Abstract
Flavonoids such as quercetin (QCT) represent a diverse class of natural compounds with unique therapeutic potential in cancer and inflammatory diseases. However, their clinical efficacy is hindered by poor aqueous solubility and stability. This study describes the in vitro evaluation of QCT-encapsulated polymeric micelles based on methoxy polyethylene glycol-b-poly(D,L-lactide) (mPEG-PLA) and methoxy polyethylene glycol-b-poly(ε-caprolactone) (mPEG-PCL) copolymers as a drug delivery platform for QCT. The copolymers were synthesized in different molecular weights (MWs) of the hydrophobic blocks to investigate the effect of polymer type and MW on the micelle properties. All copolymers exhibited critical micelle concentrations (CMCs) in the micromolar range or lower and produced QCT-loaded micelles with particles sizes < 100 nm. mPEG5K-PLA3K, with the highest predicted compatibility with QCT as indicated by the Flory-Huggins interaction parameter, was able to achieve the highest loading capacity and encapsulation efficiency. Drug loading also exhibited a strong correlation with the hydrophilic-lipophilic balance (HLB) of the copolymers. In vitro release of the micelles followed a biphasic profile, with an initial burst phase followed by a controlled release phase, and showed a clear dependence on drug-copolymer compatibility and copolymer MW. This work represents the first report on the use of mPEG-PLA micelles to encapsulate QCT. It also emphasizes the importance of tuning formulation variables as they influence the properties of polymeric micelles for the design of a successful nanomedicine for QCT and similar drugs.
Similar content being viewed by others
References
Shi J, Votruba AR, Farokhzad OC, Langer R (2010) Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett 10(9):3223–3230
Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2(12):751–760
Petros RA, DeSimone JM (2010) Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov 9(8):615–627
Ikoba U, Peng H, Li H, Miller C, Yu C, Wang Q (2015) Nanocarriers in therapy of infectious and inflammatory diseases. Nano 7(10):4291–4305
Davis ME, Chen ZG, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 7(9):771–782
Sunoqrot S, Hamed R, Abdel-Halim H, Tarawneh O (2017) Synergistic interplay of medicinal chemistry and formulation strategies in nanotechnology – from drug discovery to nanocarrier design and development. Curr Top Med Chem 17(13):1451–1468
Kataoka K, Harada A, Nagasaki Y (2001) Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev 47(1):113–131
Huynh L, Neale C, Pomes R, Allen C (2012) Computational approaches to the rational design of nanoemulsions, polymeric micelles, and dendrimers for drug delivery. Nanomedicine 8(1):20–36
Yan J, Ye Z, Chen M, Liu Z, Xiao Y, Zhang Y, Zhou Y, Tan W, Lang M (2011) Fine tuning micellar core-forming block of poly(ethylene glycol)-block-poly(epsilon-caprolactone) amphiphilic copolymers based on chemical modification for the solubilization and delivery of doxorubicin. Biomacromolecules 12(7):2562–2572
Letchford K, Liggins R, Burt H (2008) Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymer micelles: theoretical and experimental data and correlations. J Pharm Sci 97(3):1179–1190
Latere Dwan'Isa JP, Rouxhet L, Preat V, Brewster ME, Arien A (2007) Prediction of drug solubility in amphiphilic di-block copolymer micelles: the role of polymer-drug compatibility. Pharmazie 62(7):499–504
Formica JV, Regelson W (1995) Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol 33(12):1061–1080
