Skip to main content
Log in

Biocompatibility study of two diblock copolymeric nanoparticles for biomedical applications by in vitro toxicity testing

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

Drugs used for chemotherapy normally carry out adverse, undesired effects. Nanotechnology brings about new horizons to tackle cancer disease with a different strategy. One of the most promising approaches is the use of nanocarriers to transport active drugs. These nanocarriers need to have special properties to avoid immune responses and toxicity, and it is critical to study these effects. Nanocarriers may have different nature, but polypeptide-based copolymers have attracted considerable attention for their biocompatibility, controlled and slow biodegradability as well as low toxicity. Little has been done regarding specific nanocarriers toxicity. In this study, we performed a thorough toxicological study of two different block copolymer nanoparticles (NPs); poly(trimethylene carbonate)-block–poly(l-glutamic acid) (PTMC-b–PGA) and poly(ethylene glycol)-block–poly(γ-benzyl-l-glutamate) (PEG-b–PBLG) with sizes between 113 and 131 nm. Low blood–serum–protein interaction was observed. Moreover, general toxicity assays and other endpoints (apoptosis or necrosis) showed good biocompatibility for both NPs. Reactive oxygen species increased in only two cell lines (HepG2 and TK6) in the presence of PTMC-b–PGA. Cytokine production study showed cytokine induction only in one cell line (A549). We also performed the same assays on human skin organ culture before and after UVB light treatment, with a moderate toxicity after treatment independent of NPs presence or absence. Interleukin 1 induction was also observed due to the combined effect of PEG-b–PBLG and UVB light irradiation. Future in vivo studies for biocompatibility and toxicity will provide more valuable information, but, so far, the findings presented here suggest the possibility of using these two NPs as nanocarriers for nanomedical applications, always taking into account the application procedure and the way in which they are implemented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ai J, Biazar E, Jafarpour M, Montazeri M, Majdi A, Aminifard S, Zafari M, Akbari HR, Rad HG (2011) Nanotoxicology and nanoparticle safety in biomedical designs. Int J Nanomed 6:1117–1127

    CAS  Google Scholar 

  • Arimura H, Ohya Y, Ouchi T (2005) Formation of core–shell type biodegradable polymeric micelles from amphiphilic poly(aspartic acid)-block–polylactide diblock copolymer. Biomacromolecules 6(2):720–725

    Article  CAS  Google Scholar 

  • Backand S, Winder C, Hayes A (2011) Cell viability and cytokine production of human alveolar epithelial cells following exposure to sulphur dioxide. Int J Occup Hyg 3:63–69

    Google Scholar 

  • Buzea C, Pacheco-Blandino II, Robbie K (2007) Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2:MR17–MR172

    Article  Google Scholar 

  • Carlsen A, Lecommandoux S (2009) Self-assembly of polypeptide-based block copolymer amphiphiles. Curr Opin Colloid Interface Sci 14(5):329–339

    Article  CAS  Google Scholar 

  • Chen Y, Wan Y, Wang Y, Zhang H, Jiao Z (2011) Anticancer efficacy enhancement and attenuation of side effects of doxorubicin with titanium dioxide NPs. Int J Nanomed 6:2321–2326

    CAS  Google Scholar 

  • Chiellini EE, Chiellini F, Solaro R (2006) Bioerodible polymeric NPs for targeted delivery of proteic drugs. J Nanosci Nanotechnol 6(9–10):3040–3047

    Article  CAS  Google Scholar 

  • Chiellini F, Bartoli C, Dinucci D, Piras AM, Anderson R, Croucher T (2007) Bioeliminable polymeric NPs for proteic drug delivery. Int J Pharm 343(1–2):90–97

    Article  CAS  Google Scholar 

  • Curtis J, Greenberg M, Kester J, Phillips S, Krieger G (2006) Nanotechnology and nanotoxicology: a primer for clinicians. Toxicol Sci 25(4):245–260

    CAS  Google Scholar 

  • Dinarello CA (2000) Proinflammatory cytokines. Chest 118:503–508

    Article  CAS  Google Scholar 

  • Dong AJ, Deng LD, Sun DX, Zhang YT, Jin JZ, Yuan YJ (2004) Studies on paclitaxel-loaded NPs of amphiphilic block copolymer. Yao Xue Xue Bao 39(2):149–152

    CAS  Google Scholar 

  • Duncan R, Ringsdorf H, Satchi-Fainaro R (2006) Polymer therapeutics I. In: Advances in polymer science. Springer, Berlin, pp 1–8

  • Geiser M, Kreyling WG (2010) Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol 7(2). doi:10.1186/1743-8977-7-2

  • Guo W, Huang N, Cai J, Xie W, Hamilton JA (2006) Fatty acid transport and metabolism in HepG2 cells. Am J Physiol Gastrointest Liver Physiol 290:528–534

    Article  Google Scholar 

  • Jeong YI, Nah JW, Lee HC, Kim SH, Cho CS (1999) Adriamycin release from flower-type polymeric micelle based on star-block copolymer composed of poly(gamma-benzyl l-glutamate) as the hydrophobic part and poly(ethylene oxide) as the hydrophilic part. Int J Pharm 188(1):49–58

