Table 2.

Physical properties and pro/cons of therapeutic radionuclides studied for glioblastoma therapy

Isotope	Range (in vivo) (mm)	T ½ (h)	Paired Isotope	Pro's for GB TRT	Cons for GB TRT	Studies in GB
225Ac 100.0% ɑ	0.04-0.10	238.10	68Ga	• In vivo range optimal for recurrent/residual GB. • High LET/RBE efficient towards hypoxic GB areals. • DOTA-complexation-simple and universal (some peptides, small molecules and mAb-fragments). • T ½ allows transport; RIT compatible; ideal if no leakage from the target site (upon compound internalization).	• Relatively long T ½ + multiple alpha particles generated (rapid decay chain) → substantial 225Ac-based cytotoxicity 105. • Recoiled daughters may influence stability. • Not readily available worldwide.	C	Substance P (NK-1) 93
						P	E4G10 mAb (Cadherin 5) 452; IA-TLs (αvβ3 integrin) 453; Pep-1L (IL13RA2) 454
213Bi 2.2% α 97.8% β-	0.05-0.10	0.77	68Ga 44Sc	• In vivo range optimal for recurrent/residual GB. • High LET/RBE efficient towards hypoxic GB areals. • DOTA-complexation - simple and universal (some peptides, small molecules and mAb-fragments). • Short T ½ + gamma-energy combination efficient even upon lack of persistent internalization 105. • Availability: 225Ac-/213Bi-generators. • Energy (440 keV) allows for PK/D assays. • Optimal formulation for intratumoral injection or CED, highly localized radioactive decay versus low off target effects 130.	• Short T ½ compromises the residence time required in essential (infiltrating) GB cells, i.e. ratio between cell membrane coverage (receptor affinity) and time is key (Note: irrelevant for intratumoral injection or CED).	C	Substance P (NK-1) 105,114,241,242
211At 42.0% ɑ 58.0% EC	0.05 127	7.20 127	123I 76Br	• In vivo range optimal for recurrent/residual GB. • High LET/RBE efficient towards hypoxic GB areals. • Longer T ½ allows for multistep synthetic procedures and transport. • Daughter (211Po): emits KX-rays useful for sample counting and in vivo scintigraphic imaging 244. • Well-suited for intratumoral injection or CED, highly localized radioactive decay versus low off target (systemic) effects 130.	• Limited to mAb (smaller fragments). • Production exclusive to a rare 25-30 MeV cyclotron (± 30 sites worldwide). • Often low biological/chemical stability 455.	C	81C6 mAb G (tenascin-C) 244
						P	L8A4 mAB (EGFRvIII) 456
131I 97.2% β- 2.8% γ	0.80 127	192.00 127	✔	• In vivo range (long) efficient on the common GB type (bulky/heterogeneous/2.6-5.0 mm). • Good availability and relatively inexpensive. • Longer T ½ allows transport, compatible for RIT. • Well-understood radiochemistry; universally applicable (peptides, small molecules, mAb). • 10% gamma emission makes it a theranostic (clinical SPECT - or gamma cameras widespread application for patient dosimetry) 260.	• Limited SPECT imaging capacity (suboptimal quantitative imaging); poor spatial resolution (high energy collimators/thick crystal detectors setup). • Radiolabeled proteins degrade rapidly when internalized into tumors; recurrence of [131I]iodo-tyrosine and 131I-activity in the blood pool → thyroid toxicity plausible.	C	81C6 mAb (tenascin-C) 98,208,209,446 BC-2/4 mAb (tenascin-C) 204,207 chTNT-1/B mAb (DNA-histone H1) 236-238 TM601 239 Phenylalanine (IPA) 458
						P	L19SIP (Fibronectin) 459,460 PARPi (PARP1) 280 I2-PARPi (PARP1) 43 L8A4 mAB (EGFRvIII) 461,462 IPQA (EGFR) 359 Hyaluronectin glycoprotein 463 Phenylalanine (IPA) 464-466
90Y 100.0% β-	5.30 127	64.10 127	68Ga 86Y 111In	• In vivo range (long) efficient on the common GB type (primary/bulky/heterogeneous/≥ 3 cm). • DOTA-complexation-simple and universal (some peptides, small molecules and mAb-fragments). • Stably retention by GB cells even after endocytosis 108. • Emits highly energetic β-particles 108, ideal for therapy of radioresistant GB. • Longer T ½ allows transport, compatible for RIT.	• Limited efficiency for minimal residual or recurrent GB: needs to be matched with GB tumor size to prevent off target (normal brain) toxicity. • Impractical for nuclear imaging, i.e. high activities (>300 MBq) required (only succeeded for microsphere-based therapies (SIRT) for treating liver tumours 162. • Limited dose administration (preventing nephrotoxic and hematotoxic side effects).	C	Octreotide (SSTR) 59-61 Lanreotide (SSTR) 62 BC-2/4 mAb (tenascin-C) 467 Biotin 149 Substance-P 241
						P	Abegrin 468
