Temperature- and pH-Dependent Drug Release of Block Copolymers of Methacrylic Acid and Poly(Ethylene Glycol) Methyl Ether Methacrylates

Eduardo C. Atayde Jr.1, Reynaldo Carlos K. Montalbo2, and Susan D. Arco1,2*

1Synthetic Organic Chemistry Research Laboratory, Institute of Chemistry,
University of the Philippines, Diliman, Quezon City 1101 Philippines
2Natural Sciences Research Institute, University of the Philippines Diliman,
Quezon City 1101 Philippines


*Corresponding authors: This email address is being protected from spambots. You need JavaScript enabled to view it.; This email address is being protected from spambots. You need JavaScript enabled to view it.



The block copolymers, poly(methacrylic acid)-b-poly(di(ethylene glycol) methyl ether methacrylate) (Block-D) and poly(methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (Block-P) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization towards the development of stimuli-responsive carriers of poorly water-soluble drugs. The structures of the copolymers and the confirmation of successful block copolymerization were studied using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Data from gel permeation chromatography (GPC) then showed polydispersity indices (PDI) close to 1.0, characteristic of RAFT polymerization. Stimuli-response studies revealed Block-D was responsive at pH 5.15 and 26°C while Block-P was responsive at pH 5.15 and 72°C. The corresponding micelles had particle sizes of 92.95-201.4 nm, as determined by dynamic light scattering (DLS), with critical micelle concentration (CMC) at about 10-1 mg/mL, per fluorescence studies. Using ibuprofen as the model drug, the drug loading content reached 11.76%, at 66.65% efficiency. In vitro release profiles then demonstrated 18% drug release within 5 h at stomach-like conditions, and 65% release within 5 h at small intestine-like conditions. Ultimately, cell viability assays of the blank and loaded micelles confirmed that neither is cytotoxic. These results show the immense potential and capability of the synthesized material as a drug delivery system for poorly water-insoluble drugs.



The oral administration of pharmaceuticals is considered the most preferred method of drug delivery. It is economical, convenient, and non-intrusive. However, several physiological factors such as gastrointestinal pH, digestive enzymes, mucus, transit time, and permeability of different sections of the gastrointestinal tract can affect the transport of the drug (Martinez & Amidon 2002). To this end, stimuli-responsive polymers have been an attractive material towards the development of efficient drug delivery systems (DDS). Polymers, in general, are widely regarded as ideal DDS due to their biocompatibility and bio-imitative characteristics (El-Say & El-Sawy 2017). Stimuli-responsive polymers are a class of polymers that are sensitive to stimuli such as pH, ionic strength, temperature, light intensity, and pressure and respond to these by undergoing reversible phase changes (Patel & Koyani 2014). . . . . . read more



