Molecular Targeted α-Particle Therapy for Oncologic Applications

Abstract

OBJECTIVE A significant challenge facing traditional cancer therapies is their propensity to significantly harm normal tissue. The recent clinical success of targeting therapies by attaching them to antibodies that are specific to tumor-restricted biomarkers marks a new era of cancer treatments. CONCLUSION In this article, we highlight the recent developments in α-particle therapy that have enabled investigators to exploit this highly potent form of therapy by targeting tumor-restricted molecular biomarkers.

Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3–Targeted Liposomes

“…To target our liposomes to GBM and associated vasculature, we conjugated a novel small molecule integrin antagonist (IA) that has been shown to target α v β 3 with a high affinity and a more optimal biodistribution compared to peptides (Figure 1A). We used standard DOTA chelation methods to radiolabel our targeted liposome with 225 Ac, as we previously reported (Figure 1B) (23,24). Our radiolabeled 225 Ac-IA-TL demonstrated uniform size and radiochemical purity (RCP) of 99.6% (Figure 1C).…”

“…Actinium ( 225 Ac) is effective for use in such strategies due to its 10 day half-life and the release of four α-particles upon its decay (23). Targeting α-particles towards tumor specific cell surface receptors can spare healthy brain tissue surrounding tumors (24). While we and others have demonstrated the potential of using targeted β-emitting radiotherapy (25), its relatively long range energy and significantly lower killing potential make β-emitting radioisotopes less attractive than α-particle emitters in resistant brain cancers that exist in the immediate vicinity of normal brain.…”

Automated cassette-based production of high specific activity [ 203/212 Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer

“…, improved relative biological effectiveness; RBE). (Sgouros, 2008; Sgouros et al, 2010; Sgouros et al, 2011; Hobbs et al, 2014; Macklis et al, 1988; Humm and Chin, 1993; Hauck et al, 1998; McDevitt et al, 1998; Behr et al, 1999; Behr et al, 2001; Jurcic et al, 2002; Akabani et al, 2003; Miao et al, 2005; Zalutsky, 2006; Sgouros, 2008; Sgouros and Song, 2008; Sgouros et al, 2010; Sgouros et al, 2011; Kim and Brechbiel, 2012; Elgqvist et al, 2014; Hobbs et al, 2014; Kratochwil et al, 2014; Wadas et al, 2014; Kratochwil et al, 2016a; Kratochwil et al, 2016b) For example, recent studies in patients with advanced-stage castration-resistant metastatic prostate cancer provide compelling evidence that α-therapy (using [ 225 Ac]PSMA617) has the potential to deliver a significantly more potent anti-cancer effect compared with β-therapy (using [ 177 Lu]PSMA617). (Kratochwil et al, 2016a; Kratochwil et al, 2016b) Numerous other studies demonstrate the potential of α-emitters for cancer therapy using radionuclides 225 Ac, 212 Bi, 213 Bi, and 211 At.…”

Multiplexed imaging for diagnosis and therapy

“…Of these, 'theranostic pair' radionuclides, comprised of a positron-or γ-emitting diagnostic nuclide and an α-, β --, or Auger/conversion-electron-emitting therapeutic complement (such as the isotopologues 64/67 Cu, 86/90 Y and 44/47 Sc or the chemically similar analogues The high linear energy transfer (LET) of α particles concentrates the high cytotoxic potential of α-emitting radionuclides (such as 225 Ac, 211 At or 213 Bi) within several cell diameters. This has stimulated intense interest in targeted alpha therapy (TAT) for micrometastatic lesions, leukaemia and adjuvant radiotherapy, wherein extended attenuation tracks of β -radiation reduce therapeutic efficacy and increase non-target toxicity [236][237][238][239] . In clinical therapy of refractory neuroendocrine liver metastases after B* immediately decays via α-emission, simultaneously inducing a high LET and a 7 Li recoil.…”