydrogen; and
wherein “n” is a positive integer,
wherein the nylon-3 homopolymer, nylon-3 random copolymer, or nylon-3 non-random copolymer comprises a lipophilic alkanoyl end group capable of inserting into a lipid film.
2. The artificial lung surfactant composition of claim 1 , wherein:
in at least one of the monomers, R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
in at least one of the monomers:
one of R 3 and R 4 combined with one of R 5 and R 6 , together with the carbon atoms to which they are attached, define a cyclic moiety “A”
wherein “A” is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
3. The artificial lung surfactant composition of claim 2 , wherein “A” is substituted or unsubstituted C 5 -C 12 cycloalkyl.
4. The artificial lung surfactant composition of claim 2 , wherein “A” is substituted or unsubstituted C 5 -C 12 cycloalkenyl.
5. The artificial lung surfactant composition of claim 2 , wherein “A” is substituted or unsubstituted five- to twelve-membered heterocyclic.
6. The artificial lung surfactant composition of claim 2 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, aryl, and C 1 -C 6 -alklyaryl.
7. The artificial lung surfactant composition of claim 2 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of substituted or unsubstituted amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
8. The artificial lung surfactant composition of claim 1 , wherein the nylon-3 homopolymer, nylon-3 random copolymer, or nylon-3 non-random copolymer is present in the artificial lung surfactant composition as an artificial lung surfactant in an amount effective to treat a respiratory distress syndrome or pulmonary disorder involving deficient or dysfunctional lung surfactant in a mammalian subject.
9. The artificial lung surfactant composition of claim 1 , wherein at least some of the monomers are cationic monomers, at least one of R 3 , R 4 , R 5 , and R 6 in each of the cationic monomers is amino or amino-C 1 -C 6 -alkyl, and the cationic monomers are present in the polymer in a proportion of less than 67% of the monomers.
10. The artificial lung surfactant composition of claim 1 , wherein the alkanoyl end group is an octadecanoyl end group.
11. An artificial lung surfactant composition comprising a polymer, wherein the polymer comprises monomers and an end group, wherein the monomers comprise a first set of monomers and a second set of monomers, wherein:
each monomer in the first set has a structure of:
wherein R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
each monomer in the second set has a structure of:
wherein:
one of R 3 and R 4 combined with one of R 5 and R 6 in each monomer in the second set, together with the carbon atoms to which they are attached, define a cyclic moiety “A”
A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 in each monomer in the second set are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
the end group is a lipophilic alkanoyl end group capable of inserting into a lipid film.
12. The artificial lung surfactant composition of claim 11 , wherein:
at least some of the monomers in the first set of monomers are cationic monomers;
at least one of R 3 , R 4 , R 5 , and R 6 in each of the cationic monomers is amino or amino-C 1 -C 6 -alkyl; and
the cationic monomers are present in the polymer in a proportion of less than ⅔ of all of the monomers in the polymer.
13. The artificial lung surfactant composition of claim 11 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 in the second set of monomers are independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
14. The artificial lung surfactant composition of claim 11 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached in each monomer in the second set is selected from the group consisting of substituted or unsubstituted C 8 -C 12 cycloalkyl, C 8 -C 12 cycloalkenyl, and eight- to twelve-membered heterocyclic; and
the polymer yields:
an average surface tension no higher than 35 mN m −1 with 0.40-mm radius bubbles composed of 1,2-diacyl-sn-glycero-3-phosphocholine (DPPC):1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG):palmitic acid (PA) at a ratio of 68:22:9 (wt:wt:wt) within 5 minutes of exposure thereto at 37° C. in static-bubble mode of pulsating bubble surfactometry;
a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry;
an average percent surface area compression of less than 26.4% to reach a surface tension of 20 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry; or
a combination thereof.
15. The artificial lung surfactant composition of claim 14 , wherein the polymer yields a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry.
16. The artificial lung surfactant composition of claim 14 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, amino, and amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl; and
A together with the carbon atoms to which it is attached in each monomer in the second set is substituted or unsubstituted C 8 cycloalkyl.
17. The artificial lung surfactant composition of claim 11 , wherein the polymer is present in the artificial lung surfactant composition as an artificial lung surfactant in an amount effective to treat a respiratory distress syndrome or pulmonary disorder involving deficient or dysfunctional lung surfactant in a mammalian subject.
18. An artificial lung surfactant composition comprising a polymer, wherein the polymer comprises monomers and an end group, wherein the monomers comprise a first set of monomers and a second set of monomers, wherein:
each monomer in the first set has a structure of:
wherein R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
each monomer in the second set has a structure of:
wherein:
one of R 3 and R 4 combined with one of R 5 and R 6 in each monomer in the second set, together with the carbon atoms to which they are attached, define a cyclic moiety “A”
A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 in each monomer in the second set are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
the end group is a lipophilic alkanoyl end group capable of increasing surfactant activity compared to a p-(tert-butyl)benzoyl end group.