AGUT W, BRÛLET A, SCHATZ C, TATON D, LECOMMANDOUX S. 2010. pH and Temperature responsive polymeric micelles and polymersomes by self-assembly of poly[2-(dimethylamino)ethyl methacrylate]-b-poly(glutamic acid) double hydrophilic block copolymers. Langmuir 26(13): 10546-54.
ARCO S, ATAYDE EJ, GUPIT C, TOLENTINO MN. 2016. Thermo-responsive block copolymers of ethylene glycol derivatives and methacrylic acid. Proc 4th Annu Int Conf Chem Chem Eng Chem Process 14-22.
BAZBAN-SHOTORBANI S, HASANI-SADRABADI MM, KARKHANEH A, SERPOOSHAN V, JACOB K, MOSHAVERINIA A, MAHMOUDI M. 2017. Revisiting structure-property relationship of pH-responsive polymers for drug delivery applications. J Control Release 253: 46-63.
CHUNG JE, YOKOYAMA M, YAMATO M, AOYAGI T, SAKURAI Y, OKANO T. 1999. Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). J Control Release 62(1-2): 115-127.
COOPERSTEIN MA, CANAVAN HE. 2013. Assessment of cytotoxicity of (N-isopropyl acrylamide) and poly (N-isopropyl acrylamide)-coated surfaces. Biointerphases 8(19): 1-12.
DIMITROV I, TRZEBICKA B, MÜLLER AHE, DWORAK A, TSVETANOV CB. 2007. Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Prog Polym Sci 32(11): 1275-1343.
DONG H, DU H, QIAN X. 2009. Prediction of pKa values for oligo-methacrylic acids using combined classical and quantum approaches. J Phys Chem B 113(2): 12857-59.
EL-SAY KM, EL-SAWY HS. 2017. Polymeric nanoparticles: Promising platform for drug delivery. Int J Pharm 528: 675-691.
GRABE M, OSTER G. 2001. Regulation of organelle acidity. J Gen Physiol 117(4): 329-44.
HU Y, DARCOS V, MONGE S, LI S. 2015. Thermo-responsive drug release from self-assembled micelles of brush-like PLA/PEG analogues block copolymers. Int J Pharm 491(1-2): 152-161.
KEDDIE DJ, MOAD G, RIZZARDO E, THANG SH. 2012. RAFT agent design and synthesis. Macromolecules 45(13): 5321-42.
LAGA R, JANOUŠKOVÁ O, ULBRICH K, POLA R, BLAŽKOVÁ J, FILIPPOV SK, ETRYCH T, PECHAR M. 2015. Thermoresponsive polymer micelles as potential nanosized cancerostatics. Biomacromolecules 16(8): 2493-2505.
LUTZ JF. 2008. Polymerization of oligo(ethylene glycol) (meth)acrylates: Toward new generations of smart biocompatible materials. J Polym Sci Part A Polym Chem 46(11): 3459–70.
MA X, WANG Y, ZHAO T, LI Y, SU L, WANG Z, HUANG G, SUMER BD, GAO J. 2014. Ultra-pH sensitive nanoprobe library with broad pH tunability and fluorescence emissions. J Am Chem Soc 136(31): 11085-92.
MAO J, BO S, JI X. 2011. pH/Temperature-responsive behavior of amphiphilic block copolymer micelles prepared using two different methods. Langmuir 27(12): 7385-91.
MAO J, LI Y, WU T, YUAN C, ZENG B, XU Y, DAI L. 2016. A simple dual-pH responsive prodrug-based polymeric micelles for drug delivery. ACS Appl Mater Interfaces 8(27): 17109-17.
MARTINEZ MN, AMIDON GL. 2002. A mechanistic approach to understanding the factors affecting drug absorption: A review of fundamentals. J Clin Pharmacol 42: 620-643.
MONDEK J, PEKAŘ M. 2015. The change in excited-state proton transfer kinetics of 1-naphthol in micelles upon the binding of polymers: The influence of hyaluronan hydration. Carbohydr Polym 129: 168-174.
PATEL P, KOYANI V. 2014. Smart polymers: Innovative drug delivery system. World J Pharm Pharm Sci 3(3): 508-527.
PELET JM, PUTNAM D. 2009. High molecular weight poly(methacrylic acid) with narrow polydispersity by RAFT polymerization. Macromolecules 42(5): 1494-99.
RITGER PL, PEPPAS NA. 1987. A simple equation for description of solute release I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, sphere, cylinders or discs. J Control Release 5: 23-36.
SANT VP, SMITH D, LEROUX J-C. 2004. Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization. J Control Release 97(2): 301-312.
SONG C, YU S, LIU C, DENG Y, XU Y, CHEN X, DAI L. 2016. Preparation of thermo-responsive graft copolymer by using a novel macro-RAFT agent and its application for drug delivery. Mater Sci Eng C 62: 45-52.
STROBER W. 2015. Trypan blue exclusion test of cell viability. Curr Protoc Immunol 111: 1-3.
SUN X-L, TSAI P-C, BHAT R, BONDER EM, MICHNIAK-KOHN B, PIETRANGELO A. 2015. Thermoresponsive block copolymer micelles with tunable pyrrolidone-based polymer cores: Structure/property correlations and application as drug carriers. J Mater Chem B 3(5): 814-823.
SWAIN J, MISHRA AK. 2015. 1-Naphthol as an ESPT fluorescent molecular probe for sensing thermotropic microenvironmental changes of pluronic F127 in aqueous media. Phys Chem Chem Phys 17: 16752-59.
WATSON P, JONES AT, STEPHENS DJ. 2005. Intracellular trafficking pathways and drug delivery: Fluorescence imaging of living and fixed cells. Adv Drug Deliv Rev 57(1): 43-61.
XIA Y, BURKE NAD, STÖVER HDH. 2006. End group effect on the thermal response of narrow-disperse poly(N-isopropylacrylamide) prepared by atom transfer radical polymerization. Macromolecules 39(6): 2275-83.
YANG YQ, ZHENG LS, GUO XD, QIAN Y, ZHANG LJ. 2011. pH-sensitive micelles self-assembled from amphiphilic copolymer brush for delivery of poorly water-soluble drugs. Biomacromolecules 12(1): 116-122.
YEH JC, HSU YT, SU CM, WANG MC, LEE TH, LOU SL. 2014. Preparation and characterization of biocompatible and thermoresponsive micelles based on poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) grafted on polysuccinimide for drug delivery. J Biomater Appl 29(3): 442–453.
YIN X, HOFFMAN AS, STAYTON PS. 2006. Poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers that respond sharply to temperature and pH. Biomacromolecules 7(5): 1381-85.