Thermo-triggered drug delivery from polymeric micelles of poly( N -isopropylacrylamide- co -acrylamide)-b-poly( n -butyl methacrylate) for tumor targeting

Abstract

Novel temperature-sensitive micelles, possessing a core-shell structure, were successfully fabricated and evaluated as possible systems for targeting anticancer drugs to solid tumors. The amphiphilic block copolymer poly(N-isopropylacrylamide-co-acrylamide)-b-poly(n-butyl methacrylate) was used to achieve a stimuli-responsive on/off release and spatial specificity. The anticancer drug methotrexate, which is poorly water soluble, was used as the model. Fourier transform–infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, gel-permeation chromatography, and critical micelle concentration were used to evaluate the successful synthesis of block copolymers with a lower critical solution temperature ~40°C. Based on transmission electron microscope images, the micelles are spherical particles with narrow size distribution. The thermally triggered release of methotrexate was observed in vitro. Quartz crystal microbalance with dissipation was used to investigate the interactions of the polymeric micelles with bovine serum albumin, to illustrate protein adsorption and cell attachment. Cytotoxicity studies were conducted on Lewis lung carcinoma cells, and the anticancer activity of methotrexate-loaded micelles was significantly enhanced in combination with hyperthermia. The thermo-sensitive characteristics of the micelles make them applicable as smart drug delivery systems, when combined with localized hyperthermia.

Keywords

Block copolymer micelle thermo-sensitive controlled drug release tumor targeting hyperthermia thermo-triggered drug delivery

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References

Wei

Yue

. Porous quaternized chitosan nanoparticles containing paclitaxel nanocrystals improved therapeutic efficacy in non-small-cell lung cancer after oral administration. Biomacromolecules 2011; 12: 4230–4239.

Lukyanov

Torchilin

. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Adv Drug Deliver Rev 2004; 56: 1273–1289.

Y-J

Wei

K-C

C-CM

. Dual targeted delivery of doxorubicin to cancer cells using folate-conjugated magnetic multi-walled carbon nanotubes. Colloid Surface B 2012; 89: 1–9.

Nguyen

Bae

Choi

. Bioreducible cross-linked Pluronic micelles: pH-triggered release of doxorubicin and folate-mediated cellular uptake. J Bioact Compat Pol 2013; 28: 341–354.

Luo

Y-L

Yuan

J-F

Liu

X-J

. Self-assembled polyion complex micelles based on PVP-b-PAMPS and PVP-b-PDMAEMA for drug delivery. J Bioact Compat Pol 2010; 25: 292–304.

Garripelli

. Nanocomposite thermogel for controlled release of small proteins. J Bioact Compat Pol 2012; 27: 198–209.

H-W

Zhang

L-M

Liu

J-Y

. Synthesis of an amphiphilic polysaccharide derivative and its micellization for drug release. J Bioact Compat Pol 2008; 23: 154–170.

Chen

Ding

. Synthesis of novel chitosan derivatives for micellar solubilization of cyclosporine A. J Bioact Compat Pol 2008; 23: 563–578.

Singla

Garg

Aggarwal

. Paclitaxel and its formulations. Int J Pharm 2002; 235: 179–192.

10.

Meyer

Shin

Kong

. Drug targeting using thermally responsive polymers and local hyperthermia. J Control Release 2001; 74: 213–224.

11.

Wang

Qin

Wei

. Preparation strategies of thermo-sensitive P(NIPAM-co-AA) microspheres with narrow size distribution. Powder Technol 2012; 236: 107–113.

12.

Cammas

Suzuki

Sone

. Thermo-responsive polymer nanoparticles with a core-shell micelle structure as site-specific drug carriers. J Control Release 1997; 48: 157–164.

13.

Kessel

Truong

Jia

. Aqueous reversible addition-fragmentation chain transfer dispersion polymerization of thermoresponsive diblock copolymer assemblies: temperature directed morphology transformations. J Polym Sci Pol Chem 2012; 50: 4879–4887.

14.

Wei

Cheng

S-X

Zhang

X-Z

. Thermo-sensitive polymeric micelles based on poly(N-isopropylacrylamide) as drug carriers. Prog Polym Sci 2009; 34: 893–910.

15.

Santos

Alves

Mano

. New thermo-responsive hydrogels based on poly(N-isopropylacrylamide)/hyaluronic acid semi-interpenetrated polymer networks: swelling properties and drug release studies. J Bioact Compat Pol 2010; 25: 169–184.

16.

hydrophilic block copolymer for drug delivery and tumor target. Biomaterials 2008; 29: 497–505.

17.

Yan

Luo

. Thermosensitive poly(N-isopropyl acrylamide-co-N,N-dimethyl acrylamide)-block-poly(d,l-lactide) amphiphilic block copolymer micelles for prednisone drug release. J Bioact Compat Pol 2013; 28: 66–85.

