Method for therapeutic administration of radionucleosides

Abstract

Methods are provided for the local radiotherapy of cancers such as locally invasive, advanced stage solid tumors, and normal tissues penetrated by processes of cancerous tissue, through administration of Auger-electron emitting radionucleoside analogs using high-flow microinfusion techniques (“convection-enhanced delivery”). Direct infusion under pressure, at flow rates in excess of at least about 0.5 microliters/min of the radionucleosides provides for their mass transport through tissue to a much higher degree than could be achieved by passive, unpressurized diffusion. The unique properties of these radionucleoside analogs that provide for surprisingly effacacious delivery by high-flow microinfusion include rapid clearance from tissues following local injection without the benefit of sustained high-flow microinfusion, rapid and complete clearance via the blood stream, poor permeation of barriers such as the blood-brain barrier, and a highly potent, non-selective, but very short range killing effect on cells that are undergoing DNA replication that incorporate radionucleosides into their chromosomes.

1 . A method of treating cancer, comprising administering via high-flow pressurized microinfusion a bioactive agent comprising an Auger-electron emitting radionucleoside or an analog or prodrug thereof directly to a volume of tissue comprising cancerous cells within the body tissue of a patient, the method comprising:
 (a) disposing at least one catheter within the tissue in proximity to the cancerous cells and not within a blood vessel; then,   (b) delivering under a pressure to the tissue through each catheter a solution or suspension comprising the bioactive agent, wherein the pressure is sufficient to maintain a flow rate of the solution or suspension into the tissue of at least about 0.5 μL/min, for a period of time.   
     
     
         2 . The method of  claim 1  wherein the Auger-electron emitting radionucleoside or analog comprises  77 Br,  80m Br,  123 I,  124 I,  125 I, or  211 At. 
     
     
         3 . The method of  claim 1  wherein the radionucleoside or analog comprises 5-[ 123 I]-iodouridine 2′-deoxyribonucleoside, 5-[ 124 I]-iodouridine 2′-deoxyribonucleoside, 5-[ 125 I]-iodouridine 2′-deoxyribonucleoside, 5-[ 77 Br]-bromouridine 2′-deoxyribonucleoside, 5-[ 80m Br]-bromouridine 2′-deoxyribonucleoside, 8-[ 123 I]-iodoadenine 2′-deoxyribonucleoside, 8-[ 124 I]-iodoadenine 2′-deoxyribonucleoside, 8-[ 125 I]-iodoadenine 2′-deoxyribonucleoside, 5-[ 77 Br]-bromoadenine 2′-deoxyribonucleoside, 5-[ 80m Br]-bromoadenine 2′-deoxyribonucleoside or 5-[ 211 At] astatouridine 2′-deoxyribonucleoside. 
     
     
         4 . The method of  claim 1  wherein the bioactive agent comprises an Auger-electron emitting nucleoside prodrug. 
     
     
         5 . The method of  claim 4  wherein the prodrug comprises a 3′- or 5′-phosphate or carboxylate ester of a deoxyribosyl or ribosyl moiety of the radionucleoside. 
     
     
         6 . The method of  claim 1  wherein in response to the delivering under pressure of the solution or suspension through each catheter, a spatial pressure gradient exists within the tissue and the solution permeates the tissue in response to the pressure gradient 
     
     
         7 . The method of  claim 1  wherein delivering under pressure comprises a temporal pressure profile of a solution pressure vs. time. 
     
     
         8 . The method of  claim 7  wherein the temporal pressure profile comprises a linear increase or decrease in pressure over time. 
     
     
         9 . The method of  claim 7  wherein the temporal pressure profile comprises a constant pressure over time. 
     
     
         10 . The method of  claim 7  wherein the temporal pressure profile comprises a stepwise increase or decrease in pressure over time. 
     
     
         11 . The method of  claim 7  wherein the temporal pressure profile comprises an exponential increase or decrease in pressure over time. 
     
     
         12 . The method of  claim 7  wherein the temporal pressure profile comprises an sinusoidal variation in pressure over time. 
     
     
         13 . The method of  claim 7  wherein the temporal pressure profile comprises any combination of constant, linear, stepwise, exponential, or sinusoidal pressure profile components. 
     
     
         14 . The method of  claim 7  wherein the temporal pressure profile is created using a system comprising a digitally controlled pump. 
     
     
         15 . The method of  claim 1  wherein the tissue comprises brain, head or neck tissues, esophagus, pancreas, intestines, bladder, ovary or prostate gland tissue or any tissue that is invaded by cancer cells. 
     
     
         16 . The method of  claim 1  wherein the cancerous cells comprise glioblastoma multiforme cells. 
     
     
         17 . The method of  claim 1  wherein the solution or suspension further comprises an emulsion, a liposome, a plurality of microparticles or nanoparticles, or any combination thereof. 
     
     
         18 . The method of  claim 1  wherein a concentration of the Auger-electron emitting radionucleoside or analog or prodrug thereof in the solution or suspension is about 1 picomolar to about 1 millimolar. 
     
     
         19 . The method of  claim 1  wherein the cancer is a brain cancer and the period of time is at least one hour. 
     
     
         20 . The method of  claim 1  wherein the period of time is about one week to about one year. 
     
     
         21 . The method of  claim 1  wherein the solution or suspension is delivered under pressure to the tissue continuously. 
     
     
         22 . The method of  claim 1  wherein the solution or suspension is delivered under pressure to the tissue intermittently. 
     
     
         23 . The method of  claim 1  wherein the at least one catheter is one catheter. 
     
     
         24 . The method of  claim 1  wherein the at least one catheter is two or more catheters. 
     
     
         25 . The method of  claim 1  wherein the cancerous cells are cells of an locally advanced stage solid tumor. 
     
     
         26 . The method of  claim 1  wherein the cancerous cells are cells of tumor processes penetrating volumes of non-cancerous tissue. 
     
     
         27 . The method of  claim 1  further comprising administration of a second anticancer agent. 
     
     
         28 . The method of  claim 1  further comprising administration of a medicament other than an anticancer agent. 
     
     
         29 . The method of  claim 1  further comprising, following step (b), delivering under pressure a physiologically-compatible solution that does not contain the Auger-electron emitting radionucleoside. 
     
     
         30 . The method of  claim 1 , further comprising, prior to step (a), 
       selecting a patient afflicted with an advanced stage solid tumor or a cancer wherein tumor processes have invaded surrounding non-cancerous tissue; then disposing the at least one catheter within the tissue in proximity to the cancerous cells and not within a blood vessel then delivering the solution or suspension comprising the bioactive agent under pressure to the tissue for the period of time. 
     
     
         31 . A method of assembly of a system adapted for practice of the method of  claim 1 , comprising connecting a source of a pressurized liquid to a catheter adapted for intratissue delivery of a liquid under pressure, wherein the pressurized liquid comprises the Auger-electron emitting radionucleoside or analog thereof.