Main‐Chain Bile Acid Based Degradable Elastomers Synthesized by Entropy‐Driven Ring‐Opening Metathesis Polymerization

Abstract

Despite the tremendous progress made in the field of biomedical engineering, many challenges still remain to be addressed-especially in the design of new materials. The biodegradable synthetic polymers currently used for biomedical applications are almost exclusively based on short aliphatic moieties, such as lactides, glycolides, e-caprolactone, and sebacic acid, which all display relatively "hard" mechanical properties that adjust poorly to those of tissues, and therefore cause considerable stress mismatches at the interface responsible for necrosis or abnormal regeneration. [1] Materials based on bile acids show great promise for drug delivery [2] and controlled release [3] applications, and their rigid steroidal backbone and amphiphilicity appear to make them candidates of choice for fine-tuning the mechanical and interfacial properties of synthetic degradable polymers. However, reports on main-chain bile acid based polyesters, polyamides, and polyurethanes are still scarce in the literature, and their synthesis constitutes a real challenge, especially when higher molecular weights are required. Most techniques used to date rely on the use of toxic coupling agents.Ring-opening polymerization (ROP) is a very versatile technique that has been applied to the synthesis of polyesters with a controlled molecular weight. In virtually all cases, small strained cycles (3-8-membered rings) are used and enthalpy drives the polymerization. However, macrocycles, including those based on esters and alkenes, could be polymerized, and afforded appreciably high molecular weights, depending on the conditions.[4] In these cases, polymerization is driven by entropy, as described by the Jacobson-Stockmayer theory for ring-chain equilibria. [5] Entropy-driven ring-opening polymerization (ED-ROP) therefore appears to be a method of choice for the synthesis of high-molecular-weight polyesters based on bile acids. Furthermore, the use of this technique means that the use of large amounts of coupling agents often required in polycondensations can be avoided, thus considerably lowering the toxicity of the material. Furthermore, metathesis chemistry has proved to be a powerful tool for both the preparation of macrocycles [6] and the polymerization of alkenes. [3a, 7] We describe here the synthesis of novel macrocycles by the simple ring-closure metathesis (RCM) of two flexible chains attached to a bile acid core through ester bonds, and their entropy-driven ring-opening metathesis polymerization (ED-ROMP) using ruthenium-based Grubbs catalysts. The polymers obtained show typical rubberlike elasticity, with elongation moduli that favorably compare to those of soft tissues and elastin [1c, 8] (Figure 1) and constitute, to the best of our knowledge, the first example of degradable thermoplastic amorphous elastomers.Cyclic bile acids 1 (38-membered ring) and 2 (35-membered ring) were synthesized (Scheme 1) in relatively high yields (73 and 59 %, respectively) from their corresponding dienes, at high dilution.[9] Cyclic oligomers were ...

Synthesis of Terpene-Based Polymers

“…High molecular weight polyesters (M n ¼ 59-152 kg/mol, PDI ¼ 1.6-1.9) are produced, besides a small fraction of cyclic oligomers (<10%), in high yields. It is noteworthy that the diene can be polymerized via acyclic diene metathesis (ADMET) polycondensation, but producing much lower molecular weight polyesters than ROMP [104].…”

“…Also, high molecular weight copolyesters Scheme 10 Entropy-driven ROMP of a lithocholic acid-based macrocycle [104] (M n ¼ 70-226 kg/mol, PDI ¼ 2.0-2.5) based on lithocholic and ricinoleic acid have been prepared [106].…”

Polymers made of bile acids: from soft to hard biomaterials

“…73,74 Gautrot et al demonstrated the use of a second-generation Grubbs catalyst in the ring-opening polymerization of cyclic CA monomers yielding high (M n above 100 kDa) molecular weight polymers. [75][76][77][78] The resulting polymers had elastomeric properties and were degradable with rates in the order of several months in phosphate-buffered saline solution at 37°C. Alternatively, these polymers may be synthesized by the use of lipase in the ringopening polymerization of the macrocyclic monomers.…”

Novel tri- and tetrafunctional cholic acid-based initiators for the synthesis of star-shaped poly(L-lactide)s

“…[2][3][4] This easily available and low-cost chemical, thanks to its intrinsic biodegradability, biocompatibility and renewability combined with the easy modifiability of the hydroxyl and carboxyl groups and the stability of steroid skeleton, was chosen by many researchers to design and synthesize new cholic acid-containing oligomeric or polymeric materials. [5,6] Various types of such polymers were produced in the last two decades: in several of these, the CAs were part of the main chain, [7][8][9][10] while in others, the CAs were connected as pendants [11][12][13] or, more recently, as the core of star-shaped polymers. [14][15][16][17][18][19] New star-shaped polymers have attracted the attention of scientists for many years in virtue of their unique physicochemical properties.…”