فایل ورد کامل سنتز آسان دندریمر های پلی استر به عنوان حامل های دارو رسانی

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تعداد صفحات این فایل: ۲۱ صفحه

به طور خلاصه، ما یک سنتز کارامد از دندریمر پلی استر  bis-MPA با انتشار یکنواخت  را با استفاده از واکنش تیول  اکریلات و واکنش استریفیکاسیون  تحت شرایط متعادل ایجاد کردیم. دندریمر ۶۴ اکریلات در چهارگام حاصل شد. و  دندریمر ۱۲۸ هیدرکسیل در ۵ گام تولید شد.  سنتز ساده و تخلیص موجب ساده تر شدن سنتز دندریمر برای تولید بزرک مقیاس شد. دندریمر های هیدروکسیل حساس به دما بودند و LCST  برابر با ۴۱ درجه بود که نزدیک به دمای فیزیولوژیکی است.   دندریمر سازگار G5-PEG  قابلیت عالی برای کپسوله سازی و ازاد سازی  کنترل شده داروی ضد سرطان نظیر DOX نشان داد.  کاربرد دندریمر ها به عنوان حامل های دور اکنون تحت مطالعه است.

عنوان انگلیسی:Facile Synthesis of Polyester Dendrimers as Drug Delivery Carriers~~en~~

INTRODUCTION Dendrimers are highly branched macromolecules characterized by monodispersity, uniform and controlled sizes, copious surface functionalities,1 and low intrinsic viscosity in solution.2 These characteristics make them ideal nanocarriers for biomedical applications,1a,3 of which polyamidoamine (PAMAM) dendrimers are the most studied.4 However, PAMAM dendrimers are not biodegradable in vivo and carry positive charges on their surface, thus inducing cytotoxicity,4a,5 hemolytic toxicity,6 rapid blood clearance,6 and quick opsonization (RES).7 These drawbacks hinder their translation to clinical applications. Aliphatic polyester dendrimers, for example the dendrimers from an AB2-type monomer 2,2- bis(hydroxymethyl)propionic acid (bis-MPA), are biodegradable and biocompatible with very low toxicity and low immunogenicity8 and thus have been proposed as carriers for in vivo biodelivery or imaging.9 The traditional polyester dendrimers were synthesized by repeated esterification of bis-MPA with protected either carboxylic acid group10 or hydroxyl groups11 followed by deprotection. These synthesis techniques are straightforward, but the protection/deprotection reactions may be incomplete and thus introduce defects amplified in the subsequent generations and also make the synthesis tedious. The azide/acetylene-based click reaction characteristic of specificity, quantitative yields, and almost perfect fidelity12 has been used extensively in synthesis of dendrimers with fewer steps, less purification procedures, and higher overall yields.13 For instance, acetylene or azide groups were separately introduced to bis-MPA to produce asymmetric clickable monomers used for speed synthesis of dendrimers.14 The thiol/allyl- or thiol/acetylene-based thiolene reactions have some characteristics of click reaction and have also been used to synthesize dendrimers.14,15 For instance, bis-MPA was functionalized with allyl or acetylene groups and was used for dendrimer synthesis via thiolene reaction.16 Very recently, Hawker and Malkoch introduced thiol and azides or acetylene and allyl groups to bis-MPA separately and obtained AB2 and CD2 monomers. Alternative azideacetylene and thiolene click reactions produced dendrimers quickly and efficiently.17 However, the radical nature of thiolene reactions caused cross-linking due to radical coupling, particularly in the synthesis of dendrimers higher than fifth generations, causing broader polydispersity (PDI > 1.2). Aliphatic polyester dendrimers without heterocyclics have better biocompatibility and biodegradability for translational nanocarriers. Taking advantage of highly efficient thiol/acrylate Michael addition reactions, we developed a simple but efficient strategy to synthesize bis-MPA-based dendrimers without any protection/deprotection steps. The monomers were easily obtained and the reactions were fast under mild conditions. A dendrimer with 128 terminal hydroxyl groups was constructed in five steps (Scheme 1) with a high overall yield. We also demonstrated an application of the dendrimer as a drug carrier. EXPERIMENTAL SECTION Materials. 2,2-Bis(hydroxymethyl)propionic acid (bis-MPA, 98%), pentaerythritol (99%), N,N-diisopropylcarbodiimide (DIC, 99%), acryloyl chloride (98%), triethylamine (Et3N, 99.5%), sodium carbonate (99%), 1-thioglycerol (99%), succinic anhydride Scheme 1. Dendrimer Synthesis from a AB2 Monomer Pair 2,2-Bis(acryloyloxymethyl)propionic Acid (ACPA) and 1- Thioglycerol (۹۹%), ۴-(N,N-dimethylamino)pyridine (DMAP, 99%), poly- (ethylene glycol) monomethyl ether (PEG2k, MW 2000 Da), and doxorubicin hydrochloride (DOX·HCl, 98%) were purchased from Sigma-Aldrich (Milwaukee, WI). Hydrochloric acid (37%), anhydrous dichloromethane (99.96%), ethyl ether (99.0%), methanol (99.0%), tetrahydrofuran (THF, 990%), and hexane (98.5%) were from Fisher Scientific (Pittsburgh, PA). Anhydrous dimethyl sulfoxide (DMSO, 99.9%) was from EMD Chemicals (Gibbstown, NJ). All chemicals were used as received. Instrumentation. Gel permeation chromatography (GPC) was performed on a Waters SEC equipped with a Waters 2414 refractive index detector, a PD2000 dynamic laser light scattering detector with 15° and 90° scattered light collecting angles, and two 300 mm SolventSaving GPC Columns (molecular weight ranges: 5 × ۱۰۲ ۳ × ۱۰۴ , ۵ × ۱۰۳ ۶ × ۱۰۵ ) set at 30 °C. THF with 3% v/v Et3N was used as eluent at a flow rate of 0.30 mL/min. Data were recorded and processed using the Waters software package. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance DRX-400 spectrometer using CDCl3 or DMSO-d6 as solvent. Chemical shifts were reported downfield from 0.00 ppm using TMS as an internal reference. Matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS; Applied Biosystems, Voyager DE Pro) was performed in a positive-ion mode with a source temperature of 200 °C at a sample concentration of about 100 M using 2,5-dihydroxybenzoic acid as the matrix. The size of the G5-PEG/ DOX was determined using a Nano-ZS Nanosizer (Malvern Instruments, Worcestershire, UK) with a laser wavelength of 632.8 nm and a scattering angle of 173°.

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