Nanoparticle loaded stem cells and their use in mri guided hyperthermia

Abstract

The present invention provides stem cells loaded with bi-functional magnetic nanoparticles (nanoparticle-loaded stem cells (NLSC)) that both: a) heat in an alternating magnetic field (AMF); and b) provide MRI contrast enhancement for MR-guided hyperthermia. The nanoparticles in the NLSC are non-toxic, and do not alter stem cell proliferation and differentiation, the nanoparticles do however, become heated in an alternating magnetic field, enabling therapeutic applications for cancer treatment. NLSC can deliver hyperthermia to hypoxic areas in tumors for sensitization of those areas to subsequent treatment, thus delivering therapy to the most treatment-resistant tumor regions. The heating of diseased tissue either results in direct cell killing or makes the tumor more susceptible to radio- and/or chemotherapy. The NLSC of the present invention can be used for MR image-guided hyperthermia in oncology, in stem cell research for cell tracking and heating, and for elimination of mis-injected stem cells.

1 . A method for treatment of cancer in a subject comprising:
 a) obtaining NLSC comprising a bi-functional magnetic nanoparticle;   b) administering to the subject, an effective amount of the NLSC;   c) allowing sufficient time for the NLSC to localize to the tumor;   d) detecting the tumor by imaging the NLSC at the tumor through MRI; and/or   e) applying a sufficient amount of an alternating magnetic field (AMF) to the subject such that the NLSC will heat the tumor in the subject when exposed to an alternating magnetic field and sensitize the tumor to further treatment.   
     
     
         2 . The method of  claim 1 , wherein the bi-functional magnetic nanoparticle comprises bionized nanoferrite (BNF) or another magnetic nanoparticle with iron content of greater than 50% (w/w), wherein the particle a) is forming a single magnetic domain b) is thermotherapeutic agent, and c) wherein the surface of the nanoparticle forms the biocompatible coating. 
     
     
         3 . The method of  claim 1 , wherein the NLSC comprises stem cells that are either autologous or allogenic in origin. 
     
     
         4 . The method of  claim 3 , wherein the stem cells are autologous, and selected from the group consisting of: a) cells derived from circulation (endothelial progenitor cells); b) cells derived from BM; and c) cells obtained from cell banks (including stem cells from amniotic fluid, umbilical cord, cord blood, placenta, and autologous hESC lines). 
     
     
         5 . The method of  claim 3 , wherein the stem cells are allogeneic, and selected from the group consisting of: a) cells derived from non-embryonic tissues (“adult” stem cells); and b) cells derived from hESC lines from in vitro fertilization (IVF) embryos (human pluripotent cell lines, iPSC, trans-differentiated SC (including stem cells derived from fat, gut, liver, and other tissues). 
     
     
         6 . The method of  claim 1 , wherein the route of administration of the NLSC to the subject is selected from the group consisting of: intravenous; intrathecal; local and intra-tumor injections; implants; systemic; parenteral; subcutaneous; intravascular; intramuscular; intraperitoneal; topical; transdermal; buccal; intravaginal; ocular; inhalation; depot injection; and devices. 
     
     
         7 . The method of  claim 1 , wherein the amount of NLSC administered to the subject is between about 1×10 3  to about 1×10 11  cells. 
     
     
         8 . The method of  claim 1 , wherein the time to allow the NLSC to localize to the tumor site is between about 3 days to about 10 days. 
     
     
         9 . The method of  claim 1 , wherein the AMF magnetic field strength administered to the subject is between about 500 Gauss to about 1500 Gauss. 
     
     
         10 . The method of  claim 9 , wherein the AMF magnetic field amplitude is between about 5 Oe to about 1000 Oe. 
     
     
         11 . The method of  claim 1 , wherein the tumor is a solid tumor. 
     
     
         12 . The method of  claim 11 , wherein the tumor is a primary tumor. 
     
     
         13 . The method of  claim 11 , wherein the tumor is a metastatic tumor. 
     
     
         14 . The method of  claim 1 , further comprising the step of administering a pharmaceutical composition comprising one or more chemotherapeutic agents before or after the NLSC are localized at the tumor site. 
     
     
         15 . The method of  claim 1 , further comprising the step of administering radiotherapy to the tumor after the NLSC are localized at the tumor site. 
     
     
         16 . A method for treatment of cancer in a subject comprising:
 a) obtaining NLSC comprising a bi-functional magnetic nanoparticle;   b) administering to the subject, an effective amount of the NLSC;   c) allowing sufficient time for the NLSC to localize to the tumor;   d) detecting the tumor by imaging the NLSC at the tumor through MRI; and/or   e) applying a sufficient amount of an alternating magnetic field (AMF) to the subject such that the NLSC will heat the tumor in the subject when exposed to an alternating magnetic field and sensitize the tumor to further treatment; and   f) administering an effective amount of a pharmaceutical composition comprising one or more chemotherapeutic agents.   
     
     
         17 . A method for treatment of cancer in a subject comprising:
 a) obtaining NLSC comprising a bi-functional magnetic nanoparticle;   b) administering to the subject, an effective amount of the NLSC;   c) allowing sufficient time for the NLSC to localize to the tumor;   d) detecting the tumor by imaging the NLSC at the tumor through MRI; and/or   e) applying a sufficient amount of an alternating magnetic field (AMF) to the subject such that the NLSC will heat the tumor in the subject when exposed to an alternating magnetic field and sensitize the tumor to further treatment; and   f) administering an effective amount of radiotherapy to the tumor.   
     
     
         18 . A method for treatment of cancer in a subject comprising:
 a) obtaining NLSC comprising a bi-functional magnetic nanoparticle;   b) administering to the subject, an effective amount of the NLSC;   c) allowing sufficient time for the NLSC to localize to the tumor;   d) detecting the tumor by imaging the NLSC at the tumor through MRI; and/or   e) applying a sufficient amount of an alternating magnetic field (AMF) to the subject such that the NLSC will heat the tumor in the subject when exposed to an alternating magnetic field and sensitize the tumor to further treatment;   f) administering an effective amount of a pharmaceutical composition comprising one or more chemotherapeutic agents; and   g) administering an effective amount of radiotherapy to the tumor.