Biobased Hyperbranched Poly(Ester)S of Precise Structure for the Release of Therapeutics Authors Bob A

Bob A. Howell, et al. Medical Research Archives vol 9 issue 1. Medical Research Archives

RESEARCH ARTICLE

Biobased Hyperbranched Poly(ester)s of Precise Structure for the Release of Therapeutics Authors Bob A. Howell1, Tracy Zhang1,2 and Patrick B. Smith2

Affiliations 1Center for Applications in Polymer Science Department of Chemistry Central Michigan University Mt. Pleasant, MI 48859

2Michigan State University, St. Andrew Campus 1910 W. St. Andrew Rd. Midland, MI 48640

Correspondence Bob A. Howell Email: [email protected]

ABSTRACT Hyperbrached poly(ester)s derived from naturally-occurring biomonomers may serve as excellent platforms for the sustained-release of therapeutics. Those generated from glycerol are particularly attractive. Traditionally, the difference in reactivity of the hydroxyl groups of glycerol has precluded the formation of well-defined polymers at high monomer conversion without gelation. Using the Martin-Smith model to select appropriate monomer ratios (ratios of functional groups), polymerization may be carried out to high conversion while avoiding gelation and with the assurance of a single type of endgroup. Various agents may be attached via esterification, amide formation or other process. Sustained release of the active agent may be readily achieved by enzyme-catalyzed hydrolysis.

Bob A. Howell, et al. Medical Research Archives vol 9 issue 1. January 2021 Page 2 of 6

INTRODUCTION containing functionality of unequal Sustained release of therapeutic reactivity. For a variety of reasons, including agents from biocompatible delivery systems widespread availability from remains an area of intense interest and transesterification of triglyceride to generate activity.1,2 The controlled release of biodiesel, glycerol has often been used as the therapeutic agents from polymeric prodrugs alcohol component in hyperbranched offers several advantages, including poly(ester) synthesis. Glycerol contains three maintenance of optimum dosage level and hydroxyl groups, two primary of one extended effectiveness, over conventional reactivity in esterification and a secondary methods of administration. The most hydroxyl group of lower reactivity (the attractive polymeric carrier materials are primary hydroxyl groups of glycerol are biocompatible, biodegradable compounds of approximately 1.4 times as reactive in well-defined structure.3,4 Hyperbranched esterification as is the secondary hydroxyl polymers are generally superior to linear group). Further, esterification of one analogs as carrier platforms.5 For similar hydroxyl group influences the reactivity of molecular weights, the hyperbranched those remaining. For this situation, traditional materials offer lower viscosity, greater gelation theory is inadequate for predicting solubility and a wealth of reactive endgroups ratios of monomers (ratios of reactive for the attachment of active agents.6 In functional groups) that will permit the particular, hyperbranched poly(ester)s formation of nongelled polymers at high derived from readily-available, nontoxic monomer conversion. A new approach is biomonomers are attractive as a base for the required. Generally, glycerol hyperbranched generation of sustained-release poly(ester)s have been produced using compositions. These materials may be empirical methods—varying monomer prepared by polycondensation of a concentration, reaction temperature or extent multifunctional alcohol with a of reaction. This approach is unsatisfactory. multifunctional carboxylic acid. If carried out In particular, polymers obtained by limiting to high monomer conversion this process the extent of reaction contain reactive leads to gelation and has long been used in endgroups of different types (hydroxyl and the coatings industry. However, for use in the carboxyl). Further reaction is possible and on preparation of sustained-release storage these materials usually gel.11-15 These formulations, gelation must be avoided. For empirical methods do not permit the targeting monomers containing functional groups of of molecular weight, degree of branching or equal reactivity, e.g. pentaerythritol and a endpoint identity from initial reactant diacid, Flory-Stockmayer theory can be used stoichiometry. Fortunately, this situation has to determine the ratio of monomers that may been remedied by the development of the be used to achieve high monomer conversion Martin-Smith model for controlled without gelation.7-10 However, this approach polymerization of multifunctional monomers is unsuitable for polymerization of monomers containing functionality of different

