Conventional self-assembled polymeric micelles typically lose their loaded drugs after systemic administration. To resolve this issue, the aim of the present study was to develop a novel polymer, methoxy-poly (ethylene glycol)-block-poly (d, l-lactic acid) grafted with four lipoic acids (mPEG-PLA-(LA)4), to prepare curcumin-loaded core cross-linked polymeric micelles (CCM). Nitrogen and alkalescent buffer (pH 8.5) were beneficial for cross-linking, and the cross-linking was nearly complete within 30 min. The micelle preparation parameters were optimized through both a single-factor experiment and orthogonality test. The choice of cryoprotector had the most important effect on micelle solution reconstruction and almost challenged our perceptions about cryoprotector. In addition the drug loading capacity greatly affected the stability of micelles. Moreover, a method for determining the cross-linking density was established, and the result of gel permeation chromatography indirectly demonstrated that dozens of polymers had successfully formed CCM. The CCM significantly enhanced stability under non-reductive conditions and could be reversibly broken in a reductive environment. Curcumin-loaded CCM also showed glutathione-response cytotoxicity to cancer cells. Overall, this fundamental study suggests CCM as a potential carrier for achieving improved controlled drug delivery.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Liu J, Chen S, Lv L, Song L, Guo S, Huang S (2013) Recent Progress in studying curcumin and its Nano preparations for Cancer therapy. Curr Pharm Des 19:1974–1993
Choudhary N, Sekhon BS (2012) Potential therapeutic effect of curcumin - an update. J Pharm Educ Res:3
Beevers HS (2011) Pharmacological and clinical properties of curcumin. Botanics: Targets and Therapy:5
Zhang DW, Fu M, Gao SH, Liu JL (2013) Curcumin and diabetes: a systematic review. Evid Based Complement Alternat Med : eCAM 2013:636053
Song Z, Zhu W, Liu N, Yang F, Feng R (2014) Linolenic acid-modified PEG-PCL micelles for curcumin delivery. Int J Pharm 471:312–321
Fan X, Zhang C, Db L, Yan J, Hp L (2013) The clinical applications of curcumin: current state and the future. Curr Pharm Des 19:2011–2031
Yallapu MM, Nagesh PK, Jaggi M, Chauhan SC (2015) Therapeutic applications of curcumin Nanoformulations. AAPS J 17:1341–1356
Ghalandarlaki N, Alizadeh AM, Ashkani-Esfahani S (2014) Nanotechnology-applied curcumin for different diseases therapy. Biomed Res Int 2014:394264
Mahmood K, Zia KM, Zuber M, Salman M, Anjum MN (2015) Recent developments in curcumin and curcumin based polymeric materials for biomedical applications: a review. Int J Biol Macromol 81:877–890
Murakami M, Cabral H, Matsumoto Y, Wu S, Kano MR, Yamori T, Nishiyama N, Kataoka K (2011) Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting. Sci Transl Med 3:64ra2
Zhang X, Liu K, Huang Y, Xu J, Li J, Ma X, Li S (2014) Reduction-sensitive dual functional nanomicelles for improved delivery of paclitaxel. Bioconjug Chem 25:1689–1696
Li Y, Xiao K, Luo J, Xiao W, Lee JS, Gonik AM, Kato J, Dong TA, Lam KS (2011) Well-defined, reversible disulfide cross-linked micelles for on-demand paclitaxel delivery. Biomaterials 32:6633–6645
Maheshwari RK, Singh AK, Gaddipati J, Srimal RC (2006) Multiple biological activities of curcumin: a short review. Life Sci 78:2081–2087
Lee SY, Kim S, Tyler JY, Park K, Cheng JX (2013) Blood-stable, tumor-adaptable disulfide bonded mPEG-(Cys)4-PDLLA micelles for chemotherapy. Biomaterials 34:552–561
Wu W-C, Kuo Y-S, Cheng C-H (2015) Dual-stimuli responsive polymeric micelles: preparation, characterization, and controlled drug release. J Polym Res 22
Chen H, Kim S, He W, Wang H, Low PS, Park K, Cheng JX (2008) Fast release of lipophilic agents from circulating PEG-PDLLA micelles revealed by in vivo Förster Resonance Energy Transfer Imaging. Langmuir 24:5213–5217
Danhier F, Feron O, Preat V (2010) To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 148:135–146
Chan Y, Wong T, Byrne F, Kavallaris M, Bulmus V (2008) Acid-labile Core cross-linked micelles for pH-triggered release of antitumor drugs. Biomacromolecules 9:1826–1836