    Article  CAS  Google Scholar 

  • Jeong YI, Kang MK, Sun HS, Kang SS, Kim HW, Moon KS, Lee KJ, Kim SH, Jung S (2004) All-trans-retinoic acid release from core–shell type NPs of poly(epsilon-caprolactone)/poly(ethylene glycol) diblock copolymer. Int J Pharm 273(1–2):95–107

    Article  CAS  Google Scholar 

  • Jeong YI, Seo SJ, Park IK, Lee HC, Kang IC, Akaike T, Cho CS (2005) Cellular recognition of paclitaxel-loaded polymeric NPs composed of poly(gamma-benzyl l-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety. Int J Pharm 296(1–2):151–161

    Article  CAS  Google Scholar 

  • Kricheldorf H (2006) Polypeptides and 100 years of chemistry of alpha-amino acid N-carboxyanhydrides. Angew Chem Int Ed Engl 45(35):5752–5784

    Article  CAS  Google Scholar 

  • Lankelma J, Dekker H, Luque FR, Luykx S, Hoekman K, Van der Valk P (1999) Doxorubicin gradients in human breast cancer. Clin Cancer Res 5:1703–1707

    CAS  Google Scholar 

  • Lanone S, Boczkowski J (2006) Biomedical applications and potential health risks of nanomaterials: molecular mechanisms. Curr Mol Med 6(6):651–663

    Article  CAS  Google Scholar 

  • Li C (2002) Poly(l-glutamic acid)–anticancer drug conjugates. Adv Drug Deliv Rev 54(5):695–713

    Article  CAS  Google Scholar 

  • Li S, Wang A, Jiang W, Guan Z (2008) Pharmacokinetic characteristics and anticancer effects of 5-fluorouracil loaded NPs. BMC Cancer 8:103–111

    Article  CAS  Google Scholar 

  • Li X, Wang L, Fan Y, Feng Q, Cui F (2012) Biocompatibility and toxicity of NPs and nanotubes. J Nanomater 2012, Article ID 548389. doi:10.1155/2012/548389

  • Mandal D, Chatterjee U (2007) Synthesis and spectroscopy of CdS NPs in amphiphilic diblock copolymer micelles. J Chem Phys 126(13):13450–13457

    Article  Google Scholar 

  • Martinez Barbosa ME, Montembault V, Cammas-Marion S, Ponchel G, Fontaine L (2007) Synthesis and characterization of novel poly(γ-benzyl-l-glutamate) derivatives tailored for the preparation of NPs of pharmaceutical interest. Polym Int 56:317–324

    Article  Google Scholar 

  • Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, Koyasu S, Matsumoto K, Takeda K, Ichijo H (2005) ROS dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol 6:587–592

    Article  CAS  Google Scholar 

  • Medina C, Santos-Martinez MJ, Radomski A (2007) Nanoparticles: pharmacological and toxicological significance. Br J Pharmacol 150:552–558

    Article  CAS  Google Scholar 

  • Monteiro-Riviere NA, Inman AO, Zhang LW (2009) Limitations and relative utility of screening assays to assess engineered NP toxicity in a human cell line. Toxicol Appl Pharmacol 234:222–235

    Article  CAS  Google Scholar 

  • Nishiyama N, Kataoka K (2006) Polymer therapeutics II. In: Advances in polymer science. Springer, Berlin, pp 67–101

  • Oberdörster G (2000) Toxicology of ultrafine particles: in vivo studies. Philos Trans R Soc Lond A 358:2719–2740

    Article  Google Scholar 

  • Oberdörster G, Oberdörster E, Oberdörster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113(7):823–839

    Article  Google Scholar 

  • Oh I, Lee K, Kwon HY, Lee YB, Shin SC, Cho CS, Kim CK (1999) Release of adriamycin from poly(gamma-benzyl-l-glutamate)/poly(ethylene oxide) NPs. Int J Pharm 181(1):107–115

    Article  CAS  Google Scholar 

  • Ponti J, Colognato R, Rauscher H, Gioria S, Broggi F, Franchin F, Pascual C, Giudetti G, Rossi F (2010) Colony forming efficiency and microscopy analysis of multi-wall carbon nanotubes cell interaction. Toxicol Lett 197:29–37

    Article  CAS  Google Scholar 

  • Portugal-Cohen M, Soroka Y, Frušić-Zlotkin M, Verkhovsky L, Brégégère FM, Neuman R, Kohen R, Milner Y (2011) Skin organ culture as a model to study oxidative stress, inflammation and structural alterations associated with UVB-induced photodamage. Exp Dermatol 20(9):749–755

    Article  CAS  Google Scholar 

  • Raab C, Simkó M, Gazsó A, Fiedeler U, Nentwich M (2008) Was sind synthetische Nanopartikel?. NanoTrust-Dossiers Nr. 002, hg. v. Institut für Technikfolgen-Abschätzung, Wien

  • Revell PA (2006) The biological effects of nanoparticles. Nanotechnol Percept 2:283–298

