The effect of surface functionalization of PLGA nanoparticles by heparin- or chitosan-conjugated Pluronic on tumor targeting Yong-Il Chung a , Jong Chul Kim a , Young Ha Kim a,b , Giyoong Tae a,b, ⁎, Seung-Young Lee c , Kwangmeyung Kim c , Ick Chan Kwon c a Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea b Department of Nanobio Materials and Electronics, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea c Biomedical Research Center, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul 136-791, South Korea abstract article info Article history: Received 12 November 2009 Accepted 8 January 2010 Available online 25 January 2010 Keywords: Tumor targeting Cellular uptake Surface functionalization PLGA nanoparticle Heparin Chitosan The poly (lactide-co-glycolide) (PLGA)-based nanoparticles, coated by the heparin- or chitosan-Pluronic conjugate, were used to improve a relatively low tumor-targeting efficiency of the bare PLGA nanoparticles. The prepared nanoparticles were in the size range of 100–150 nm, and the surface exposure of the functional moiety (heparin or chitosan) was confirmed by negatively or positively increased zeta potential values, respectively. The viability tests for both normal and tumor cells displayed minimal cytotoxicity of the nanoparticles. The stable surface coating, which was evident from no change in the size distribution profiles in spite of the surface charge changes in serum environment, effectively provided the desired functionalized surface that clearly enhanced the in vitro cellular uptake of the nanoparticles for both heparin and chitosan functionalization. The in vivo tumor model study, which was carried out in SCC7 tumor-bearing athymic mice, demonstrated that there was a limited, but positive effect of surface functionalization, more effective for chitosan functionalization. The accumulation of chitosan-functionalized PLGA nanoparticles in tumor was 2.4 folds higher than that of the control, PLGA nanoparticles coated with bare Pluronic, and the accumulation in liver was lower than the control. In the case of heparin functionalization, the mean value was 2.2 folds higher than that of the control, but the accumulation in liver was similar to that of the control. Therefore, the surface-functionalization by the chitosan- or heparin-conjugated Pluronic may be an effective approach for the hydrophobic nanoparticle systems aiming for the enhanced tumor imaging and therapy. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Nanoparticles of biodegradable polymers have been widely used as drug delivery vehicles because of their sustained drug action on the lesion, reduced systemic side effects, facilitated extravasation into the tumor, high capability to cross various physiological barriers, and controlled and targeted delivery of the drug [1–3]. Poly (lactide-co- glycolide) (PLGA) is an FDA-approved synthetic biodegradable copoly- mer, which is the most widely used biomaterials, including drug carriers for hydrophobic as well as hydrophilic drugs [4]. Typically, PLGA nanoparticles are prepared by using the nanoprecipitation/solvent diffusion method, thus, in the particle preparation process, target drugs can be effectively entrapped into the precipitated rigid core of nanoparticles. PLGA nanoparticle is also attractive for tumor-targeted therapy and imaging; it can be stabilized with the surface hydrogel layer of polyethylene glycol (PEG) to minimize opsonization by the mononuclear phagocytic system and prolong blood circulation [5], and this surface layer can be functionalized with a variety of biological moieties for tumor-specific targeting [6–9]. However, compared to other flexible polymeric micelle systems [10,11], PLGA nanoparticles having a core rigidity have shown a relatively low tumor-targeting efficacy, mainly due to high localization in liver [12–15]. On the other hand, the flexible nanoparticle systems containing target drugs may have limitations associated with the change in physic-chemical properties (diameter, polydispersity, and elastic properties) after drug loading and usually fast release of loaded drugs [16–18]. In the present study, the PEG (Pluronic F127) surface layer of PLGA nanoparticle was functionally modified with heparin or chitosan to see the effect of surface functionalization on the tumor-targeting efficacy. The decision to introduce heparin as a functional moiety was based on the presence of high-affinity binding and internalization of heparin to dividing vascular endothelial cells, which are abundant in tumors [19–21]. This property suggests that heparin or heparin derivatives might target rapidly dividing tumor endothelial cells. Furthermore, systemically administrated heparin might be recruited into the tumor tissues expressing high levels of heparin-binding angiogenic growth factors [22]. Journal of Controlled Release 143 (2010) 374–382 ⁎ Corresponding author. Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500- 712, South Korea. Tel.: +82 62 970 2305; fax: +82 62 970 2304. E-mail address: gytae@gist.ac.kr (G. Tae). 0168-3659/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2010.01.017 Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel NANOMEDICINE