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(12) Patent Application Publication (10) Pub. No.: US 2017/0056513 A1 Hedrick Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0056513 A1 Hedrick Et Al US 2017.0056513A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0056513 A1 Hedrick et al. (43) Pub. Date: Mar. 2, 2017 (54) THERAPEUTIC COMPOSITIONS Publication Classification COMPRISING N-ALKYL-HYDROXY POLYMERS (51) Int. Cl. A6II 47/48 (2006.01) (71) Applicant: INTERNATIONAL BUSINESS A6IR 48/00 (2006.01) MACHINES CORPORATION, A63L/73 (2006.01) Armonk, NY (US) (52) U.S. Cl. CPC ...... A61K 47/48192 (2013.01); A61 K3I/713 (72) Inventors: James Hedrick, San Jose, CA (US); (2013.01); A61K 48/00 (2013.01) Dylan BODAY, San Jose, CA (US); Jeannette GARCIA, San Jose, CA (US); Rudy WOJTECKI, San Jose, (57) ABSTRACT CA (US); Yi Yan YANG, The Nanos (SG); Chuan Yang. The Nanos (SG) The disclosure describes methods and therapeutic composi tions comprising polymers modified with N-alkyl-hydroxy (21) Appl. No.: 14/836,614 groups comprising one or more carbon atoms. The compo sitions are useful for gene delivery, and exhibit broad (22) Filed: Aug. 26, 2015 spectrum antiviral activity and low toxicity in vitro. Patent Application Publication Mar. 2, 2017 Sheet 1 of 2 US 2017/0056513 A1 10. 0.15 eq. Paraformaldehyde 2 9. 8 s 5 4. c 3. 2 s g & S As ss N. Concentration (ng) Figure 1A 1. 0.30 eg. Paraformaidehyde 9 - 8 f S 5 a 30 2 . xx 22---- 2 S. $, $ so tie is is S s & 9 y & Sy sys s & S Concentration (ng) Figure 1B Patent Application Publication Mar. 2, 2017. Sheet 2 of 2 US 2017/0056513 A1 0.75 eg. Paraformaldehyde 3 - Concentration (ing) Figure 1C 1 O 3. 8 80 5 a - 3. C - is SiA, Concentration (gi. Figure 1D US 2017/0056513 A1 Mar. 2, 2017 THERAPEUTIC COMPOSITIONS SUMMARY COMPRISING N-ALKYL-HYDROXY POLYMERS 0005. A therapeutic composition is described having at least one polymer comprising amine end groups, secondary FIELD amine groups, tertiary amine groups, and alkyl-hydroxy groups, wherein at least 5% of the secondary and tertiary 0001. The disclosure relates to methods and therapeutic amine groups comprise N-alkyl-hydroxy groups, and compositions comprising polymers modified with N-alkyl wherein at least 5% of the amine end groups comprise hydroxy groups. The compositions are useful for gene N-alkyl-hydroxy groups. delivery, and exhibit broad-spectrum antiviral activity and 0006. A method for producing a therapeutic composition low toxicity in vitro. is also described that includes forming a reaction mixture comprising a solvent, a polymeric amine and a N-alkyl BACKGROUND hydroxy group precursor, and heating the mixture at a temperature from about 25°C. to about 150° C. to produce 0002 Nucleic acid-based therapies involving gene trans a polymer comprising secondary and tertiary amine groups, ference hold great promise in the treatment of human wherein at least 5% of the secondary and tertiary amine diseases. In principle, faulty and defective genes may be groups are N-alkyl-hydroxy groups. corrected and replaced by functional ones, but redundant gene expression may also be repressed to a normal level by BRIEF DESCRIPTION OF THE DRAWINGS the use of RNA interference. There are two major gene AND FIGURES delivery vectors, viral and non-viral. Viral vectors have Superior transduction capabilities, but the immunogenic and 0007 So that the manner in which the above recited oncogenic potentials of viral vectors have limited their features of the present disclosure can be understood in detail, clinical applications. To solve this problem, non-viral gene a more particular description of the disclosure, briefly sum delivery systems have been developed, and feature number marized above, may be had by reference to embodiments, of advantages including improved biosafety, lower produc some of which are illustrated in the appended drawings and tion costs, ease of transportation and storage, and reproduc figures. It is to be noted, however, that the appended ibility. Despite these advantages, non-viral systems have drawings and figures illustrate only typical embodiments of thus required specific molecular tailoring for specific inter the disclosure and are therefore not to be considered limiting action with certain nucleic acids and cell Surfaces. To of its scope, for the disclosure may admit to other equally improve on the state of the art, there is a need for new effective embodiments. non-viral gene delivery systems that display high therapeutic 0008 FIGS. 1A-1D are charts representing data collected activity, low toxicity and exhibit broad recognition for the according to some embodiments of the disclosure. myriad of nucleic acids and cell Surfaces found in nature. 