    Google Scholar 

  • Sanson C, Schatz C, Le Meins JF, Brulet A, Soum A, Lecommandoux S (2010a) Biocompatible and biodegradable poly(trimethylene carbonate)-b–poly(l-glutamic acid) polymersomes: size control and stability. Langmuir 26(4):2751–2760

    Article  CAS  Google Scholar 

  • Sanson C, Schatz C, Le Meins JF, Soum A, Thévenot J, Garanger E, Lecommandoux S (2010b) A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Control Release 147:428–435

    Article  CAS  Google Scholar 

  • Sanson C, Diou O, Thevenot J, Ibarboure E, Soum A, Brûlet A, Miraux S, Thiaudière E, Tan S, Brisson A, Dupuis V, Sandre O, Lecommandoux S (2011) Doxorubicin loaded magnetic polymersomes: theranostic nanocarriers for MR imaging and magneto-chemotherapy. ACS Nano 5:1122–1140

    Article  CAS  Google Scholar 

  • Satchi-Fainaro R, Duncan R, Barnes C (2006) Polymer therapeutics II. In: Advances in polymer science. Springer, Berlin, pp 1–65

  • Schanen BC, Karakoti AS, Seal S, Drake DR, Warren WL, Self WT (2009) Exposure to titanium dioxide nanomaterials provokes inflammation of an in vitro human immune construct. ACS Nano 3:2523–2532

    Article  CAS  Google Scholar 

  • Sioutas C, Delfino RJ, Singh M (2005) Exposure assessment for atmospheric ultrafine particles (UFPs) and implications in epidemiologic research. Environ Health Perspect 113(8):947–955

    Article  Google Scholar 

  • Stone V, Tuinman M, Vamvakopoulos JE, Shaw J, Brown D, Petterson S, Faux SP, Borm P, MacNee W, Michaelangeli F, Donaldson K (2000) Increased calcium influx in a monocytic cell line on exposure to ultrafine carbon black. Eur Respir J 15(2):297–303

    Article  CAS  Google Scholar 

  • Svobodova A, Walterova D, Vostalova J (2006) Ultraviolet light induced alteration to the skin. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 150(1):25–38

    Article  CAS  Google Scholar 

  • Tang H, Guo J, Sun Y, Chang B, Ren Q, Yang W (2011) Facile synthesis of pH sensitive polymer-coated mesoporous silica NPs and their application in drug delivery. Int J Pharm 421:388–396

    Article  CAS  Google Scholar 

  • Tian F, Cui D, Schwarz H, Estrada GG, Kobayashi H (2006) Cytotoxicity of single-wall carbon nanotubes on human fibroblasts. Toxicol In Vitro 20:1202–1212

    Article  CAS  Google Scholar 

  • Tomoda K, Watanabe A, Suzuki K, Inagi T, Terada H, Makino K (2012) Enhanced transdermal permeability of estradiol using combination of PLGA nanoparticles system and iontophoresis. Colloids Surf B 97:84–89

    Article  CAS  Google Scholar 

  • Upadhyay KK, Agrawal HG, Upadhyay C, Schatz C, Le Meins JF, Misra A, Lecommandoux S (2009) Role of block copolymer nanoconstructs in cancer therapy. Crit Rev Ther Drug Carr Syst 26(2):157–205

    Article  CAS  Google Scholar 

  • Vega-Villa KR, Takemoto JK, Yáñez JA, Remsberg CM, Forrest ML, Davies NM (2008) Clinical toxicities of nanocarrier systems. Adv Drug Deliv Rev 60:929–938

    Article  CAS  Google Scholar 

  • Yang Y, Qu Y, Lü X (2010) Global gene expression analysis of the effects of gold NPs on human dermal fibroblasts. J Biomed Nanotechnol 6:234–246

    Article  CAS  Google Scholar 

  • Yost GS, Veranth JM, Reilly CA, Veronesi B (2006) Chapter 8: vanilloid receptors in the respiratory tract. In: Gardner DE (ed) Toxicology of the lung, 4th edn. Taylor and Francis Group, Boca Raton, pp 297–350

    Google Scholar 

  • Zhang LW, Zeng L, Barron AR, Monteiro-Riviere NA (2007) Biological interactions of functionalized single-wall carbon nanotubes in human epidermal keratinocytes. Int J Toxicol 26:103–113

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the European Commission FP7 Programme 2007–2013 under NANOTHER project (www.nanother.eu), Grant Agreement Number CP-IP 213631-2 NANOTHER. We want to particularly acknowledge the patients enrolled in the blood serum study for their participation and the Basque Biobank for Research-OEHUN for its collaboration.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pedro Heredia.

Additional information

Felipe Goñi-de-Cerio and Valentina Mariani have contributed equally.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 31 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goñi-de-Cerio, F., Mariani, V., Cohen, D. et al. Biocompatibility study of two diblock copolymeric nanoparticles for biomedical applications by in vitro toxicity testing. J Nanopart Res 15, 2036 (2013). https://doi.org/10.1007/s11051-013-2036-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-013-2036-0

Keywords

Navigation