Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer-90Y conjugates in treatment of prostate tumors

https://doi.org/10.1016/j.nucmedbio.2013.12.002Get rights and content

Abstract

Introduction

The treatment of prostate cancer using a radiotherapeutic 90Y labeled N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer can be enhanced with localized tumor hyperthermia. An 111In 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 90Y 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 111In for imaging or 90Y 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 90Y HPMA copolymer conjugates. Histological analysis confirmed treatment efficacy and safety.

Conclusion

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.

Introduction

Prostate cancer is the most frequently diagnosed cancer in the U.S. [1]. Typically this disease affects men in their later years of life. With early screening the majority of patients can be appropriately treated with much success. However, it remains difficult to treat when the cancer is found in late or advanced stages. Treatment options typically start with surgical resection followed by hormone therapy, chemotherapy, biologic therapy or radiation therapy. Each of these treatments can cause distal or local adverse effects that can lead to lesser quality of life. Therefore, there remains a need to develop novel methods to treat prostate cancer that minimize the potential for side effects.

Macromolecular systems for delivery of therapeutics have been shown to passively target the tumor tissue via the enhanced permeability and retention (EPR) effect [2]. Leaky vasculature from angiogenesis due to the rapid tumor growth generates increased extravasation rates of macromolecules within the tumor region. Macromolecules do not easily diffuse from the normal vessels because the gaps in vascular walls are largely tight and intact. Evidence suggests that increased concentrations of these delivery systems containing therapeutics improve the treatment of cancer [3], [4].

The use of radionuclides for imaging and as radiotherapeutics has been shown to be effective in the diagnosis and treatment of many cancer types [5]. Yet, radiotherapeutics for cancer treatment have had limited application. This is in part due to insufficient localization and the non-specific uptake of radionuclides in the patient causing undesirable non-targeted tissue damage from radiation exposure. Several clinically approved radionuclides for therapy are conjugated to macromolecular tumor targeting monoclonal antibodies (MoAbs) in order to target only the specific diseased tissue [6]. However, tumor targets are heterogeneous in various patients and within individual tumors due to a variety of expression levels of the targeted antigen. One other shortfall of targeted delivery using MoAbs is that the target receptor is rarely only expressed on the targeted disease tissue which may lead to increased uptake in nonspecific tissues thereby increasing the chance of treatment related toxicity. There remains a need to target tumors using other macromolecular systems.

Use of water-soluble polymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) is one potential method to increase radiotherapeutic accumulation in the tumor [7], [8], [9]. HPMA copolymers are ideal macromolecular carriers for radionuclide delivery because of their ability to be synthesized in a size controlled manner and presence of a variety of comonomers available to incorporate drugs, imaging agents or tumor targeting ligands [9], [10], [11], [12]. Because of their macromolecular nature they are also able to passively target tumors via the enhanced permeability and retention (EPR) effect [2]. However, the delivery of HPMA copolymers and other macromolecules via the EPR effect has been variable from patient to patient [13]. Therefore, other methods must be considered to increase localization within the tumor.

Previous studies have shown the advantage of localized hyperthermia to increase HPMA copolymer conjugate localization and efficacy in treating prostate tumors [14], [15], [16]. Hyperthermia can be easily controlled and localized using plasmonic photothermal therapy (PPTT) [17]. PPTT uses the surface plasmon resonance of gold nanorods (GNR) when activated by the appropriate wavelength of light for controlled activation of heat [17]. Delivery of GNRs to the tumor is also based on passive accumulation and once localized to tumors can be irradiated by laser to augment the localization of subsequently injected polymer therapeutics [15].

The central hypothesis of this work is that by using localized hyperthermia with gold-nanorod-mediated plasmonic photothermal therapy, it is possible to enhance the delivery of HPMA copolymer-yttrium 90 conjugates to prostate tumors and improve radiotherapeutic efficacy. The overall design of the copolymer system described in this work includes side chain conjugated 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for chelation of either 111In for imaging of the biodistribution of the HPMA copolymers after hyperthermia treatment, or 90Y for radiotherapeutic treatment of the tumor. 90Y is a pure beta emitting isotope which is not an ideal imaging agent for γ-ray detection. Nuclear medicine techniques such as single photon emission computerized tomography (SPECT) offer relatively high resolution and quantitative images [18], [19]. Therefore imaging of HPMA copolymer 111In using SPECT should provide more detailed information as to the quantity and kinetics of tumor localization and enable correlation of such localization with therapy. Correlation performed in this study between these two conjugates can give us a potential personalized therapy for use in treating prostate cancer.

Section snippets

Chemicals

N-(3-Aminopropyl)methacrylamide hydrochloride (APMA) was acquired from Polysciences (Warrington, PA). 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxysuccinimide ester) (DOTA-NHS-ester) was obtained from Macrocyclics (Dallas, TX). 2,2′-Azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) was obtained from Wako Chemicals (Richmond, VA). [90Y]YCl3 and [111In]InCl3 were obtained from the Intermountain Radiopharmacy (Salt Lake City, UT). All other reagents were

Results and Discussion

The overall goal for this study was to evaluate a polymer containing both an imaging agent and a radiotherapeutic in conjunction with localized hyperthermia. The polymer was designed to reduce non-specific uptake, allow urinary clearance and assure sufficient uptake within the tumor mass. Characteristics of the copolymers are shown in Table 1. A polymer of less than 45 kDa was desired in order to minimize the lifetime of the HPMA copolymer in the body [2]. The DOTA content was expected to be 10 

Conclusion

The HPMA copolymers radiolabeled with 90Y for combination radiotherapy and hyperthermia were found to be effective in treatment of prostate tumors in a mouse model. HPMA copolymers were successfully monitored by SPECT imaging for biodistribution effects related to hyperthermia. The radioactive treatment was found to be primarily accumulated in the tumor. Histological examination of the various organs did not show evidence of any radioactive related toxicity. Overall, the conjugates were proven

Acknowledgments

The authors would like to thank the Small Animal Imaging Core Lab at the University of Utah for their assistance in performing the SPECT/CT imaging and analysis in these experiments. We would also like to thank Dr. Lawrence McGill of ARUP Laboratories for his assistance in examining the histology results.

References (33)

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    Citation Excerpt :

    Despite the gentle growth of tumor volume, the therapeutic effect of dual PTT/PDT was considerably better than PDT. GNR-mediated hyperthermia was also applied in enhancing the radiotherapeutic efficacy of HPMA copolymer-90Y in treatment of prostate tumors [265]. The analysis of SPECT images showed that hyperthermia had significantly increased the accumulation of HPMA copolymer-111In in the tumor.

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1

Present address: Department of Materials, Imperial College London, London, SW7, 2BP, United Kingdom.

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