Patent Application
20200062951
The present invention relates to composite polymeric compositions and, in particular, to composite polymeric compositions exhibiting thermal activity upon exposure to electromagnetic radiation.
Microbial species exist everywhere in the environment. Many microbial species are benign and play critical roles in the proper functioning of various ecosystems. However, a number of microbial species can induce serious or life threatening diseases in humans and animals Surfaces in health treatment facilities, such as hospitals and nursing homes, are extremely susceptible to accumulation of harmful microbial species and associated biofilms. Surfaces of medical diagnostic equipment are also often in danger of microbial and/or biofilm accumulation. Accordingly, these surfaces are routinely cleaned with one or more antimicrobial compositions. In many cases, the cleaning is incomplete and microbial species regenerate quickly, risking the spread of disease. In some instances, heat treatments are employed to effectively kill microbial species. While effective, heat treatments have limited application to large surfaces and equipment comprising sensitive components.
In one aspect, composite polymeric compositions are described herein which, in some embodiments, are thermally responsive to electromagnetic radiation for the destruction of microbes and/or associated biofilms Briefly, a composite polymeric composition comprises a polymeric matrix and photo-thermal particles comprising conjugated polymer dispersed in the polymeric matrix. In some embodiments, the photo-thermal particles are nanoparticles, microparticles or mixtures thereof.
In another aspect, articles employing the composite polymeric compositions are provided. In some embodiments, an article comprises one or more surfaces and a coating over the one or more surfaces, the coating comprising a polymeric matrix and photo-thermal nanoparticles comprising conjugated polymer dispersed in the polymeric matrix. Any article not inconsistent with the objectives of the present invention can have surfaces coated with the composite polymeric composition. As described further herein, articles supporting high concentrations of microbes and associated biofilms can be coated with composite polymeric compositions described herein. Various hospital surfaces, medical devices and/or implants can be coated with composite polymeric compositions described herein. In other embodiments, articles can be formed of composite polymeric compositions described herein. In such embodiments, the article can be employed as a heat source for enhancing uptake and/or efficacy of various pharmaceutical compositions, including antimicrobial or antibacterial compositions and/or chemotherapeutic compositions. The article can also exhibit antimicrobial properties in the presence or absence of applied electromagnetic radiation.
In a further aspect, methods of cleaning surfaces are provided. A method of cleaning a surface comprises heating the surface via exposure to electromagnetic radiation to kill and/or disperse microbes, the surface comprising a composite polymeric composition including a polymeric matrix and photo-thermal nanoparticles comprising conjugated polymer dispersed in the polymeric matrix.
These and other embodiments are described in greater detail in the detailed description which follows.
Embodiments described herein can be understood more readily by reference to the following detailed description and examples and their previous and following descriptions. Elements, apparatus and methods described herein, however, are not limited to the specific embodiments present in the detailed description and examples. It should be recognized that these embodiments are merely illustrative of principles of the present invention. Numerous modifications and adaptations will be readily apparent to those of skill in the art without departing from the spirit and scope of the invention.
In one aspect, composite polymeric compositions are described herein which, in some embodiments, are thermally responsive to electromagnetic radiation for the destruction of microbes and/or associated biofilms. In some embodiments, a composite polymeric composition comprises a polymeric matrix and photo-thermal particles comprising conjugated polymer dispersed in the polymeric matrix.
Photo-thermal particles are operable to provide thermal energy to the environment surrounding the polymeric composite when irradiated with radiation falling within the absorption profile of the conjugated polymer. Various conjugated polymeric species exhibiting a thermal response to radiation may be employed in the photo-thermal nanoparticles. For example, conjugated polymeric species having a bandgap ranging from about 1.1 eV to about 1.8 eV can be used in the photo-thermal particles. Bandgap and associated radiation absorption profile of the conjugated polymer can be tailored to spectral requirement(s) of a particular application. As discussed further herein, photo-thermal particles comprising conjugated polymer having an absorption profile in the near infrared region (NIR) can be used for treatment applications where radiation is required to penetrate tissue to reach the nanoparticles. For example, polymeric species of the photo-thermal particles can have an absorption profile of 700 nm to 1200 nm. Further, the spectral response of the photo-thermal particles can be broadened or narrowed by the use of multiple polymeric species or a single polymeric species respectively. In some embodiments, composite polymeric compositions described herein are not damaged or destroyed by the heat generated by the photo-thermal particles in response to radiation. This permits reuse of the polymeric composites over a number of heating cycles.
