Biomacromolecules 2005, 6, 2570-2582
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Controlled Delivery of Paclitaxel from Stent Coatings Using Poly(hydroxystyrene-b-isobutylene-b-hydroxystyrene) and Its Acetylated Derivative Laszlo Sipos, Abhijit Som, and Rudolf Faust* Polymer Science Program, Department of Chemistry, University of Massachusetts Lowell, One University Avenue, Lowell, Massachusetts 01854
Robert Richard,* Marlene Schwarz, Shrirang Ranade, Mark Boden, and Ken Chan Corporate Research & Advanced Technology, Boston Scientific Corporation, One Boston Scientific Place, Natick, Massachusetts 01760 Received April 28, 2005; Revised Manuscript Received June 30, 2005
A poly(styrene-b-isobutylene-b-styrene) (SIBS) triblock polymer is employed as the polymer drug carrier for the TAXUS Express2 Paclitaxel-Eluting Coronary Stent system (Boston Scientific Corp.). It has been shown that the release of paclitaxel (PTx) from SIBS can be modulated by modification of either drugloading ratio or altering the triblock morphology by blending. In the present work, results toward achieving release modulation of PTx by chemical modification of the styrenic portion (using hydroxystyrene or its acetylated version) of the SIBS polymer system are reported. The synthesis of the precursor poly{(p-tertbutyldimethylsilyloxystyrene)}-b-isobutylene-b-{(p-tert-butyldimethylsilyloxystyrene} triblock copolymers was accomplished by living sequential block copolymerization of isobutylene (IB) and p-(tert-butyldimethylsiloxy)styrene (TBDMS) utilizing the capping-tuning technique in a one-pot procedure in methylcyclohexane/CH3Cl at -80 °C. This procedure involved the living cationic polymerization of IB with the 5-tert-butyl-1,3-bis(1-chloro-1-methylethyl)benzene/TiCl4 initiating system and capping of living difunctional polyisobutylene (PIB) chain ends with 1,1-ditolylethylene (DTE) followed by addition of titanium(IV) isopropoxide (Ti(OIp)4) to lower the Lewis acidity before the introduction of TBDMS. Deprotection of the product with tetrabutylammonium fluoride yielded poly(hydroxystyrene-b-isobutylene-b-hydroxystyrene), which was quantitatively acetylated to obtain the acetylated derivative. The hydroxystyrene and acetoxystyrene triblock copolymers have acceptable mechanical properties for use as drug delivery coatings for coronary stent applications. It was concluded that the hydrophilic nature of the endblocks and polarity effects on the drug/polymer miscibility lead to enhanced release of PTx from these polymers. The drug-polymer miscibility was confirmed by differential scanning calorimetry and atomic force microscopy evaluations. Introduction The development and commercialization of drug eluting coronary stents (DES) has provided a revolutionary new treatment for cardiovascular restenosis. Currently, DES technologies are available and have demonstrated outstanding results in controlled clinical trials.1-7 Polymer coatings used in stent applications must withstand sterilization, stent expansion, and deployment without compromising the physical integrity of the coating. In addition, the coating must exhibit vascular compatibility and biostability.8 A poly(styrene-bisobutylene-b-styrene) (SIBS) triblock polymer is employed as the drug carrier matrix for the TAXUS Express2 PaclitaxelEluting Coronary Stent system (Boston Scientific Corp.). The SIBS copolymer has demonstrated noninflammatory properties in the coronary vascular system and the chemical and physical properties required for stent coating applications. The miscibility of paclitaxel (PTx) (Chart 1) in SIBS is very low; no measurable solubility was detected using conven* Authors to whom correspondence should be addressed.
