TY - JOUR
T1 - Dermatan carriers for neovascular transport targeting, deep tumor penetration and improved therapy
AU - Ranney, David
AU - Antich, Peter
AU - Dadey, Eric
AU - Mason, Ralph
AU - Kulkarni, Padmakar
AU - Singh, Onkar
AU - Chen, Huagang
AU - Constantanescu, Anca
AU - Parkey, Robert
N1 - Funding Information:
This work was supported by ACCESS Pharmaceuticals, Inc., Dallas, TX, USA and the Department of Radiology, Southwestern Medical Center, Dallas, TX, USA. The authors thank Prof. Drs. Guiseppe Mascellani, Pietro Bianchini and Giorgio Veronesi, Opocrin S.p.A., Modena, Italy, for providing dermatan sulfates; Drs. Jaweed Fareed and Debra Hoppenstead-Moorman, Hemostasis and Thrombosis Program, Loyola Univ. Med. Ctr., Maywood, IL, USA, for advice on dermatan sulfate assays; ACCESS Pharmaceuticals, Inc, Dallas, TX, USA, for providing dermatan agents; Gina Mangold, Daniel Dexter and Susan Hilsenbeck, Institute for Drug Development, San Antonio, TX, USA, for performing the tumor xenograft tests; Daniel D. Von Hoff, M.D., Director, Cancer Therapeutics Program, Arizona Health Sciences Center, Tucson, AZ, USA, for advice on the xenograft tests; Prof. Dr. Peter Peschke, DKFZ, Heidelberg, Germany, for providing AT1 tumor cells; and Howard Callahan, Julie Carver, Greg Eberhardt and Dr. John Rice of ACCESS Pharmaceuticals, Inc., for technical assistance.
PY - 2005/12/5
Y1 - 2005/12/5
N2 - A new approach to functional tumor imaging and deep interstitial penetration of therapeutic agents is to target the upregulated transport activities of neovascular endothelium. Agents are formulated with the anionic glycosaminoglycan, 435-type dermatan sulfate (DS 435, 22.2 kDa), chemically enriched for oligosaccharide sequences that confer high heparin cofactor II binding and correlate with high tumor uptake. A magnetic resonance (MR) imaging agent is prepared as self-assembling, 5-nm nanoparticles of Fe +3:deferoxamine (Fe:Df) bound by strong ion pairing to DS, which forms the outer molecular surface (Zeta potential - 39 mV). On intravenous (i.v.) injection, Fe:Df-DS rapidly (< 7 min) and selectively targets and transports at high capacity across the neovascular endothelium of large (2-cm) Dunning prostate R3327 AT1 rat tumors; releases from the abluminal surface, due to reversible binding of its multivalent, low-affinity (Kd 10 - 4 to 10- 5) oligosaccharide ligands; and progressively penetrates the interstitium from its initial site of high uptake in the well-perfused outer tumor rim, into the poorly perfused central subregion. By gamma camera imaging of 67Ga:Df-DS, the agent avoids normal site uptake and clears through the kidneys with a t1/2 of 18 min. A therapeutic formulation of DS-doxorubicin (DS-dox) is prepared by aqueous high-pressure homogenization of the drug and DS 435, which produces 11-nm nanoparticles of doxorubicin cores coated with DS (Zeta potential - 39 mV) that are stable to lyophilization. Microscopic analysis of tumor sections 3 h after i.v. injection shows much higher overall tumor fluorescence and deeper matrix penetration for DS-dox than conventional doxorubicin (dox): > 75 vs. < 25 μm between the nearest microvessels. DS-dox also results in enhanced tumor-cell internalization and nuclear localization of the drug. Therapeutic efficacies in established (250 ± 15 mg) MX-1 human breast tumor xenografts at maximum tolerated doses (MTDs) are (control vehicle, dox, dox-DS) (a) median days to 7-fold tumor growth: 8.3, 25.6 (p = 0.0007), 43.2 (p = 0.0001); (b) complete 90-day tumor regressions: 0/10, 0/10, 4/10. These results demonstrate the potential to develop a novel class of carbohydrate-targeted neovascular transport agents for sensitive, high-resolution (100-μm) MR imaging and improved treatment of larger sized human tumor metastases.
AB - A new approach to functional tumor imaging and deep interstitial penetration of therapeutic agents is to target the upregulated transport activities of neovascular endothelium. Agents are formulated with the anionic glycosaminoglycan, 435-type dermatan sulfate (DS 435, 22.2 kDa), chemically enriched for oligosaccharide sequences that confer high heparin cofactor II binding and correlate with high tumor uptake. A magnetic resonance (MR) imaging agent is prepared as self-assembling, 5-nm nanoparticles of Fe +3:deferoxamine (Fe:Df) bound by strong ion pairing to DS, which forms the outer molecular surface (Zeta potential - 39 mV). On intravenous (i.v.) injection, Fe:Df-DS rapidly (< 7 min) and selectively targets and transports at high capacity across the neovascular endothelium of large (2-cm) Dunning prostate R3327 AT1 rat tumors; releases from the abluminal surface, due to reversible binding of its multivalent, low-affinity (Kd 10 - 4 to 10- 5) oligosaccharide ligands; and progressively penetrates the interstitium from its initial site of high uptake in the well-perfused outer tumor rim, into the poorly perfused central subregion. By gamma camera imaging of 67Ga:Df-DS, the agent avoids normal site uptake and clears through the kidneys with a t1/2 of 18 min. A therapeutic formulation of DS-doxorubicin (DS-dox) is prepared by aqueous high-pressure homogenization of the drug and DS 435, which produces 11-nm nanoparticles of doxorubicin cores coated with DS (Zeta potential - 39 mV) that are stable to lyophilization. Microscopic analysis of tumor sections 3 h after i.v. injection shows much higher overall tumor fluorescence and deeper matrix penetration for DS-dox than conventional doxorubicin (dox): > 75 vs. < 25 μm between the nearest microvessels. DS-dox also results in enhanced tumor-cell internalization and nuclear localization of the drug. Therapeutic efficacies in established (250 ± 15 mg) MX-1 human breast tumor xenografts at maximum tolerated doses (MTDs) are (control vehicle, dox, dox-DS) (a) median days to 7-fold tumor growth: 8.3, 25.6 (p = 0.0007), 43.2 (p = 0.0001); (b) complete 90-day tumor regressions: 0/10, 0/10, 4/10. These results demonstrate the potential to develop a novel class of carbohydrate-targeted neovascular transport agents for sensitive, high-resolution (100-μm) MR imaging and improved treatment of larger sized human tumor metastases.
KW - Dermatan/carbohydrate carriers
KW - Doxorubicin nanoparticles
KW - MR imaging polymers
KW - Neovascuar targeting
KW - Tumor penetration
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U2 - 10.1016/j.jconrel.2005.09.022
DO - 10.1016/j.jconrel.2005.09.022
M3 - Article
C2 - 16290245
AN - SCOPUS:28444494693
SN - 0168-3659
VL - 109
SP - 222
EP - 235
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1-3
ER -