177Lu 100.0% β-	0.62-2.00 127	158.40 127	✔ or 68Ga 89Zr 99mTc	• Isotope characteristics capable of affecting GB lesions typically ⌀ < 3 mm diameter 474. • Longer T ½ is compatible with the PK/D and radiochemistry for mAb and proteins 127. • Fairly straightforward conjugation chemistry 127,470. • Good availability and low cost 469. • Emission of low-energy gamma - true theranostic 127. • [177Lu]Lu-mAb: higher specificity index (i.e. less non-specific cell killing) than analogous [90Y]Y-mAb 156.	• Moderately nephrotoxic and hematotoxic (< 90Y).	C	Substance-P (NK-1) 241 PSMA-617 84,86
						P	6A10 Fab (CAXII) 471 CXCR4-L (CXCR4) 472 VH-DO33 (LDLR) 473 2.5D/2.5F (Integrin) 474 L8A4 mAb (EGFRvIII) 475,476 IIIA4 mAb (EphA3) 77
188Re 100.0% β-	5.00-10.8	16.98	✔	• In vivo range (long) efficient on the common GB type (primary/bulky/heterogeneous/≥ 3 cm). • Readily available and inexpensive via 188W-/188Re-generator (carrier-free, high specific activity). • Gamma emission suitable for imaging (better image quality than 186Re).	Unfavorably-low energy characteristics 114. Radioactive source material for generator production: Reactor-based 188W production only in 2-3 reactors worldwide 482.	C	Nimotuzumab (EGFR) 248,483
						P	PEG-nanoliposome 440 BMSC implantation 479 Nanocarriers (CXCR4) 150 Lipid nanocapsules 480,481 Microspheres in fibrin glue gel 482 U2 DNA aptamer (EGFRvIII) 483,484
64Cu 18.0% β+ 39.0% β- 42.5% EC 0.5% γ	β 1.00 AE 0.13 485	12.70	✔	• Readily available. • Radiometal complexation well understood and universally applicable (most peptides/mAb/small molecules and nanoparticles). • Combined β+/β- emission makes it a true theranostic. • Radioisotope salts ([64Cu]CuCl2): the higher intratumoral accumulation of Cu correlates with overexpression of human copper transporter 1 (hCTR1) in GB cancer cells 486. • AE cascade from EC are considered high LET radiation with ~ 2 keV of average energy 485.	• Radiometal complexation can be unstable in vivo 486,487. • Lack of radiometal-specific chelating agents. • Radiation dosimetry: complex decay scheme affects absorbed dose from high-LET AE emissions 485.	P	CuCl2 54,75,184,498,489 Cyclam-RAFT-c(RGDfK)4 (αvβ3 integrin) 54 Pep-1L (IL13RA2) 454 ATSM (Hypoxia) 75 IIIA4 mAb (EphA3) 77 TNYL-RAW (EPHR) 40 1C1 mAb (EphA2) 362
67Cu 100.0% β-	0.20	62.40	✔ or 64Cu	• Treats small residual or recurrent GB lesions (⌀ ≤5 mm) 56. • Combined β+/β- emission makes it a true theranostic. • Supports SPECT imaging of patient dosimetry 490. • Biochemistry of copper is well studied; radiometal complexation well understood and universally applicable (most peptides/mAb/small molecules and nanoparticles) 56,491. • No off-target toxicity reported (bone or organs). • Radioisotope salts ([67Cu]CuCl2): the higher intratumoral accumulation of copper correlates with overexpression of human copper transporter 1 (hCTR1) in GB cancer cells 486.	• Large amounts rarely available; limits research and clinical trial design 491.	P	RAFT-c(RGDfK)4 (αvβ3 integrin) 56
125I 100.0% EC	0.002	1425.60	111In	• Isotope applicable in brachytherapy for GB. • Systemic immune-therapy well tolerated 163.	• Very long T½ may impose limitations for clinical use (radioprotection, therapeutic efficacy, slow dose rate). • Gamma emission energy not siutable for nuclear imaging. • Range and energy is not effective for heterogeneous radioresistent GB.	C	425 mAb (EGFR) 163,166,167,227,492,495
						P	L8A4 mAB (EGFRvIII) 499,500 UdR 165,496 806 mAb (EGFRvIII) 363
123I 97.0% EC3.0% γ	0.001-0.01	13.20	✔	• Short T ½ and gamma emission energy suitable for scintigraphic imaging in vivo. • More suitable choice for potential use in RIT (as to 125I) 156.	• Not widely available (<131I). • T ½ is not compatible for PK/D investigation.	P	MAPi (PARP1) 382
111In 100.0% EC	0.04	67.20	✔	• Characteristic suitable for in vitro GB studies. • True theranostic: gamma emission energy allows scintigraphic imaging in vivo.	• Complexation chemistry required; incorporation kinetics slow for radiolabeling mAb (no direct radiometal conjugation).	P	GA17 Ab (α3 integrin) 497 806 mAb (EGFRvIII) 497

(✔) Theranostic radionuclide, (*) human case study, convection enhanced delivery (CED), pharmacokinetic/dosimetry studies (PK/D), glioblastoma (GB), radioimmunotherapy (RIT), oxygen enhancement ratio (OER), polyethylene glycol (PEG), Bone-marrow mesenchymal stem cells (BMSC), electron capture (EC), linear energy transfer (LET), Auger electron (AE), single-photon emission computed tomography (SPECT), physiological half-life (T ½ ).