Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer-90Y conjugates in treatment of prostate tumors.
BACKGROUND
The treatment of prostate cancer using a radiotherapeutic (90)Y labeled N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer can be enhanced with localized tumor hyperthermia. An (111)In labeled HPMA copolymer system for single photon emission computerized tomography (SPECT) was developed to observe the biodistribution changes associated with hyperthermia. Efficacy studies were conducted in prostate tumor bearing mice using the (90)Y HPMA copolymer with hyperthermia.


METHODS
HPMA copolymers containing 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthesized by reversible addition-fragmentation transfer (RAFT) copolymerization and subsequently labeled with either (111)In for imaging or (90)Y for efficacy studies. Radiolabel stability was characterized in vitro with mouse serum. Imaging and efficacy studies were conducted in DU145 prostate tumor bearing mice. Imaging was performed using single photon emission computerized tomography (SPECT). Localized mild tumor hyperthermia was achieved by plasmonic photothermal therapy using gold nanorods.


RESULTS
HPMA copolymer-DOTA conjugates demonstrated efficient labeling and stability for both radionuclides. Imaging analysis showed a marked increase of radiolabeled copolymer within the hyperthermia treated prostate tumors, with no significant accumulation in non-targeted tissues. The greatest reduction in tumor growth was observed in the hyperthermia treated tumors with (90)Y HPMA copolymer conjugates. Histological analysis confirmed treatment efficacy and safety.


CONCLUSIONS
HPMA copolymer-DOTA conjugates radiolabeled with both the imaging and treatment radioisotopes, when combined with hyperthermia can serve as an image guided approach for efficacious treatment of prostate tumors.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA.
Brandon
B
Buckway
Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
Nick
N
Frazier
Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
Adam J
AJ
Gormley
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA.
Abhijit
A
Ray
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: hamid.ghandehari@pharm.utah.edu.
Hamidreza
H
Ghandehari
D000178:Acrylamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006046:Gold / Q000737:chemistry* / Q000627:therapeutic use*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D051379:Mice; D043942:Nanotubes; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D015899:Tomography, Emission-Computed, Single-Photon; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
D000178:Acrylamides; D006573:Heterocyclic Compounds, 1-Ring; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D006046:Gold; C032976:N-(2-hydroxypropyl)methacrylamide
(111)In; (90)Y; HPMA; Hyperthermia; Radiotherapy; SPECT imaging