Any thermally responsive conjugated polymer not inconsistent with the objectives of the present invention can be used in the photo-thermal particles. In some embodiments, the conjugated polymer is a homopolymer. For example, a homopolymer can be constructed of a donor monomeric species (D), wherein D is a monocyclic, bicyclic or polycyclic arylene or monocyclic, bicyclic or polycyclic heteroarylene. The arylene structures, in some embodiments, can be fused or linked. A conjugated homopolymer, in some embodiments, is constructed of a monomer selected from the group consisting of aniline, pyrrole, thiophene, 3-substituted thiophene, bithiophene, terthiophene, selenophene, 3-substituted selenophene, isothianaphthene, p-phenylenevinylene, ethylenedioxythiophene, propylenedioxythiophene, 2,7-fluorene, substituted 2,7-fluorene, 2,7-carbazole, substituted 2,7-carbazole, thieno[3,2-b]thiophene, thieno[3,4-b]thiophene, dithienothiophene, cyclopenta[2,1-b:3,4-b′]dithiophene, substituted cyclopenta[2,1-b;3,4-b′]dithiophene, dithieno[3,2-b:2′,3′-d]silole, benzo[1,2-b;4,5-b′]dithiophene, benzo[1,2-b;3,4-b]dithiophene, indolo[3,2-b]carbazoles, dithieno[3,2-b:2′,3′-d]pyrrole, diketopyrrolopyrrole, pentacene, heptacene and perylenediimine. Some suitable donor monomeric species are further illustrated in
Additionally, a conjugated homopolymer of the photo-thermal particles can be constructed of an acceptor monomeric species (A, A1, A2, A3 in formula herein), wherein the acceptor monomeric species is a monocyclic, bicyclic or polycyclic arylene or monocyclic, bicyclic or polycyclic heteroarylene. The arylene structures, in some embodiments, can be fused or linked A conjugated homopolymer, in some embodiments, is constructed of a monomer selected from the group consisting of pyrrole, aniline, thiophene, ethlyenedioxythiophene, p-phenylenevinylene, benzothiadiazole, pydridinethiadiazole, pyridineselenadiazole, benzoxadiazole, benzoselenadiazole, thieno[3,4-b]pyrazine, thieno[3,4-b]thiophene, thieno[3,2-b]thiophene, [1,2,5]thiadiazolo[3,4-g]quinoxaline, pyrazino[2,3-g]quinoxaline, thienopyrrolidinone and isothianaphthene. Some suitable acceptor monomeric species (A, A1, A2, A3) are further illustrated in
wherein R1 and R2 are defined above.
Alternatively, in some embodiments, a conjugated polymer of the photo-thermal particles is a copolymer of two or more repeating units. For example, a conjugated polymer can be constructed of two or more monomeric species selected from the group consisting of D and A monomeric species described herein. In some embodiments, conjugated polymer is a copolymer of a donor-acceptor (D-A) architecture. For example, a D-A conjugated polymer can be composed of cyclopentadithiophene and 2,1,3-benzothiadiazole (PCPDTBT) or cyclopentadithiophene and 2,1,3-benzoselenadiazole (PCPDTBSe). In some embodiments, a conjugated polymer has the structure of Formula (I):
wherein D is a donor monomeric species described herein, A is an acceptor monomeric species described herein, and each X is independently O, N, S or Se. In some embodiments, a D-A conjugated polymer of the photo-thermal particles is of formula:
wherein D is a donor monomeric species described herein, A1 and A2 are acceptor monomeric species described herein. In some embodiments, m and n range from 1 to 100.
