Enrui Chen1, Shangcong Han1, Bo Song2, Lisa Xu1, Haicheng Yuan2, Mingtao Liang3, Yong Sun1. 1. Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People's Republic of China. 2. Department of Neurology, Qingdao Central Hospital, Qingdao, People's Republic of China. 3. Department of Pharmaceutics, School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
Abstract
BACKGROUND: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. MATERIALS AND METHODS: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. RESULTS: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. CONCLUSION: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.
BACKGROUND: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. MATERIALS AND METHODS: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. RESULTS: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. CONCLUSION: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.
Authors: Live Eikenes; Ingunn Tufto; Edrun A Schnell; Astrid Bjørkøy; Catharina De Lange Davies Journal: Anticancer Res Date: 2010-02 Impact factor: 2.480
Authors: Clifford J Whatcott; Haiyong Han; Richard G Posner; Galen Hostetter; Daniel D Von Hoff Journal: Cancer Discov Date: 2011-09 Impact factor: 39.397
Authors: Daniela Pankova; Yulong Chen; Masahiko Terajima; Mark J Schliekelman; Brandi N Baird; Monica Fahrenholtz; Li Sun; Bartley J Gill; Tegy J Vadakkan; Min P Kim; Young-Ho Ahn; Jonathon D Roybal; Xin Liu; Edwin Roger Parra Cuentas; Jaime Rodriguez; Ignacio I Wistuba; Chad J Creighton; Don L Gibbons; John M Hicks; Mary E Dickinson; Jennifer L West; K Jane Grande-Allen; Samir M Hanash; Mitsuo Yamauchi; Jonathan M Kurie Journal: Mol Cancer Res Date: 2015-12-02 Impact factor: 5.852