Synthesis,characterization,and property of biodegradable PEG-PCL-PLA terpolymers with miktoarm star and triblock architectures as drug carriers

Abstract

A series of amphiphilic terpolymers with miktoarm star and triblock architectures of poly(ethylene glycol) (PEG), poly(ε-caprolactone) (PCL) and poly(l-lactide acid) (PLLA) or poly(DL-lactide acid) (PDLLA) terpolymers were synthesized as carriers for drug delivery. The architecture, molecular weight and crystallization behavior of the terpolymers were characterized. Anticancer drug doxorubicin was encapsulated in the micelles to investigate their drug loading properties. The miktoarm star terpolymers exhibited stronger crystallization capability, smaller size and better stability than that of triblock polymeric micelle, owing to the lower CMC values of miktoarm star polymeric micelle. Furthermore, the drug-loaded miktoarm star polymeric micelles showed the cumulative DOX release account of the micelles with PDLLA blocks was 65.3% while the release account of the corresponding micelles containing PLLA blocks was 45.2%. The IC₅₀ values of drug-loaded miktoarm star polymeric micelle were lower than triblock polymeric micelle. Meanwhile, Confocal laser scanning microscopy (CLSM) and Flow Cytometry results demonstrated that the miktoarm star micelles were more favorable for cellular internalization. The miktoarm star micelles with PDLLA blocks were promising carriers for anticancer drug delivery.

Keywords

Miktoarm polymeric micelle drug delivery doxorubicin anticancer activity

Get full access to this article

View all access options for this article.

References

Giovanella

Stehlin

Hinz

et al . Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)- camptothecin (Rubitecan). Int J Oncol 2002; 20: 81–88.

Verschraegen

Natelson

Giovanella

et al . A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor. Anticancer Drugs 1998; 9: 36–44.

Gao

Ming

et al . Preparation and characterization of novel polymeric micelles for 9-nitro-20(S)-camptothecin delivery. Eur J Pharmaceut Sci 2008; 34: 85–93.

Gao

Liang

Peng

et al . In situ injection of phenylboronic acid based low molecular weight gels for efﬁcient chemotherapy. Biomaterials 2016; 105: 1–11.

Qiu

and Bae

YH.

Polymer architecture and drug delivery. Pharm Res 2006; 23: 1–30.

Chen

Liang

Yang

et al . Effects of pH-sensitive groups on poly (ethylene oxide)-block-poly (ϵ-caprolactone) block copolymer micelles used as drug carriers. Macromol Chem Phys 2011; 212: 2511–2521.

and Liu

Supramolecular self-assembly of nonlinear amphiphilic and double hydrophilic block copolymers in aqueous solutions. Macromol Rapid Commun 2009; 30: 1523–1532.

Zhou

Liu

Y-Y

Niu

L-Y

et al . Self-assemblies of the six-armed star triblock ABC copolymer: pH-tunable morphologies and drug release. Polym Chem 2015; 6: 2934–2944.

Stefani

Hönzke

Camacho

JLC

et al . Hyperbranched glycerol-based core-amphiphilic branched shell nanotransporters for dermal drug delivery. Polymer 2016; 96: 156–166.

10.

Nakamura

Koziolová

Etrych

et al . Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice. Eur J Pharm Biopharm 2015; 90: 90–96.

11.

Jie

Venkatraman

Min

et al . Micelle-like nanoparticles of star-branched PEO–PLA copolymers as chemotherapeutic carrier. J Control Release 2005; 110: 20–33.

12.

Zhang

Chen

et al . Synthesis and evaluation of cholesterol-grafted PEGylated peptides with pH-triggered property as novel drug carriers for cancer chemotherapy. Colloid Surface B: Biointerfaces 2016; 142: 55–64.

13.

Maglio

Nicodemi

Conte

et al . Nanocapsules based on linear and Y-shaped 3-miktoarm star-block PEO-PCL copolymers as sustained delivery system for hydrophilic molecules. Biomacromolecules 2011; 12: 4221–4229.

14.

Khanna

Varshney

Kakkar

Miktoarm star polymers: advances in synthesis, self-assembly, and applications. Polym Chem 2010; 1: 1171–1185.

15.

Alizadeh

and Ghaemy

pH-responsive ABC type miktoarm star terpolymers: Synthesis via combination of click reaction and SET-LRP, characterization, self-assembly, and controlled drug release. Polymer 2015; 66: 179–191.

16.

Huan

Wang

Dong

et al . Supramolecular ABC miktoarm star terpolymer based on host–guest inclusion complexation. Macromolecules 2012; 45: 5941–5947.