In some embodiments, conjugated polymeric species of the photo-thermal particles comprise polyethylenedioxythiophene (PEDOT). The photo-thermal particles, for example, can be formed of PEDOT or a polymeric mixture comprising PEDOT. In some embodiments, photo-thermal particles comprise PEDOT-polystyrene sulfonate (PSS).
Composition of the photo-thermal particles can be uniform or substantially uniform in a composite composition. Alternatively, photo-thermal particle composition can vary in the composite composition. Photo-thermal particles of differing composition can be dispersed in the polymeric matrix. In some embodiments, photo-thermal particles may be of the same conjugated polymer, but differing molecular weight and/or size. In this way, properties of composite polymeric compositions described herein can be tailored.
Conjugated polymeric species of the photo-thermal particles, in some embodiments, have sufficient molecular weight to red-shift the absorption profile of the conjugated polymeric species into the red region of the visible spectrum and/or into the near infrared region. In some embodiments, for example, a conjugated polymeric species of the photo-thermal particles has a number average molecular weight (Mn) of at least 7500. Molecular weight of a polymeric species in the photo-thermal nanoparticles, in some embodiments, is selected from Table I.
Photo-thermal particles of composite polymeric compositions described herein can have any desired size. Size of the photo-thermal particles can be selected according to several considerations including, but not limited to, compatibility of the particles with the polymeric matrix, concentration of the particles in the polymeric matrix, thermal responsiveness of the composite composition and/or mechanical properties of the composite composition. In some embodiments, photo-thermal particles are nanoparticles, microparticles or mixtures thereof. The photo-thermal particles can exhibit bimodal or multimodal particle size distributions.
In some embodiments, a photo-thermal nanoparticle has particle size in the range of 0.1 nm to 500 nm. A photo-thermal nanoparticle can have a size selected from Table II.
As described herein, the photo-thermal particles are dispersed in a polymeric matrix. Any polymeric matrix not inconsistent with the objectives of the present invention can be employed. Polymeric matrices may be selected according to several considerations including, but not limited to, spectral characteristics, thermal conductivity, desired mechanical properties and/or dispersibility of the photo-thermal particles in the matrix. In some embodiments, the polymeric matrix can be transparent to visible radiation. Alternatively, the polymeric matrix can be colored or opaque. Suitable polymeric matrices can be formed of thermoplastics, thermosets and/or elastomers. For example, polymeric matrix can be selected from the group consisting rubber, silicone elastomer, siloxanes, polyisoprene and polyisobutylene. Photo-thermal particles can be present in the polymeric matrix in any desired amount or concentration. In some embodiments, photo-thermal particles are present in the polymeric matrix at a concentration of 0.1 mg/ml to 100 mg/ml. Photo-thermal particles can also be present in the polymeric matrix at a concentration selected from Table III.
In some embodiments, photo-thermal particles are present in an amount or concentration sufficient for the destruction of microbes and associated biofilms. As shown in the examples detailed herein, the composite polymeric compositions are effective in killing bacteria and associated bacterial biofilms. In some embodiments, photo-thermal particles of composite polymeric compositions described herein can have composition and properties described in U.S. patent application Ser. Nos. 14/394,198 and 15/303,171 which are incorporated herein by reference in their entireties. Photo-thermal particles, for example, can exhibit a hybrid architecture comprising a low molecular weight conjugated polymer component and a high molecular weight conjugated polymer component. The low and high molecular weight conjugated polymers may be of the same or different composition.
Photo-thermal particles can be combined or dispersed in the polymeric matrix in any desired manner. In some embodiments, photo-thermal particles are physically mixed with the polymeric matrix. In other embodiments, the photo-thermal particles are present during polymerization and/or cross-linking of the polymeric matrix. Photo-thermal particles, for example, can be added to the polymerization reaction mixture.
