Lee B Sims1, Keegan C Curry2, Sindhu Parupalli1, Gwynneth Horner3, Hermann B Frieboes1,4,5, Jill M Steinbach-Rankins6,7,8,9. 1. Department of Bioengineering, University of Louisville, 505 S. Hancock, CTR 623, Louisville, Kentucky, 40202, USA. 2. Department of Biology, University of Louisville, Louisville, Kentucky, USA. 3. School of Medicine, University of Louisville, Louisville, Kentucky, USA. 4. James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA. 5. Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA. 6. Department of Bioengineering, University of Louisville, 505 S. Hancock, CTR 623, Louisville, Kentucky, 40202, USA. jmstei01@louisville.edu. 7. Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA. jmstei01@louisville.edu. 8. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA. jmstei01@louisville.edu. 9. Center for Predictive Medicine, University of Louisville, Louisville, Kentucky, USA. jmstei01@louisville.edu.
Abstract
PURPOSE: Hypovascularization of cervical tumors, coupled with intrinsic and acquired drug resistance, has contributed to marginal therapeutic outcomes by hindering chemotherapeutic transport and efficacy. Recently, the heterogeneous penetration and distribution of cell penetrating peptide (CPP, here MPG) and polyethylene glycol (PEG) modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were evaluated as a function of tumor type and morphology in cervical cancer spheroids modeling hypovascularized tumor nodules. Building upon this work, this study investigates the efficacy imparted by surface-modified Doxorubicin-loaded NPs transported into hypovascularized tissue. METHODS: NP efficacy was measured in HeLa, CaSki, and SiHa cells. NP internalization and association, and associated cell viability, were determined in monolayer and spheroid models. RESULTS: MPG and PEG-NP co-treatment was most efficacious in HeLa cells, while PEG NPs were most efficacious in CaSki cells. NP surface-modifications were unable to improve efficacy, relative to unmodified NPs, in SiHa cells. CONCLUSIONS: The results highlight the dependence of efficacy on tumor type and the associated microenvironment. The results further relate previous NP transport studies to efficacy, as a function of surface-modification and cell type. Longer-term, this information may help guide the design of NP-mediated strategies to maximize efficacy based on patient-specific cervical tumor origin and characteristics.
PURPOSE:Hypovascularization of cervical tumors, coupled with intrinsic and acquired drug resistance, has contributed to marginal therapeutic outcomes by hindering chemotherapeutic transport and efficacy. Recently, the heterogeneous penetration and distribution of cell penetrating peptide (CPP, here MPG) and polyethylene glycol (PEG) modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were evaluated as a function of tumor type and morphology in cervical cancer spheroids modeling hypovascularized tumor nodules. Building upon this work, this study investigates the efficacy imparted by surface-modified Doxorubicin-loaded NPs transported into hypovascularized tissue. METHODS:NP efficacy was measured in HeLa, CaSki, and SiHa cells. NP internalization and association, and associated cell viability, were determined in monolayer and spheroid models. RESULTS:MPG and PEG-NP co-treatment was most efficacious in HeLa cells, while PEGNPs were most efficacious in CaSki cells. NP surface-modifications were unable to improve efficacy, relative to unmodified NPs, in SiHa cells. CONCLUSIONS: The results highlight the dependence of efficacy on tumor type and the associated microenvironment. The results further relate previous NP transport studies to efficacy, as a function of surface-modification and cell type. Longer-term, this information may help guide the design of NP-mediated strategies to maximize efficacy based on patient-specific cervical tumor origin and characteristics.
Authors: Hermann B Frieboes; Xiaoming Zheng; Chung-Ho Sun; Bruce Tromberg; Robert Gatenby; Vittorio Cristini Journal: Cancer Res Date: 2006-02-01 Impact factor: 12.701
Authors: Hermann B Frieboes; Mary E Edgerton; John P Fruehauf; Felicity R A J Rose; Lisa K Worrall; Robert A Gatenby; Mauro Ferrari; Vittorio Cristini Journal: Cancer Res Date: 2009-04-14 Impact factor: 12.701
Authors: Katrina M Comerford; Timothy J Wallace; Jörn Karhausen; Nancy A Louis; Michael C Montalto; Sean P Colgan Journal: Cancer Res Date: 2002-06-15 Impact factor: 12.701
Authors: Kevin M Tyo; Amanda B Lasnik; Longyun Zhang; Mohamed Mahmoud; Alfred B Jenson; Joshua L Fuqua; Kenneth E Palmer; Jill M Steinbach-Rankins Journal: J Control Release Date: 2020-02-05 Impact factor: 9.776