0003. Many of the desirable characteristics that are DETAILED DESCRIPTION sought after in non-viral gene delivery systems have utility 0009. The present disclosure describes new therapeutic and application in the field of antiviral therapeutics. In recent compositions that are useful for gene delivery, prevention of years, viral infections have emerged as the preeminent viral infection, and are transparent to viral mutation, thus global public health problem because of an increasing mitigating resistance development. The mode of action of human population, aging, global warming, and medical the new therapeutic compositions comprising N-alkyl-hy treatments that Suppress the immune system, including droxy Substituted polymers is related to non-specific Supra irradiation therapy, anti-cancer chemotherapy and organ molecular interactions, such as hydrogen-bonding and elec transplantation. Effective treatment of viral infections is trostatic interactions, between the functional groups of the elusive because of the variance in virus structure (enveloped therapeutic composition polymer(s) and biological com and non-enveloped viruses) together with their ability to pounds such as nucleic acids, genes, proteins, RNA, DNA rapidly mutate and garner resistance. and virus/cell surfaces. The polymers of the therapeutic 0004 To solve the aforementioned problems found with composition may have N-alkyl-hydroxy groups, secondary the current materials and compositions in these fields, new and tertiary amine groups, and charged groups (cationic therapeutic compositions that display efficacy in both gene groups), Such as quaternary amine groups at biological pH. delivery and in antiviral applications have been developed, For the purposes of the disclosure, binding generally refers and are the subject of the present disclosure. The new to chemical interactions including but not restricted to: compositions involve N-alkyl-hydroxy modified polymers, chemical bonding, covalent bonding, hydrogen bonding, which exhibit: a) high gene transfection efficiency in vitro, polar attraction, and dissimilar charge attraction Such as b) display broad-spectrum antiviral activity, c) remain active positive and negative charge attraction. despite viral mutation(s), d) exhibit high virus selectivity, e) 0010. In some embodiments, an N-alkyl-hydroxy substi display low toxicity in vitro; and f), are biodegradable. tuted polymer of the therapeutic composition may form a US 2017/0056513 A1 Mar. 2, 2017 complex with nucleic acids such as therapeutic DNA and/or mers comprising amine groups may have high cationic RNA, and the complex may be further internalized into (positive) charge density at physiological pH, wherein about cells. Upon and after cell uptake, the N-alkyl-hydroxy 50% to about 90% of the amine groups have a positive groups and the secondary and tertiary amine groups of the charge due to the binding of a proton (H). Specifically, and nucleic acid/polymer complex may aid, deliver or otherwise in combination with the hydrogen bonding interactions, the enable the release of the nucleic acid from the complex. In positively charged amine groups may engage in electrostatic other embodiments, the therapeutic composition may form interactions with negatively charged nucleic acids, nucleic polymer-virus and polymer-cell assemblies based on the acid residues, and/or proteins over a broad pH range. The aforementioned interactions. The formation of said assem combination of hydrogen bonding and electrostatic interac blies is not affected, negatively impacted, nor dependent on tions may generally result in the strong bonding of thera viral mutation, thus preventing viral resistance to the peutic N-alkyl-hydroxy polymers to nucleic acids and virus/ therapy. For example, the polymer N-alkyl hydroxy groups cell Surfaces. of polymer-virus and polymer-cell assemblies may further 0014. In one embodiment, the therapeutic composition neutralize endosomal pH (absorb or bind H') thus creating an may include more than one N-alkyl-hydroxy substituted inhospitable environment for viral replication and further polymer. For example, the composition may be a mixture of viral infection. N-alkyl-hydroxy modified polymers with differing molar 0011. The aforementioned therapeutic activity may be amounts of N-alkyl-hydroxy substitutions on the polymer realized when at least 5% of the amine groups of the chain. In another embodiment, the therapeutic composition composition are substituted with N-alkyl hydroxy groups, may have at least one N-alkyl-hydroxy substituted polymer, which have at least one carbon atom. The polymers of the which may be linear or branched, or a mixture of N-alkyl therapeutic composition may further include a plurality of hydroxy substituted polymers that may be linear or polymer chain amine end groups (terminal groups) and/or branched. N-alkyl-hydroxy substitution may be found at pendantamine end groups, wherein at least 5% of the groups amine groups integrated in the polymer chain backbone or may be substituted with at least one N-alkyl hydroxy group repeating units, amine groups located at polymer chain ends, comprising at least one carbon atom. The 5% substitution or at sites where the amine groups may be pendant end produces a therapeutic composition that generally comprises groups or are a part of a pendant group or a branch. For the a plurality of secondary and tertiary amine groups with purposes of this disclosure amine groups not integrated in N-alkyl-hydroxy group Substitution, and secondary and ter the polymer backbone may be thought of as amine end tiary amine groups that may be unsubstituted.
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