18.

Wei

Chen

W-Q

Chang

. Synthesis of star block, thermo sensitive poly(l-lactide)-star block-poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide) copolymers and their self-assembled micelles for controlled release. J Phys Chem C 2008; 112: 2888–2894.

19.

Cheng

Wei

Zhang

. Thermo-triggered and biotinylated biotin-P(NIPAAm-co-HMAAm)-b-PMMA micelles for controlled drug release. J Biomed Mater Res A 2009; 88: 814–822.

20.

Chaw

Chooi

Liu

. Thermally responsive core-shell nanoparticles self-assembled from cholesteryl end-capped and grafted polyacrylamides: drug incorporation and in vitro release. Biomaterials 2004; 25: 4297–4308.

21.

Yang

Ding

Zhang

. Novel thermosensitive polymeric micelles for docetaxel delivery. J Biomed Mater Res A 2007; 81: 847–857.

22.

Shen

Terao

Maki

. Synthesis and phase behavior of aqueous poly(N-isopropylacrylamide-co-acrylamide), poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) and poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate). Colloid Polym Sci 2006; 284: 1001–1007.

23.

Chung

Yokoyama

Okano

. Inner core segment design for drug delivery control of thermo-responsive polymeric micelles. J Control Release 2000; 65: 93–103.

24.

Chung

Yokoyama

Yamato

. Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). J Control Release 1999; 62: 115–127.

25.

Torchilin

. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release 2001; 73: 137–172.

26.

Denkova

Mendes

Coppens

M-O

. Non-equilibrium dynamics of block copolymer micelles in solution: recent insights and open questions. Soft Matter 2010; 6: 2351–2357.

27.

Haliloglu

Bahar

Erman

. Relative contributions of coupled rotations and small-amplitude torsions to conformational relaxation in polymers. Macromolecules 1996; 29: 8942–8947.

28.

Dormidontova

. Micellization kinetics in block copolymer solutions: scaling model. Macromolecules 1999; 32: 7630–7644.

29.

Soppimath

Tan

DCW

Yang

. pH-triggered thermally responsive polymer core–shell nanoparticles for drug delivery. Adv Mater 2005;17: 318–320.

30.

Cheng

Wei

Zhu

J-L

. Functionalized thermoresponsive micelles self-assembled from biotin-PEG-b-P(NIPAAm-co-HMAAm)-b-PMMA for tumor cell target. Bioconjugate Chem 2008; 19: 1194–1201.

31.

Wei

Zhang

X-Z

Zhou

. Self-assembled thermoresponsive micelles of poly(N-isopropylacrylamide-b-methyl methacrylate). Biomaterials 2006; 27: 2028–2034.

32.

Liu

Tong

Yang

Y-Y

. Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(d,l-lactide-co-glycolide) with varying compositions. Biomaterials 2005; 26: 5064–5074.

33.

Liu

S-Q

Wiradharma

Gao

S-J

. Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs. Biomaterials 2007; 28: 1423–1433.

34.

Wei

Zhang

Cheng

. Self-assembled, thermosensitive micelles of a star block copolymer based on PMMA and PNIPAAm for controlled drug delivery. Biomaterials 2007; 28: 99–107.

35.

Wei

Zhang

Zhou

. Self-assembled thermoresponsive micelles of poly(N-isopropylacrylamide-b-methyl methacrylate). Biomaterials 2006; 27: 2028–2034.

36.

Yang

Ding

Zhang

. Novel thermosensitive polymeric micelles for docetaxel delivery. J Biomed Mater Res A 2007; 81: 847–857.

37.

Chan

Orme

Fricker

. Remote and local control of stimuli responsive materials for therapeutic applications. Adv Drug Deliver Rev 2012; 65: 497–514.

38.

Van Lehn

Alexander-Katz

. Penetration of lipid bilayers by nanoparticles with environmentally-responsive surfaces: simulations and theory. Soft Matter 2011; 7: 11392–11404.

39.

Chen

. Computational investigation of interaction between nanoparticles and membranes: hydrophobic/hydrophilic effect. J Phys Chem B 2008; 112: 16647–16653.

40.

Xie

Tong

. Effect of PEG conformation and particle size on the cellular uptake efficiency of nanoparticles with the HepG2 cells. J Control Release 2007; 118: 7–17.

41.

Chung

Yokoyama

Yamato

. Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). J Control Release 1999; 62: 115–127.

42.

Tsuda

Kikuchi

Yamato

. Control of cell adhesion and detachment using temperature and thermoresponsive copolymer grafted culture surfaces. J Biomed Mater Res A 2004; 69: 70–78.

43.

Yamada

Okano

Sakai

. Thermo-responsive polymeric surfaces; control of attachment and detachment of cultured cells. Makromol Chem Rapid Comm 1990; 11:571–576.

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