Park CH, Chang JY, Hahm ER, Park S, Kim HK, Yang CH (2005) Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun 328(1):227–234
Murakami A, Ashida H, Terao J (2008) Multitargeted cancer prevention by quercetin. Cancer Lett 269(2):315–325
Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton Jr E, Lee MT (1999) Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol 128(5):999–1010
Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FB, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87(4):595–600
Xu G, Shi H, Ren L, Gou H, Gong D, Gao X, Huang N (2015) Enhancing the anti-colon cancer activity of quercetin by self-assembled micelles. Int J Nanomedicine 10:2051–2063
Khonkarn R, Mankhetkorn S, Hennink WE, Okonogi S (2011) PEG-OCL micelles for quercetin solubilization and inhibition of cancer cell growth. Eur J Pharm Biopharm 79(2):268–275
Yang X, Zhu B, Dong T, Pan P, Shuai X, Inoue Y (2008) Interactions between an anticancer drug and polymeric micelles based on biodegradable polyesters. Macromol Biosci 8(12):1116–1125
Sunoqrot S, Bae JW, Pearson RM, Shyu K, Liu Y, Kim DH, Hong S (2012) Temporal control over cellular targeting through hybridization of folate-targeted dendrimers and PEG-PLA nanoparticles. Biomacromolecules 13(4):1223–1230
Sunoqrot S, Hasan L, Alsadi A, Hamed R, Tarawneh O (2017) Interactions of mussel-inspired polymeric nanoparticles with gastric mucin: implications for gastro-retentive drug delivery. Colloid Surface B 156:1–8
Basu Ray G, Chakraborty I, Moulik SP (2006) Pyrene absorption can be a convenient method for probing critical micellar concentration (CMC) and indexing micellar polarity. J Colloid Interface Sci 294(1):248–254
Gao W, Kim JY, Anderson JR, Akopian T, Hong S, Jin YY, Kandror O, Kim JW, Lee IA, Lee SY, McAlpine JB, Mulugeta S, Sunoqrot S, Wang Y, Yang SH, Yoon TM, Goldberg AL, Pauli GF, Suh JW, Franzblau SG, Cho S (2015) The cyclic peptide ecumicin targeting ClpC1 is active against mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother 59(2):880–889
Bae JW, Pearson RM, Patra N, Sunoqrot S, Vukovic L, Kral P, Hong S (2011) Dendron-mediated self-assembly of highly PEGylated block copolymers: a modular nanocarrier platform. Chem Commun 47(37):10302–10304
Owen SC, Chan DPY, Shoichet MS (2012) Polymeric micelle stability. Nano Today 7(1):53–65
Maysinger D, Lovrić J, Eisenberg A, Savić R (2007) Fate of micelles and quantum dots in cells. Eur J Pharm Biopharm 65(3):270–281
Diezi TA, Bae Y, Kwon GS (2010) Enhanced stability of PEG-block-poly(N-hexyl stearate L-aspartamide) micelles in the presence of serum proteins. Mol Pharm 7(4):1355–1360
Lu Y, Park K (2013) Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs. Int J Pharm 453(1):198–214
Adams ML, Kwon GS (2002) The effects of acyl chain length on the micelle properties of poly(ethylene oxide)-block-poly(N-hexyl-L-aspartamide)-acyl conjugates. J Biomater Sci Polym Ed 13(9):991–1006
Gaucher G, Dufresne M-H, Sant VP, Kang N, Maysinger D, Leroux J-C (2005) Block copolymer micelles: preparation, characterization and application in drug delivery. J Control Release 109(1–3):169–188
Cho H, Lai TC, Tomoda K, Kwon GS (2015) Polymeric micelles for multi-drug delivery in cancer. AAPS PharmSciTech 16(1):10–20
Wang BL, Gao X, Men K, Qiu J, Yang B, Gou ML, Huang MJ, Huang N, Qian ZY, Zhao X, Wei YQ (2012) Treating acute cystitis with biodegradable micelle-encapsulated quercetin. Int J Nanomedicine 7:2239–2247
Dian L, Yu E, Chen X, Wen X, Zhang Z, Qin L, Wang Q, Li G, Wu C (2014) Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles. Nanoscale Res Lett 9:684