Chart 1. Paclitaxel
tional techniques, such as differential scanning calorimetry (DSC). It has been shown that the release of paclitaxel from SIBS can be modulated by changing the drug loading9 or by introduction of a second polymer or copolymer.10-12 Block copolymers such as SIBS are an important class of polymeric materials that have been proven effective in biomedical device applications.13 Suitable compositions of ABA triblock copolymers consisting of a rubbery center block and glassy outer blocks yield phase-separated morphologies with nanometer-sized hard block domains dispersed in the continuous rubbery matrix. The hard block do-
10.1021/bm050299j CCC: $30.25 © 2005 American Chemical Society Published on Web 08/23/2005
Controlled Delivery of Paclitaxel
mains act as physical cross-linkers. As a result, these thermoplastic elastomers (TPEs) exhibit properties similar to chemically cured elastomers at room temperature but can be processed as conventional plastics at elevated temperatures.14 In contrast to vulcanized rubbers, TPEs are fully soluble in a good solvent for both blocks and can be cast from solution. Living polymerization, which proceeds in the absence of chain-breaking events (e.g., chain transfer and termination), is undoubtedly the simplest and most convenient method for the synthesis of block copolymers. Compared with living anionic polymerization and the introduction of poly(styreneb-diene-b-styrene) TPEs, the development of living cationic polymerization is rather recent. It was not until the mid 1980s that living cationic polymerization was reported first with vinyl ethers15 and then with isobutylene16 (IB) and styrenic17 monomers. Since then, great progress has been made in the field of living cationic polymerization for the synthesis of well-defined homopolymers and block copolymers with precisely controlled architectures. Particularly, polyisobutylene (PIB)-based block copolymers have attracted considerable attention because of their UV and thermo-oxidative stability due to the saturated backbone structure, high mechanical damping, gas barrier property, biocompatibility, and biostability. Their general synthesis and commercial potential have been reviewed recently.18 Most often block copolymers are synthesized by sequential monomer addition using living polymerizations. Living carbocationic sequential block copolymerization has been utilized for the preparation of a wide variety of linear and star-branched block copolymers with PIB as the rubbery block segment and plastic end segments based on styrene and styrene derivatives. PTx contains several sites suitable for hydrogen bonding, including ester, amide, and hydroxyl functionalites; therefore, recent efforts in our laboratory have focused on PIB based TPEs with polar end segments.19,20 Many polar monomers (e.g., cyclic esters, acrylates, methacrylates, etc.), however, do not polymerize by cationic polymerization. Although the combination of cationic polymerization with other living polymerization techniques has been successful for the synthesis of PIB block copolymers with, for example, poly(L-lactide),21 poly(pivalolactone),22 poly(-caprolactone),23 and poly(methyl methacrylate)24 end segments, mechanistic transformation reactions are rather complicated. It is more useful to introduce (protected) polar functional groups to monomers that undergo cationic polymerization, since block copolymer synthesis may be accomplished in a relatively simple one-pot procedure using these monomers. Poly(p-hydroxystyrene) (PHOS) (Tg ∼ 149-185 °C) is an attractive candidate to obtain amphiphilic poly(PHOS-bIB-b-PHOS) TPE. Chen and co-workers attempted the synthesis of poly(PHOS-b-IB-b-PHOS) by hydrolysis of the acetoxy derivative prepared by the combination of living cationic and atom transfer radical polymerization.25 However, in the preparation of the precursor, the polymerization of p-acetoxystyrene resulted in insufficient initiation, most likely because of low miscibility of p-acetoxystyrene with the PIB macroinitiator.26 For elastomeric properties, the Mn of the
