A perspective on the radiopharmaceutical requirements for imaging and therapy of glioblastoma

Abstract

Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular.

Keywords: PET SPECT imaging; glioblastoma; radiochemistry; targeted radionuclide therapy; theranostics.

Figure 1

Routine PET imaging in neuro-oncology. PET/CT techniques for neuropathologic imaging are dominated by radiopharmaceuticals focussing on altered glucose metabolism (desoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG)), amino acid metabolism (L-[¹¹C]-methyl-methionine ([¹¹C]MET), O-2-[¹⁸F]fluoroethyl-L-tyrosine ([¹⁸F]FET), 3,4-dihydroxy-6-[¹⁸F]fluoro-L-phenylalanine ([¹⁸F]F-DOPA)), proliferation (3'-deoxy-3'-[¹⁸F]fluoro-thymidine [¹⁸F]FLT)), tumoral hypoxia sensing ([¹⁸F]fluoro-misonidazole ([¹⁸F]FMISO), [¹⁸F]fluoro-azomycin arabinoside ([¹⁸F]FAZA)), and lipid metabolism ([¹¹C]choline ([¹¹C]Cho), [¹⁸F]fluoroethyl-choline ([¹⁸F]FCho)). Abbreviations: High affinity choline transporter (CHT), choline kinase (CHK), equilibrative nucleoside transporter (ENT), 2'-fluoro-2'-deoxy glucose-6-phosphate (FDG-6-P), glucose transporter (GLUT), hexokinase (HK), nitroreductase (NTR), partial pressure of oxygen (pO₂), Na+-independent plasma membrane amino acid transport (System L), thymidine kinase (TK). Adapted with permission from , copyright 2017 Codon Publications.

Figure 2

Overview of current clinical and preclinical targeted radionuclide therapy studies in glioblastoma. Abbreviations and footnoted content: Anaplastic astrocytoma (AA), convection enhanced delivery (CED), glioblastoma (GB), recurrent (rec), deoxyribonucleidic acid (DNA), monoclonal antibody (mAb), targeted radionuclide therapy (TRT), (*) human case study ,,,-,,,,,,,,,,,,,-,,,,,-,,,,,,,-,-,,,,,,,,,,,,,,-.

Figure 3

Mechanisms for transport of radiopharmaceuticals across the blood-brain barrier. Abbreviations: convection enhanced delivery (CED), cell-penetrating peptides (CPP), monoclonal antibody (mAb), P-glycoprotein (P-gp), tight-junction (TJ).

Figure 4

Convection enhanced delivery (CED) of a radiopharmaceutical. CED is a strategy whereby a drug is delivered directly into the tumor parenchyma via implanted catheters. Catheters are coupled with a pump to provide continuous positive-pressure microinfusion. Unlike systemic therapy, CED bypasses the blood-brain barrier (BBB) therefore making drug distribution relatively independent of its molecular charge and size .

Figure 5

Strategies to enhance blood-brain barrier (BBB) penetration. (1) harnessing the homing ability of certain stem cells, (2) low affinity to efflux pumps or co-administration with inhibitors of efflux pumps, (3) targeted irradiation, (4) a combination of low-intensity focused ultrasound (FUS) pulses and circulating microbubbles, (5) infusion of hypertonic solutions, such as mannitol or vasodilatator and bradykinin analog RMP-7 and (6) nanoparticle-mediated delivery systems .

Figure 6

Characteristics of β-emitting radionuclides versus α particle- and Auger electron-emitting radionuclides. Abbreviations: Linear energy transfer (LET), relative biological effectiveness (RBE), specific activity (SA) ,,,.

Figure 7

Illustration of glioblastoma (GB) cell invasion at the tumor lesion rim in an orthotopic F98 GB rat model. (A) Contrast enhanced T1-weighted magnetic resonance image. Higher contrast leakage in the tumour rim and in the centre of the tumour corresponds to central tumour necrosis. (B) Hematoxylin & Eosin staining. (C) 4′,6-diamidino-2-phenylindole (DAPI) nuclear staining of another F98 GB rat brain section. (D-E-F) Tumour cells infiltrating the surrounding normal brain tissue, see arrows. (E-F) Abundant blood vessels in the perinecrotic tumour, see dashed arrows. Adapted with permission from , copyright 2014 Journal of Neuro-Oncology.

Figure 8

Contrast-enhanced T1-weighted brain magnetic resonance imaging (MRI) of glioblastoma (GB). (A) Common presentation of bulky bifrontal GB with irregular (nodular) contrast enhancement surrounding central tumor necrosis. (B) Illustration of radiation necrosis appearing as multiple foci of pathological contrast enhancement, periventricular in the left and right frontal lobe as well as anteriorly and posteriorly in the corpus callosum. (C) Nodular contrast-enhancement in a GB tumor on T1-weighted brain MRI pre-resection. (D) New irregular contrast-enhancement at the resection cavity at 1 year after a complete surgical resection reflecting tumor recurrence or treatment-related changes which have a similar appearance on MRI .

Figure 9

Quality data required for translation of a radiopharmaceutical. The sequential approach to an adequate validation of radiopharmaceuticals is illustrated; certain tests and validation steps may not depend on each other and are therefore often performed in parallel. Abbreviated and footnoted content: Absorption Distribution Metabolism Excretion (ADME), good manufacturing practice (GMP), molar activity (MA), specific activity (SA), glioblastoma (GB), positron emission tomography (PET), single-photon emission computed tomography (SPECT). ($) i.e.: target validation, (*) a requirement only for the validation of therapeutic radiopharmaceuticals, (#) not required for microdosing e.g. radiopharmaceuticals (<100 µg); e.g. genotoxicity, safety pharmacology, repeat dose toxicity. (+) radiolabelling may alter the pharmacological characterisation of the targeting molecule; pharmacological effects should be ruled out at the anticipated clinical dose .

Figure 10

Future scenario: combined targeted radionuclide therapy of glioblastoma tumours. The prospective glioblastoma management will include practicing of various combinations of therapeutic tools. Abbreviated content: glioblastoma (GB), targeted radionuclide therapy (TRT), temozolomide (TMZ), external beam radiotherapy (EBRT), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT).

Figure 11

Summary of targeted radionuclide therapy of glioblastoma. Main consideration for the development of new radiopharmaceuticals for brain tumours, comparing three different radiolabelled vectors (small molecules, peptides and monoclonal antibodies (mAbs). Abbreviations and footnoted contents: Auger electron (AE), blood-brain barrier (BBB), convection-enhanced delivery (CED), cell-penetrating peptides (CPP), intravenous (IV), organs at risk (OAR), reticulo-endothelial system (RES), receptor-mediated transport (RMT), specific activity (SA), targeted radionuclide therapy (TRT), carrier-mediated transport (CMT), half-life (T1/2).