In another aspect, articles employing the composite polymeric compositions are provided. In some embodiments, an article comprises one or more surfaces and a coating over the one or more surfaces, the coating comprising a polymeric matrix and photo-thermal particles comprising conjugated polymer dispersed in the polymeric matrix. The coating can have any desired thickness. Coating thickness can be selected according to several considerations including, but not limited to, light absorption and/or heating characteristics of the coating, wettability of the coating on article surfaces and adhesion of the coating to article surfaces. In some embodiments, the coating is a single layer. In other embodiments, the coating is multilayer. In multilayer embodiments, individual layers can have the same or differing compositions and/or properties. Individual coating layers, for example, can have the same or substantially the same thickness and/or composition. In other embodiments, individual coating layers can have differing thicknesses and/or composition. Specific coating architecture can be tailored to the desired spectral absorption and associated heating requirements of the coating.
In some embodiments, a layer having good compatibility with article surfaces can serve as the base layer of the coating for enhancing coating adhesion. The base layer may or may not have desirable absorbance or hearting characteristics. However, subsequent layers of the coating can mitigate any performance deficiencies of the base layer. Surfaces of the article can also be prepared to enhance coating adhesion. In some embodiments, article surfaces can be mechanically treated to enhance coating adhesion. Mechanical treatment can include roughing or smoothing article surfaces. Article surfaces may also be chemically treated prior to applications of coatings described herein. Chemical treatment can alter surface energies, thereby enhancing compatibility with the coating. One or more adhesion layers may also be applied to article surfaces. In some embodiments, the adhesion layers do not comprise photo-thermal particles.
Any article not inconsistent with the objectives of the present invention can have surfaces coated with the composite polymeric composition. As described further herein, articles supporting high concentrations of microbes and associated biofilms can be coated with composite polymeric compositions described herein. Various hospital surfaces, medical devices and/or implants can be coated with composite polymeric compositions described herein. In further embodiments, articles can be formed of composite polymeric compositions described herein. In such embodiments, the articles can be employed as heat sources for enhancing uptake and/or efficacy of various pharmaceutical compositions including antimicrobial or antibacterial compositions and/or chemotherapeutic compositions.
In a further aspect, methods of cleaning surfaces are provided. A method of cleaning a surface comprises heating the surface via exposure to electromagnetic radiation to kill and/or disperse microbes, the surface comprising a composite polymeric composition including a polymeric matrix and photo-thermal nanoparticles comprising conjugated polymer dispersed in the polymeric matrix.
These and other embodiments are further illustrated in the following non-limiting examples.
All reagents were purchased from common commercial sources and used without further purification unless otherwise noted. 4H-Cyclopenta-[1,2-b:5,4-b]dithiophene was purchased from Astar Pharma. THF was dried over Na/benzophenone ketal. 4,4-Bis(2-ethylhexyl)-2,6-bis(trimethylstannyl)-4H-cyclopenta-[2,1-b;3,4-b′]dithiophene, 4,7-dibromo-2,1,3-benzothiadiazole and 4,7-dibromo-2,1,3-benzoselenadiazole were synthesized according to their literature procedures (see J. Hou, T. L. Chen, S. Zhang, H.-Y. Chen, Y. Yang, J. Phys. Chem. C 2009, 113, 1601-1607; Z. Zhu, D. Waller, R. Gaudiana, M. Morana, D. Muhlbacher, M. Scharber, C. Brabec, Macromolecules 2007, 40, 1981-1986; C. W. Bird, G. W. H. Cheeseman, A. A. Sarsfield, J. Chem. Soc. 1963, 4767-4770; I. H. Jung, H. Kim, M.-J. Park, B. Kim, J.-H. Park, E. Jeong, H. Y. Woo, S. Yoo, H.-K. Shim, J. Polym. Sci. Part A: Polym. Chem. 2010, 48, 1423-1432; X. Li, W. Zeng, Y. Zhang, Q. Hou, W. Yang, Y. Cao, Eur. Polym. J. 2005, 41, 2923-2933; and Y. Tsubata, T. Suzuki, T. Miyashi, Y. Yamashita, J. Org. Chem. 1992, 57, 6749-6755, the entireties of which are hereby incorporated by reference). Poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b′]dithiophene-2,6-diylalt-2,1,3-benzothiadiazole-4,7-diyl] (PCPDTBT) and poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b′]dithiophene-2,6-diylalt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe) were synthesized using a Stille coupling procedure under microwave radiation. The polymerization procedure is outlined below.