Zhang L, Liu W, Lin L, Chen D, Stenzel MH (2008) Degradable disulfide Core-cross-linked micelles as a drug delivery system prepared from vinyl functionalized nucleosides via the RAFT process. Biomacromolecules 9:3321–3331
Jiang X, Liu S, Narain R (2009) Degradable thermoresponsive core cross-linked micelles: fabrication, surface functionalization, and biorecognition. Langmuir 25:13344–13350
Rijcken CJ, Snel CJ, Schiffelers RM, van Nostrum CF, Hennink WE (2007) Hydrolysable core-crosslinked thermosensitive polymeric micelles: synthesis, characterisation and in vivo studies. Biomaterials 28:5581–5593
Talelli M, Barz M, Rijcken CJ, Kiessling F, Hennink WE, Lammers T (2015) Core-crosslinked polymeric micelles: principles, preparation, biomedical applications and clinical translation. Nano Today 10:93–117
Thurmond kB, Kowalewski T, Wooley KL (1996) Water-soluble Knedel-like structures: the preparation of Shell-cross-linked small particles. J Am Chem Soc 118:7239–7240
Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glockner-Pagel J, Canny S, Du K, Lukacs GL, Caplan MJ (2004) Curcumin, a major constituent of turmeric, Corrects Cystic Fibrosis Defects. Science 304
Shi Y, van Nostrum CF, Hennink WE (2015) Interfacially Hydrazone cross-linked thermosensitive polymeric micelles for acid-triggered release of paclitaxel. ACS Biomater Sci Eng 1:393–404
Sun J, Chen X, Lu T, Liu S, Tian H, Guo Z, Jing X (2008) Formation of reversible Shell cross-linked micelles from the biodegradable amphiphilic Diblock copolymer poly(L-cysteine)-block-poly(L-lactide). Langmuir 24:10099–10106
Wicki A, Witzigmann D, Balasubramanian V, Huwyler J (2015) Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J Control Release 200:138–157
Lee P-Y, Tuan-Mu H-Y, Hsiao L-W, Hu J-J, Jan J-S (2017) Nanogels comprising reduction-cleavable polymers for glutathione-induced intracellular curcumin delivery. J Polym Res 24
Han X, Gong F, Sun J, Li Y, Liu X, Chen D, Liu J, Shen Y (2018) Glutathione-responsive core cross-linked micelles for controlled cabazitaxel delivery. J Nanopart Res 20
Stefely J, Markowitz MA, Regen SL (1988) Permeability characteristics of lipid bilayers from lipoic acid derived phosphatidylcholines: comparison of monomeric, cross-linked and non-cross-linked polymerized membranes. J Am Chem Soc 110:1463–7469
Hansen RE, Ostergaard H, Norgaard P, Winther JR (2007) Quantification of protein thiols and dithiols in the picomolar range using sodium borohydride and 4,4′-dithiodipyridine. Anal Biochem 363:77–82
Kumari P, Muddineti OS, Rompicharla SVK, Ghanta P, B B N AK, Ghosh B, Biswas S (2017) Cholesterol-conjugated poly(D, L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy. Drug Deliv 24:209–223
Syed HK, Liew KB, Loh GO, Peh KK (2015) Stability indicating HPLC-UV method for detection of curcumin in Curcuma longa extract and emulsion formulation. Food Chem 170:321–326
Han X, Chen D, Sun J, Zhou J, Li D, Gong F, Shen Y (2016) A novel cabazitaxel-loaded polymeric micelle system with superior in vitro stability and long blood circulation time. J Biomater Sci Polym Ed 27:626–642
Koo AN, Min KH, Lee HJ, Lee SU, Kim K, Kwon IC, Cho SH, Jeong SY, Lee SC (2012) Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links. Biomaterials 33:1489–1499
This work was supported by the Shanghai Leading Academic Discipline Project [project number B505]; the National Special Fund for the State Key Laboratory of Bioreactor Engineering [grant number 2060204], and the National Natural Science Foundation of China [grant number 81673969].
Conflict of interest
The authors declare no completing financial interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Chen, D., Gong, F., Han, X. et al. Preparation and characterization of glutathione-responsive polymeric micelles functionalized with core cross-linked disulfide linkage for curcumin delivery. J Polym Res 26, 103 (2019). https://doi.org/10.1007/s10965-019-1768-7
- Glutathione-responsive polymeric micelles
- Preparation parameters optimization