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PIB should be much higher than that used in the study (Mn ) 7800). Therefore, this technique is unlikely to yield TPEs. Though the living cationic polymerization of p-hydroxystyrene (HOS) has been reported in acetonitrile at or above ambient temperature using a BF3‚OEt2 co-initiator,27 this system is not applicable for block copolymerization with IB. Protected versions of HOS, p-tert-butoxystyrene and p-(tertbutyldimethylsiloxy)styrene (TBDMS), have been polymerized by living cationic28 and anionic29 polymerization, respectively, to yield polymers with controlled molecular weights and narrow molecular weight distributions. A thorough search of the literature revealed that the cationic polymerization of TBDMS has not been reported. Our preliminary experiments showed that TBDMS undergoes cationic polymerizations under conditions commonly employed for the living cationic polymerization of IB, that is, in methylcyclohexane/methyl chloride (MeChx/MeCl) 60/40 v/v at -80 °C. The reactivity of TBDMS, however, is much higher than that of IB; therefore, when IB is polymerized first, simple sequential monomer addition yields low crossover efficiency. Previously, we reported on a novel method for the synthesis of block copolymers by living carbocationic sequential block copolymerization when the second monomer is more reactive than the first one.30 It involves capping the living PIB end with a highly reactive but non-(homo)polymerizable monomer such as 1,1-diarylethylene followed by tuning the Lewis acidity to the reactivity of the second monomer. The Lewis acidity moderation may be accomplished by the addition of titanium alkoxides forming the weaker TiCl4-n(OR)n Lewis acids in situ. In this paper, we report on the application of this method for the synthesis of poly(TBDMS-b-IB-bTBDMS). Hydrolysis of this triblock copolymer gives rise to poly(PHOS-bIB-b-PHOS), which can be further chemically modified to modulate the polarity of styrenic portion of the block copolymer. It has been found that by using this approach, the miscibility of PTx in the polymer carrier and the subsequent release of PTx can be modulated. Experimental Section Materials. TiCl4 (Aldrich, 99.9%), titanium(IV) isopropoxide (Aldrich, 99.999%), 2,6-di-tert-butylpyridine (DTBP) (Aldrich 97%), tetrabutylammonium fluoride (Aldrich, 1.0 M solution in tetrahydrofuran), methylcyclohexane (MeChx) (Aldrich, anhydrous grade), tert-butyldimethylsilyl chloride (Sigma), and imidazole (Aldrich) were used as received. 2-Chloro-2,4,4-trimethylpentane (TMPCl) was prepared by hydrochlorination of 2,4,4-trimethyl-1-pentene (Aldrich, 99%) with hydrogen chloride gas in dry dichloromethane at 0 °C. 5-tert-Butyl-1,3-bis(1-chloro-1-methylethyl)-benzene (t-BudiCumCl) and 1,1-di-p-tolylethylene (DTE) were prepared as described earlier.31 p-(tert-Butyldimethylsilyloxy)styrene was either prepared as described below or bought from Gelest, Inc (97%) and was purified by column chromatography using a basic alumina column with hexanes as eluent followed by vacuum distillation. Methyl chloride (MeCl) and isobutylene (IB) (Matheson) were passed through
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in-line gas purifier columns packed with barium oxide/ Drierite and were condensed at -80 °C prior to polymerization. For the acetylation process, THF was refluxed for 1 day over lithium aluminum hydride and was distilled before use. Acetic anhydride was left over phosphorus pentoxide overnight, poured off, and left over potassium carbonate overnight again, and then it was distilled at atmospheric pressure. The fraction with boiling point between 137 and 138 °C was collected. Anhydrous crystalline paclitaxel was obtained from Indena, SpA. Milan, Italy, and was used as received. Synthesis of p-(tert-Butyldimethylsilyloxy)styrene (TBDMS). p-Acetoxystyrene, AcOS (52.27 g, 0.322 mol), was mixed with 10% potassium hydroxide (440 mL, 0.71 mol) solution at 0 °C under nitrogen atmosphere and was stirred for 5 h. In the last hour, the temperature was raised to room temperature. After neutralization of the solution with hydrochloric acid until pH 6-7, the mixture was filtered. The white material was dried in a vacuum overnight beside P2O5 (35.5 g, 91.8%). tert-Butyldimethylsilyl chloride (42.17 g, 0.28 mol) in 100 mL anhydrous dimethylformamide was added dropwise into a stirred solution of p-hydroxystyrene (33.57 g, 0.28 mol) and imidazole (20.9 g, 0.307 mol) in 100 mL DMF at 0 °C under nitrogen atmosphere. After complete addition, the solution was warmed to room temperature and was stirred overnight. The mixture was poured into 200 mL dichloromethane, washed with 200 mL 5% KOH solution, and extracted with a large quantity of water (∼2 L). The organic layer was dried over Na2SO4, concentrated, and distilled in a vacuum (