Flash chromatography was performed on a Biotage Isolera™ Flash Purification System using Biotage SNAP Flash Purification Cartridges as the stationary phase. Microwave assisted polymerizations were carried out using a CEM Discover Microwave reactor. 300 and 500 MHz 1H-NMR spectra were recorded on Bruker Avance DPX-300 and DRX-500 Instruments, respectively. 13C NMR spectra were recorded on a Bruker Avance DRX-500 instrument at 125.76 MHz. UV-Vis absorption spectra were recorded on an Agilent 8453 diode-array spectrophotometer operating over a range of 190-1100 nm. GC-MS were recorded on an Agilent 6850 Series GC system coupled to an Agilent 5973 mass selective detector run in electron impact mode. Infrared spectra were recorded either on a Mattson Genesis II FT-IR spectrometer or on a Perking-Elmer Spectrum 10 spectrometer with an ATR sampling accessory equipped with a diamond anvil Raman spectra were recorded on a DeltaNu Advantage 532 Raman spectrometer at 532 nm.
4,4-Bis(2-ethylhexyl)-2,6-bis(trimethylstannyl)-4H-cyclopenta-[2,1-b;3,4-b′]dithiophene was added to a microwave tube along with 4,7-dibromo-2,1,3-benzothiadiazole (1.05:1 equivalent) and 2 mL of chlorobenzene. The tube was stirred for 5 minutes to dissolve the monomers. Pd(PPh3)4 (2.5 mol %) was then added and the tube was sealed with a crimp cap and placed in a microwave reactor where it was heated to 200° C. for 10 minutes. Upon cooling to room temperature a viscous solution of green polymer was observed in the reaction vessel. The polymer was precipitated in methanol and collected by vacuum filtration. The solid was then transferred to a Soxhlet thimble and subjected to extraction with MeOH (3 hrs), hexanes (6 hrs), and finally chloroform (6 hrs). The chloroform extract was evaporated almost to completion and methanol was added to precipitate the polymer, which was filtered and dried under vacuum for 24 hours. 1H-NMR is comparable to the literature values.
The synthesis of PCPDTBSe follows the same procedure as PCPDTBT above, except 4,7-dibromo-2,1,3-benzoselenadiazole (1.05:1 equivalent) was used instead of 4,7-dibromo-2,1,3-benzothiadiazole. 1H-NMR was comparable to the literature values.
1 mL of low molecular weight PCPDTBSe [2.15 mg/mL in THF] and 1 mL of high molecular weight PCPDTBSe [1 mg/mL in THF] were premixed and injected under continuous horn sonication (10% amplitude, 1 minute) into 8 mL of Pluronic F127 [5 mg/mL in water]. This solution was centrifuged (30 minutes 12,600 Gs) to pellet large nanoparticles; the resulting supernatant was then centrifuged (4 hours 12,600 Gs) to pellet small nanoparticles.
1 mL of high molecular weight PCPDTBSe [1 mg/mL in THF] followed by 1 mL of low molecular weight PCPDTBSe [2.15 mg/mL in THF] was injected under continuous horn sonication (10% amplitude, 1 minute) into 8 mL of Pluronic F127 [5 mg/mL in water]. This solution was centrifuged (30 minutes 12,600 Gs) to pellet large nanoparticles; the resulting supernatant was then centrifuged (4 hours 12,600 Gs) to pellet small nanoparticles.
PCPDTBSe photo-thermal nanoparticles described herein were combined with elastomeric matrix to produce thermally-active polymeric composites detailed in Appendix A.
