The Radioisotope

The size and presentation of the disease are both critical considerations when evaluating the most appropriate radionuclide for potential treatment. As disease does not present in an exclusive form, fractionation of both chemotherapeutics and external beam radiation are routine regimens. It logically follows that no single radionuclide is likely to address every therapeutic need. Unfortunately, isotope selection is also often driven by economic rather than biomedical considerations, which could negatively impact both pre-clinical and clinical trials. Ultimately, the limitations of the tar-

Radio- Type Half-life Emax (MeV) Mean range Imageable nuclide (mm)

131I 177Lu 153Sm 186Re

67Cu

225Ac 213Bi 212Bi

211At

212Pb

125I 123I

67Ga 195mPt

Auger Auger Auger, Auger

2.7 days 8.0 days

6.7 days 2.0 days

3.8 days

60.1 days

3.3 days 4.0 days

2.3 0.81 0.50 0.80 1.1 2.1 0.57 5.83 5.87 6.09 5.87 0.57 0.35 0.16 0.18 0.13

2.76 0.40 0.28 0.53 0.92 2.43 0.6 0.04-0.1 0.04-0.1 0.04-0.1 0.04-0.1 0.6 0.001-0.02 0.001-0.02 0.001-0.02 0.001-0.02

No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes No

Table 6.2. Therapeutic radio-nuclides (Milenic et al. 2004)

Auger Auger Auger, Auger

H

□ p-emitters □ Auger electrons a-emitters

He

U

Be

B

c

N

O

F

Ne

KB

Mg

M

SI

P

S

a

Ai

K

CS

s:

H

V

Cr

Ml

Fe

CO

141

cu

21

G3

Ge

AS

se

Br

Kl

RD

sr

Y

Zt

NO

Me

TE

Rj

nh

Pd

Cd

n

sn

St)

Te

1

X=

CS

Sa

U

HI

~B

'.V

Re

OS

tr

Ft

Au

Hg

TI

Pb

Ei

Fo

Al

ai

Fl

Ra

AC

Ce

Fr

Pm

5m

Eu

Cd

TE

oy

MO

El

Tm

Yt>

Lu

in

Pa

U

Mp

PU

Am

Cm

EK

er

ES

FBI

MO

MO

Fissionable

Fig. 6.2. A periodic table highlighting elements of interest for nuclear medicine and radiation oncology applications color coded by emission type. With the exception of the halogens, the majority of the medically relevant radionuclides require chelating chemistry for attachment to proteins or other targeting vehicles. Specific radionuclides from cyclotrons or reactors may be obtained in pure form for longer-lived isotopes, or as the products of generator elutions for short-lived isotopes (Milenic et al. 2004)

geting vehicles and radionuclides will be more clearly defined and a rational plan for future clinical trials will follow.

Some of the critical considerations for successful targeted radiation are those variables pertaining to the radiation including emission type, energy and range of emission, and the radionuclide half-life. A sampling of available isotopes (Table 6.2) results in several options comprising (Fig. 6.2) three types of emission: a- or (3-particles, or Auger electrons (Srivastava and Dada-chova 2001). Historically, P-emitters have received the greatest attention.

The emission path lengths of P-emitters are relatively long, yet sparse, with an average range of 275 nm and a maximum range of 500-600 nm (for 90Y). P-emitters have a relatively low linear energy transfer (LET) and thus energy deposition takes place some distance from the actual decay event (Humm 1986). Therapeutic benefit results from "crossfire" where the targeted cell is not necessarily the effective target of the decay event as there is a substantial amount of irradiation of neighboring receptor-negative tumor cells as well as potentially normal cells. As such, some of the limitations of P-emitters are clearly illustrated: P-emitters cannot adequately address the treatment of small tumor burdens including single cell metastatic disease (Humm 1986). However, one great advantage of P-emitters includes the ability to bypass tumor antigen heteroge neity through the differential penetration of the labeled mAb. The ability to uniformly target an entire lesion becomes possible when the particle emission range exceeds the radius of the targeted lesion (O'Donoghue et al. 1995).