17.

Kumar

Ravikumar

and Domb

Biodegradable block copolymers. Adv Drug Deliv Rev 2001; 53: 23–44.

18.

Wang

Zhao

and Wang

Syntheses of poly (lactic acid)-poly (ethylene glycol) serial biodegradable polymer materials via direct melt polycondensation and their characterization. J Appl Polym Sci 2006; 102: 577–587.

19.

Miyajima

Koshika

Okada

et al . Effect of polymer crystallinity on papaverine release from poly (L-lactic acid) matrix. J Control Release 1997; 49: 207–215.

20.

Yang

Zhang

et al . Redox-responsive flower-like micelles of poly (L-lactic acid)-b-poly (ethylene glycol)-b-poly (L-lactic acid) for intracellular drug delivery. Polymer 2016; 90: 351–362.

21.

Nakajima

Fujiwara

et al . Nano-structured micelle particles of polylactide-poly (oxyethylene) block copolymers with different block sequences: specific influence of stereocomplex formation of the polylactide blocks. Polymer 2015; 66: 160–166.

22.

Mao

Shan

Bao

et al . Thermoresponsive physical hydrogels of poly (lactic acid)/poly (ethylene glycol) stereoblock copolymers tuned by stereostructure and hydrophobic block sequence. Soft Matter 2016; 12: 4628–4637.

23.

Korzhikov

Averianov

Litvinchuk

et al . Polyester-based microparticles of different hydrophobicity: the patterns of lipophilic drug entrapment and release. J Microencapsul 2016; 33: 1–10.

24.

Tamboli

Mishra

and Mitra

AK.

Novel pentablock copolymer (PLA–PCL–PEG–PCL–PLA)-based nanoparticles for controlled drug delivery: effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles. Colloid Polym Sci 2013; 291: 1235–1245.

25.

Nederberg

Appel

Tan

et al . Simple approach to stabilized micelles employing miktoarm terpolymers and stereocomplexes with application in paclitaxel delivery. Biomacromolecules 2009; 10: 1460–1468.

26.

Nabid

Rezaei

SJT

Sedghi

et al . Self-assembled micelles of well-defined pentaerythritol-centered amphiphilic A 4 B 8 star-block copolymers based on PCL and PEG for hydrophobic drug delivery. Polymer 2011; 52: 2799–2809.

27.

Kang

Park

et al . pH-triggered unimer/vesicle-transformable and biodegradable polymersomes based on PEG-b-PCL–grafted poly (β-amino ester) for anti-cancer drug delivery. Polymer. 2013; 54: 102–110.

28.

Song

Zhang

Cao

et al . Arginine modified polymeric micelles as a novel drug delivery system with enhanced endocytosis efficiency. Colloids Surf B Biointerf 2016; 148: 181–192.

29.

Zalipsky

Functionalized poly (ethylene glycols) for preparation of biologically relevant conjugates. Bioconjugate Chem 1995; 6: 150–165.

30.

Nair

Podgo´rski

Chatani

et al . The thiol-Michael addition click reaction: a powerful and widely used tool in materials chemistry. Chem Mater 26: 724–744. 2013

31.

Ding

Zhou

et al . Biodegradable gemini multiblock poly (ε-caprolactone urethane) s toward controllable micellization. Soft Matter 2010; 6: 2087–2092.

32.

Peng

Zhang

Chen

et al . Synthesis and crystallization of well-defined biodegradable miktoarm star PEG-PCL-PLLA copolymer. Mater Lett 2016; 171: 83–86.

33.

Davis

and Shin

DM.

Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 2008; 7: 771–782.

34.

Mikac

Sepe

Baumgartner

et al . The influence of high drug loading in xanthan tablets and media with different physiological ph and ionic strength on swelling and release. Mol Pharmaceut 2016; 13: 1147–1157.

35.

Martens

Remaut

Demeester

et al . Intracellular delivery of nanomaterials: how to catch endosomal escape in the act. Nano Today 2014; 9: 344–364.

36.

Liang

Gao

Peng

et al . Near infrared light responsive hybrid nanoparticles for synergistic cancer therapy. Biomaterials 2016; 100: 76–90.

37.

Yang

Liu

Venkataraman

et al . Structure-directing star-shaped block copolymers: supramolecular vesicles for the delivery of anticancer drugs. J Control Release 2015; 208: 93–105.

38.

Liang

Deng

Zhang

et al . Terminal modification of polymeric micelles with π-conjugated moieties for efficient anticancer drug delivery. Biomaterials 2015; 71: 1–10.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.99 MB