Dermatan carriers for neovascular transport targeting, deep tumor penetration and improved therapy.
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 (K(d) 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 (67)Ga:Df-DS, the agent avoids normal site uptake and clears through the kidneys with a t(1/2) 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 microm 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-microm) MR imaging and improved treatment of larger sized human tumor metastases.
Ranney
David
D
Global BioMedical Solutions, Dallas, TX 75234, USA. globemed@comcast.net
Antich
Peter
P
Dadey
Eric
E
Mason
Ralph
R
Kulkarni
Padmakar
P
Singh
Onkar
O
Chen
Huagang
H
Constantanescu
Anca
A
Parkey
Robert
R
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000473:pathology; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003676:Deferoxamine / Q000737:chemistry; D003871:Dermatan Sulfate / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D019786:Gadolinium DTPA; D006493:Heparin / Q000737:chemistry; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051381:Rats
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D002241:Carbohydrates; D004337:Drug Carriers; D007502:Iron Chelating Agents; D003871:Dermatan Sulfate; D004317:Doxorubicin; D006493:Heparin; D003676:Deferoxamine; D019786:Gadolinium DTPA