Bob A. Howell, et al. Medical Research Archives vol 9 issue 1. January 2021 Page 3 of 6 reactivity.16 This model is based on reactive terminal groups for the attachment of Macosko-Miller statistical probability and therapeutic agents. Hyperbranched accounts for both differences in functional poly(ester)s derived from naturally- group reactivity and changes in reactivity as occurring, nontoxic monomers may be a consequence of partial substitution.17-19 It particularly useful for the construction of has been verified experimentally and used to sustained-release formulations.21, 23 Because predict ratios of reactants to permit of its abundance, widespread availability and polymerization to high degrees of monomer modest cost, glycerol is commonly used as conversion without gelation. These materials the alcohol component of hyperbranched have well-defined structure and a single type poly(ester) synthesis.11-16 A variety of of endgroup. Gelation does not occur on dicarboxylic acids may be used in the storage. This approach has been utilized for preparation.20 Perhaps the most useful is the preparation of structurally-precise adipic acid.16 Both glycerol and adipic acid polymers to serve as platforms for the are available from biosources and have long development of useful sustained-release been recognized as safe by the U.S. Food and compositions.20,21 Drug Administration. Using the Martin- Smith model for the selection of appropriate RESULTS AND DISCUSSION reactant stoichiometry, polymerization may Polymeric materials that are be carried out to high conversion without biocompatible and biodegradable are being gelation to provide materials with well- widely utilized as platforms for the defined structure and single endgroup formulation of sustained-release functionality (Figure 1)16. A variety of compositions containing a variety of active therapeutic agents may be attached via agents.22 Hyperbranched polymers often esterification using the terminal hydroxyl display good solubility and offer a wealth of groups.21

Figure 1. Glyerol/Adipic Acid Hyperbranched Poly(ester) Containing Hydroxyl Terminal Groups.

Bob A. Howell, et al. Medical Research Archives vol 9 issue 1. January 2021 Page 4 of 6

A simple example is the attachment of salicylic acid as illustrated in Scheme 1.

Scheme 1. Attachment of Salicylic Acid to the Periphery of a Hydroxyl-Terminal Glycerol/Adipic Acid Hyperbranched Poly(ester).

A stable conjugate is obtained. Release of salicylic acid may be readily achieved under the influence of enzymatic catalysis (rat liver microsomes).21 The release rate is depicted in Figure 2.

Figure 2. Release of Salicylic Acid from the Glycerol/Adipic Acid Hyperbranched Poly(ester) Conjugate.

CONCLUSIONS conversion without gelation and the Glycerol-derived hyperbranched assurance of a single endgroup functionality poly(ester)s of well-defined structure and a (hydroxyl or carboxyl). Active agents may be single type of endgroup may serve as attached by esterification (or other for excellent platforms for the sustained-release carboxyl terminal polymers). Therapeutic of therapeutics. Using the Martin-Smith agents may be smoothly released in a model to select appropriate monomer ratios, sustained manner by enzyme-catalyzed polymerization may be carried out to high hydrolysis.

Bob A. Howell, et al. Medical Research Archives vol 9 issue 1. January 2021 Page 5 of 6

REFERENCES:

(1) J. Wang, H. Zhang, J. Xu, H. Qian, R. Pentaerythritol”, Macromolecules, Liu, Z. Xu and H. Zhu, “Sustained- 2008, 41, 5651-5657. release Ibuprofen Prodrug Particle: (8) P. J. Flory, “Molecular Size Distribution Emulsifier and Initiator Regulate the in Three-dimensional Polymers. VI. Diameter and Distribution”, J. Appl. Branched Polymers Containing A-R- Polym. Sci., 2020, Bf-1 Type Units”, J. Am. Chem. Soc., doi.org/110.1002/app.49779 1952, 74, 2718-2723. (2) B. Demirdirek and K. E. Uhrich, “Novel (9) W. H. Stockmayer, “Theory of Salicylic Acid-based Chemically Molecular Size Distribution and Gel Crosslinked pH-Sensitive Hydrogels as Formation in Branched-chain Potential Drug Delivery Systems”, Int. Polymers”, J. Chem. Phys., 1943, 11, J. Pharm., 2017, 528, 406-415. 45. (3) B. A. Howell and D. Fan, (10) W. H. Stockmayer, “Theory of “Poly(amidoamine) Dendrimer- Molecular Size Distribution and Gel supported Organoplatinum Antitumor Formation in Branched Polymers. II. Agents”, Proc. R. Soc. A, 2010, 466, General Crosslinking”, J. Chem. Phys., 1515-1526. 1944, 12, 125. (4) S. Tang, S. M. June, B. A. Howell and (11) J.-F. Stumbe and B. Bruchmann, M. Chai, “Synthesis of Salicylate “Hyperbranched Polyesters Based on Dendrimer Prodrugs”, Tetrahedron Adipic Acid and Glycerol”, Macrol. Lett., 2006, 47, 7671-7675. Rapid Commun., 2004, 25, 921-924. (5) Y. Hed, Y. Zhang, O. C. J. Andren, X. (12) V. T. Wyatt, “Lewis Acid-catalyzed Zeng, A. M. Nystrom and M. Malkoch, Synthesis of Hyperbranched Polymers “Side-by-side Comparison of Dendritic- Based on Glycerol and Diacids in linear Hybrids and their Hyperbranched Toluene”, J. Am. Oil Chem. Soc., 2012, Analogs as Micellar Carriers of 89, 313-319. Chemotherapeutics”, J. Polym. Sci., (13) V. T. Wyatt and G. D. Strahan, “Degree Part A: Polym. Chem., 2013, 51, 3992- of Branching in Hyperbranched 3996. Poly(glycerol-co-diacid)s Synthesized (6) D. Yan, C. Cao and H. Frey, Eds., in Toluene”, Polymer, 2012, 4, 396-407. Hyperbranched Polymers: Synthesis, (14) Y. Li, W. D. Cook, C. Moorhoff, W.-C. Properties, and Applications, John Huang and Q.-Z. Chen, “Sythesis, Wiley and Sons, Inc., Hoboken, NJ, Characterization and Properties of 2011. Biocompatible Poly(glycerol sebacate) (7) H. R. Kricheldork and G. Behnken, Prepolymer and Gel”, Polym. Int., 2013, “Biodegradable Hyperbranched 62, 534-547. Aliphatic Polyesters Derived from (15) Y. Yang, W. Lu, J. Cai, Y. Hou, S. Ouyang, W. Xie and R. A. Gross,

Bob A. Howell, et al. Medical Research Archives vol 9 issue 1. January 2021 Page 6 of 6

“Poly(oleic acid-co-glycerol): (20) T. Zhang, B. A. Howell, and P. B. Comparison of Polymer Structure Smith, “Rational Synthesis of Resulting from Chemical and Lipase Hyperbranched Poly(ester)s”, Ind. Eng. Catalysis”, Macromolecules, 2011, 44, Chem. Res., 2017, 56, 1661-1670. 1977-1985. (21) T. Zhang, B. A. Howell, D. Zhang, B. (16) T. Zhang, B. A. Howell, A. Dumitrascu, Zhu, and P. B. Smith, “Hyperbranched S. J. Martin and P. B. Smith, “Synthesis Poly(ester)s for Delivery of Small and Characterization of Glycerol- Molecule Therapeutics”, Polym. Adv. Adipic Acid Hyperbranched Technol., 2018, 29, 2352-2363. Poly(ester)s”, Polymer, 2014, 55, 5065- (22) A. Muniandy, C. S. Lee, W. H. Lim, M. 5072. R. Pichika and K. K. Mak, (17) C. W. Macosko and D. R. Miller, “A “Hyperbranched Poly(glycerol New Derivation of Average Molecular esteramide): A Biocompatible Drug Weights of Nonlinear Polymers”, Carrier From Glycerol Feedstock and Macromolecules, 1976, 9, 199-206. Dicarboxylic Acid”, J. Appl. Polym. (18) D. R. Miller and C. W. Macosko, Sci., 2020, “Average Property Relations for doi.org/110.1002/app.50126. Nonlinear Polymerization with Unequal (23) B. A. Howell, T. Zhang and P. B. Smith, Reactivity,” Macromolecules, 1978, 11, “Hyperbranched Poly(ester)s from 656-662. Renewable Biomonomers by Design: (19) D. R. Miller and C. W. Macosko, Nontoxic Platforms for the Delivery of “Substituent Effects in Property Therapeutic Agents”, Sci. J. Research & Relations for Stepwise Polyfunctional Rev., 2019, 2(2). Polymerization”, Macromolecules, 1980, 13, 1063-1069.