19. The artificial lung surfactant composition of claim 18 , wherein:
at least some of the monomers in the first set of monomers are cationic monomers;
at least one of R 3 , R 4 , R 5 , and R 6 in each of the cationic monomers is amino or amino-C 1 -C 6 -alkyl; and
the cationic monomers are present in the polymer in a proportion of less than ⅔ of all of the monomers in the polymer.
20. The artificial lung surfactant composition of claim 18 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached in each monomer in the second set is selected from the group consisting of substituted or unsubstituted C 8 -C 12 cycloalkyl, C 8 -C 12 cycloalkenyl, and eight- to twelve-membered heterocyclic; and
the polymer yields:
an average surface tension no higher than 35 mN m −1 with 0.40-mm radius bubbles composed of 1,2-diacyl-sn-glycero-3-phosphocholine (DPPC):1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG):palmitic acid (PA) at a ratio of 68:22:9 (wt:wt:wt) within 5 minutes of exposure thereto at 37° C. in static-bubble mode of pulsating bubble surfactometry;
a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry;
an average percent surface area compression of less than 26.4% to reach a surface tension of 20 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry; or
a combination thereof.
21. The artificial lung surfactant composition of claim 20 , wherein the polymer yields a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry.
22. The artificial lung surfactant composition of claim 20 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, amino, and amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl; and
A together with the carbon atoms to which it is attached in each monomer in the second set is substituted or unsubstituted C 8 cycloalkyl.
23. The artificial lung surfactant composition of claim 18 , wherein the polymer is present in the artificial lung surfactant composition as an artificial lung surfactant in an amount effective to treat a respiratory distress syndrome or pulmonary disorder involving deficient or dysfunctional lung surfactant in a mammalian subject.
24. An artificial lung surfactant composition comprising a polymer, wherein the polymer comprises monomers and an end group, wherein the monomers comprise a first set of monomers and a second set of monomers, wherein:
each monomer in the first set has a structure of:
wherein R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
each monomer in the second set has a structure of:
wherein:
one of R 3 and R 4 combined with one of R 5 and R 6 in each monomer in the second set, together with the carbon atoms to which they are attached, define a cyclic moiety “A”
A together with the carbon atoms to which it is attached is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 in each monomer in the second set are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; and
the end group is an octadecanoyl end group.
25. The artificial lung surfactant composition of claim 24 , wherein:
at least some of the monomers in the first set of monomers are cationic monomers;
at least one of R 3 , R 4 , R 5 , and R 6 in each of the cationic monomers is amino or amino-C 1 -C 6 -alkyl; and
the cationic monomers are present in the polymer in a proportion of less than ⅔ of all of the monomers in the polymer.
26. The artificial lung surfactant composition of claim 24 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl;
A together with the carbon atoms to which it is attached in each monomer in the second set is selected from the group consisting of substituted or unsubstituted C 8 -C 12 cycloalkyl, C 8 -C 12 cycloalkenyl, and eight- to twelve-membered heterocyclic; and
the polymer yields:
an average surface tension no higher than 35 mN m −1 with 0.40-mm radius bubbles composed of 1,2-diacyl-sn-glycero-3-phosphocholine (DPPC):1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG):palmitic acid (PA) at a ratio of 68:22:9 (wt:wt:wt) within 5 minutes of exposure thereto at 37° C. in static-bubble mode of pulsating bubble surfactometry;
a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry;
an average percent surface area compression of less than 26.4% to reach a surface tension of 20 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry; or
a combination thereof.
27. The artificial lung surfactant composition of claim 26 , wherein the polymer yields a maximum average surface tension less than 45 mN m −1 and a minimum average surface tension less than 2 mN m −1 with 0.40-mm radius bubbles composed of DPPC:POPG:PA at a ratio of 68:22:9 (wt:wt:wt) at 5 minutes pulsation at 37° C. in dynamic-bubble mode of pulsating bubble surfactometry.
28. The artificial lung surfactant composition of claim 26 , wherein:
R 3 , R 4 , R 5 , and R 6 in each monomer in the first set are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, amino, and amino-C 1 -C 6 -alkyl, wherein at least one of R 3 , R 4 , R 5 , and R 6 is amino or amino-C 1 -C 6 -alkyl; and
A together with the carbon atoms to which it is attached in each monomer in the second set is substituted or unsubstituted C 8 cycloalkyl.
29. The artificial lung surfactant composition of claim 24 , wherein the polymer is present in the artificial lung surfactant composition as an artificial lung surfactant in an amount effective to treat a respiratory distress syndrome or pulmonary disorder involving deficient or dysfunctional lung surfactant in a mammalian subject.