title: Multistage Nanovectors Enhance the Delivery of Free and Encapsulated Drugs.
abstract: Nanoparticles have considerable potential for cancer imaging and therapy due to their small size and prolonged circulation. However, biological barriers can impede the delivery of a sufficient dose of a drug to the target site, thereby also resulting in the accumulation of toxic compounds within healthy tissues, and systemic toxicity. Multistage nanovectors (MSV) preferentially accumulate on inflamed endothelium, and can thus serve as carriers for drugs and nanoparticles. Herein, we describe the loading of free (i.e., melittin) and nano-encapsulated (i.e., doxorubicin-loaded micelles) drugs into MSV, and report the impact of surface charge and pore size on drug loading. For both drug formulations, negatively charged MSV (i.e., oxidized) with larger pores were shown to retain higher concentrations of payloads compared to positively charged (i.e., APTES-modified) MSV with small pores. Treatment of human umbilical vein endothelial cells (HUVEC) with melittin-loaded MSV (MEL@MSV) resulted in an 80% reduction in cell viability after 3 days. Furthermore, MEL@MSV conjugated with antivascular endothelial growth factor receptor 2 (VEGFR2) antibodies displayed preferential targeting and delivery of MEL to activated HUVEC expressing VEGFR2. Treatment of HUVEC and MCF7 cells with doxorubicin-loaded micelles (DOXNP@MSV) resulted in a 23% and 47% reduction in cell viability, respectively. Taken together, these results demonstrate increased loading of a payload in oxidized, large pore MSV, and effective delivery of free and nano-encapsulated drugs to endothelial and cancer cells.
authors.affiliation: Houston Methodist Research Institute, 6670 Bertner Avenue MS R7-414, Houston, TX 77030-2602, USA. jomartinez@HoustonMethodist.org.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Martinez
authors.forename: Michael
authors.initials: M
authors.lastname: Evangelopoulos
authors.forename: Rohan
authors.initials: R
authors.lastname: Bhavane
authors.forename: Stefania
authors.initials: S
authors.lastname: Acciardo
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Ennio
authors.initials: E
authors.lastname: Tasciotti
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D002214:Capsules; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008555:Melitten / Q000494:pharmacology*; D008823:Micelles; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000906:Antibodies; D002214:Capsules; D008823:Micelles; D008555:Melitten; D004317:Doxorubicin; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2