PCPDTBSe (“BSE”) nanoparticles were synthesized in accordance with Example 1 herein. The BSE nanoparticles were combined with a silicone matrix as set forth in
The Si-BSE composites of Example 4 were tested for ablation efficacy of microbial species. In particular, the Si-BSE composites were combined with planktonic S. Aureus and subjected to near infrared (NIR), 8 W laser treatment at 60 s and 120 s. The results of the testing are provided in
The antimicrobial activity of Si-BSE composites of Example 4 were tested against S. Aureus biofilms with and without laser irradiation. Two near infrared (NIR) laser irradiation conditions were employed: (1) 8 W for 60 seconds and (2) 8 W for 120 seconds. The results of the testing are provided in
The antimicrobial activity of Si-BSE composites of Example 4 were tested against S. Aureus biofilms without laser irradiation. The results are provided in
The antimicrobial activity of Si-BSE composites of Example 4 were tested against S. Aureus biofilms with and without laser irradiation. Two near infrared (NIR) laser irradiation conditions were employed: (1) 8 W for 60 seconds and (2) 8 W for 120 seconds. The results of the testing are provided in
Si-BSE composites of Example 4 were combined with the antibiotic Gentamicin and tested against S. Aureus under varying NIR laser treatment conditions. The NIR laser treatment conditions were 3 W for 60 seconds, 5 W for 60 seconds and 8 W for 60 seconds. The results are provided in
Si-BSE composites of Example 4 were combined with the antibiotic Gentamicin and tested against S. Aureus biofilm under NIR laser treatment at 8 W and 60 seconds. The results are provided in
5 mg of polyethylenedioxythiophene (PEDOT) nanotubes and 1 g of silicone base (Sylgard 184) were ground using a pestile. After completion of the grinding, 3 drops (0.01 g) of Sylgard 184 crosslinker were added to the mixture. Two pieces of VINCON® tubing (12 cm diameter) were coated with the resulting mixture and placed in an oven at 50° C. for curing. This process was repeated up to 4 times to provide tubing comprising 4 layers of the polymeric composite. The samples were subsequently tested for light absorbance. The results are provided in
A 1 cm piece was cut from each sample and inserted into a well of a 24-well plate filled with 2 mL of water. A continuous wave, 5 W, 970 nm laser was used to irradiate the samples for various time periods, and the temperature change in the water was measured. Irradiation times were 30 seconds, 60 seconds, 90 seconds, 120 seconds, 180 seconds, 240 second and 300 seconds. All samples were conducted in triplicate, and a 1 cm piece of uncoated VINCON® in 2 ml of water was used as the control.
5 mg of polyethylenedioxythiophene (PEDOT) nanotubes and 1 g of silicone base (Sylgard 184) were mixed with a spatula. After completion of the mixing, 3 drops (0.01 g) of Sylgard 184 crosslinker were added to the mixture. Two pieces of VINCON® tubing (12 cm diameter) were coated with the mixture and placed in an oven at 50° C. for curing. This process was repeated up to 4 times to provide tubing comprising 4 layers of the polymeric composite.
A 1 cm piece was cut from each sample and inserted into a well of a 24-well plate filled with 2 mL of water. A continuous wave, 5 W, 970 nm laser was used to irradiate the samples for various time periods, and the temperature change in the water was measures. Irradiation times were 30 seconds, 60 seconds, 90 seconds, 120 seconds, 180 seconds, 240 second and 300 seconds. All samples were conducted in triplicate, and a 1 cm piece of uncoated VINCON® in 2 ml of water was used as the control.
The heating profiles of the 4-layer samples of Examples 11 and 12 were examined with respect to LIQUICLEAN® detergent, commercially available from Ruholf Corporation of Mineola, N.Y. The same laser treatment of Examples 11 and 12 was applied in the present example. The results are provided in
Various embodiments of the invention have been described in fulfillment of the various objectives of the invention. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous modifications and adaptations thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.
The present application claims priority pursuant to 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Ser. No. 62/491,500 filed Apr. 28, 2017 which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2018/030146 | 4/30/2018 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62491500 | Apr 2017 | US |
