title: Size and Surface Charge of Engineered Poly(amidoamine) Dendrimers Modulate Tumor Accumulation and Penetration: A Model Study Using Multicellular Tumor Spheroids.
abstract: An enormous effort has been put into designing nanoparticles (NPs) with controlled biodistributions, prolonged plasma circulation times, and/or enhanced tissue targeting. However, little is known about how to design NPs with precise distributions in the target tissues. In particular, understanding NP tumor penetration and accumulation characteristics is crucial to maximizing the therapeutic potential of drug molecules carried by the NPs. In this study, we employed poly(amidoamine) (PAMAM) dendrimers, given their well-controlled size (<10 nm) and surface charge, to understand how the physical properties of NPs govern their tumor accumulation and penetration behaviors. We demonstrate for the first time that the size and surface charge of PAMAM dendrimers control their distributions in both a 3D multicellular tumor spheroid (MCTS) model and a separate extracellular matrix (ECM) model, which mimics the tumor microenvironment. Smaller PAMAM dendrimers not only diffused more rapidly in the ECM model but also efficiently penetrated to the MCTS core compared to their larger counterparts. Furthermore, cationic, amine-terminated PAMAM dendrimers exhibited the greatest accumulation in MCTS compared to either charge-neutral or anionic dendrimers. Our findings indicate that the size and surface charge of PAMAM dendrimers may tailor their tumor accumulation and penetration behaviors. These results suggest that controlled tumor accumulation and distinct intratumoral distributions can be achieved by simply controlling the size and surface charge of dendrimers, which may also be applicable for other similarly sized NPs.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois , Chicago, Illinois 60612, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Bugno
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois , Chicago, Illinois 60612, United States.
authors.forename: Hao-Jui
authors.initials: HJ
authors.lastname: Hsu
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois , Chicago, Illinois 60612, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Pearson
authors.affiliation: Department of Optometry, Seoul National University of Science and Technology , Seoul 139-743, Korea.
authors.forename: Hyeran
authors.initials: H
authors.lastname: Noh
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois , Chicago, Illinois 60612, United States.|Departments of Integrated OMICs for Biomedical Science and Pharmacy and Underwood International College, Yonsei University , Seoul 120-749, Korea.
authors.forename: Seungpyo
authors.initials: S
authors.lastname: Hong
mesh_terms: D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007624:KB Cells; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D011073:Polyamines / Q000008:administration & dosage* / Q000737:chemistry*; D018874:Spheroids, Cellular / Q000737:chemistry*
chemical_list: D002412:Cations; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; C531249:Poly(amidoamine); D011073:Polyamines
keywords: PAMAM; multicellular tumor spheroids; nanoparticles; tumor penetration