Peng W, X-y J, Zhu Y, Omari-Siaw E, Deng W-w, Yu J-n, Xu X-m, W-m Z (2015) Oral delivery of capsaicin using MPEG-PCL nanoparticles. Acta Pharm Sin 36(1):139–148
Mahmud A, Patel S, Molavi O, Choi P, Samuel J, Lavasanifar A (2009) Self-associating poly (ethylene oxide)-b-poly (α-cholesteryl carboxylate-ε-caprolactone) block copolymer for the solubilization of STAT-3 inhibitor cucurbitacin I. Biomacromolecules 10(3):471–478
Patel SK, Lavasanifar A, Choi P (2010) Prediction of the solubility of cucurbitacin drugs in self-associating poly (ethylene oxide)-b-poly (α-benzyl carboxylate ɛ-caprolactone) block copolymer with different tacticities using molecular dynamics simulation. Biomaterials 31(2):345–357
Li Y, Yang L (2015) Driving forces for drug loading in drug carriers. J Microencapsul 32(3):255–272
Shuai X, Ai H, Nasongkla N, Kim S, Gao J (2004) Micellar carriers based on block copolymers of poly (ε-caprolactone) and poly (ethylene glycol) for doxorubicin delivery. J Control Release 98(3):415–426
Carstens MG, de Jong PH, van Nostrum CF, Kemmink J, Verrijk R, De Leede LG, Crommelin DJ, Hennink WE (2008) The effect of core composition in biodegradable oligomeric micelles as taxane formulations. Eur J Pharm Biopharm 68:596–606
Glavas L, Odelius K, Albertsson AC (2015) Tuning loading and release by modification of micelle core crystallinity and preparation. Polym Advan Technol 26(7):880–888
Xiao RZ, Zeng ZW, Zhou GL, Wang JJ, Li FZ, Wang AM (2010) Recent advances in PEG-PLA block copolymer nanoparticles. Int J Nanomedicine 5:1057–1065
Kwon GS, Kataoka K (2012) Block copolymer micelles as long-circulating drug vehicles. Adv Drug Deliv Rev 64:237–245
Kamaly N, Yameen B, Wu J, Farokhzad OC (2016) Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev 116(4):2602–2663
Kim SH, Tan JPK, Nederberg F, Fukushima K, Colson J, Yang C, Nelson A, Yang Y-Y, Hedrick JL (2010) Hydrogen bonding-enhanced micelle assemblies for drug delivery. Biomaterials 31(31):8063–8071
Mikhail AS, Allen C (2010) Poly(ethylene glycol)-b-poly (ε-caprolactone) micelles containing chemically conjugated and physically entrapped docetaxel: synthesis, characterization, and the influence of the drug on micelle morphology. Biomacromolecules 11(5):1273–1280
Falamarzian A, Lavasanifar A (2010) Optimization of the hydrophobic domain in poly (ethylene oxide)-poly (ɛ-caprolactone) based nano-carriers for the solubilization and delivery of amphotericin B. Colloid Surface B 81(1):313–320
Falamarzian A, Lavasanifar A (2010) Chemical modification of hydrophobic block in poly (ethylene oxide) poly (caprolactone) based nanocarriers: effect on the solubilization and hemolytic activity of amphotericin B. Macromol Biosci 10(6):648–656
Acknowledgements
This project was financially supported by the Deanship of Academic Research and Graduate Studies at Al-Zaytoonah University of Jordan. The authors would like to thank Dr. Dima Sabbah from Al-Zaytoonah University of Jordan for assistance with MOE software, and Dr. Imad Hamadneh from the University of Jordan for assistance with NMR spectroscopy.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
ESM 1
(PDF 3.02 MB)
Rights and permissions
About this article
Cite this article
Sunoqrot, S., Alsadi, A., Tarawneh, O. et al. Polymer type and molecular weight dictate the encapsulation efficiency and release of Quercetin from polymeric micelles. Colloid Polym Sci 295, 2051–2059 (2017). https://doi.org/10.1007/s00396-017-4183-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00396-017-4183-9