Convenience, availability, and familiarity with radiolabeling chemistry have traditionally supported the use of the iodine isotopes such as 131I. Other clinically relevant (3-emitters include 90Y, 67Cu, 186Re, and more recently 177Lu, with others having either been investigated or proposed (vide infra). Discussion of these will be limited here except to state that emission energy and half-life requirements can be met with a small cross-section of isotopes that are already available (Humm 1986). Direct radio-iodination of tyrosine moieties of the mAb has dominated this field. However, the convenience of this method is overshadowed by the rapid deiodination of the protein post-cellular inter-nalization - a characteristic bypassed when radio-metals are used (Mattes et al. 1997; Zhang et al. 2001). 90Y has a pure |3-emission which delivers ~4.5 times more radiation per mCi to a tumor than does 131I. The greater emission range (typically 1-10 mm) of 90Y means that the maj ority of the decay energy is deposited in tumors with a diameter of at least 1 cm. Unlike 1311,90Y lacks an imageable emission, thereby requiring dosimetry with mIn for y-scintigraphy and single photon emission computed tomography (SPECT). However, 90Y and mIn have different chemistries and as such this approach may not prove sufficiently accurate. Furthermore, the longer emission range associated with 90Y may result in a significant degree of irradiation of normal surrounding tissue. Notably myelosuppression, with a nadir at approximately 2 weeks post-radioim-munotherapy (RIT), due to longer range -emissions that occur during circulation, is a consistent dose limiting toxicity (Knox and Meredith 2000).

177Lu and 67Cu, lower-energy (3-emitters with much shorter ranges, may offer distinct advantages for treating smaller lesions and micrometastases. 177Lu and 67Cu have both been evaluated in clinical trials for therapeutic efficacy (Mulligan et al. 1995; Alvarez et al. 1997; O'Donnell et al. 1999). Both possess imageable y-emissions permitting determination of disease extent, calculation and prediction of dosimetry, and monitoring of therapeutic efficacy. It should be noted that this same -emission contributes to normal tissue toxicity, illustrating the desires and compromises that must be balanced in radionuclide selection. Scientists are also beginning to consider the fact that different -particle combinations may work synergistically. Notably, a successful 177Lu/90Y combination radionuclide therapy has been reported (de Jong et al. 2005). Despite these concerns and limitations, use of -emitters continues to dominate pre-clinical and clinical trials. Therefore, it is of no surprise that Zevalin and Bexxar, the first radiolabeled monoclonal antibodies to receive FDA approval, are both armed with -emitters.

The list of -emitting radionuclides qualified for targeted radiation therapy is short owing largely to half-life constraints. Presently 212Bi, 213Bi, and 211At are actively being studied (McDevitt et al. 1998; Hassfjell and Brechbiel 2001). Additionally, 225Ac (Table 6.2) has shown promise despite concerns about the lengthy half-life and trafficking of free decay products in vivo (McDevitt et al. 2001). The bismuth radioisotopes, 212Bi and 213Bi, are available from generators based on 224Ra and 225Ac, respectively, and decay via branched pathways that results in both a- and (3-emissions. Thirty-two percent of 212Bi decay includes a high energy y-emission which 213Bi lacks. As such 213Bi is generally considered a more attractive candidate for RIT (Geerlings 1993). Protocols analogous to radio-iodination chemistry were initially applied for 211At. However, this has been supplanted with linking reagents that address the inherent instability of direct tyrosine protein labeling with this isotope (Vaidyanathan and Zalutsky 1996).

As a group, the -emitters have high-energy particles (4-9 MeV), which travel relatively short distances (40-100 |im). They are characterized by dense emission path lengths of high LET which is approximately 400 times greater than that of -emitters (80 vs 0.2 keV/|im), with energy deposition taking place immediately at the decay site (Fig. 6.2) (Humm 1986). Alpha-particle radiation is exquisitely cytotoxic at a dose rate of 1 cGy/h (Kurtzman et al. 1988). The short emission range limits their use to a complementary scale of disease. Most, if not all, of the therapy results from the direct emission of the a-particle, which makes the targeted cell and immediate neighboring cells the effective targets. In contrast to -emitters, a very low number of nuclear traversals (approximately 1-3) are all that is required to kill a cell with an a-emitter, as seen in Fig. 6.3 (Humm 1986). The inherent physical limitation of a-emitters is their relatively short physical half-life. This, coupled with a short emission path length, has generally been thought to limit their use to

Fig. 6.3. A comparison of the path lengths and density of emission tracks of a- vs P--particle emissions is depicted. The |3--particle emissions occur in a spectrum of path lengths. The sparse energy track from these emissions is deposited over many cell diameters some distance from the decay event. The a-particle emissions occur at a discrete energy and path length resulting in high linear energy transfer. The dense energy track from these emissions is deposited directly from the decay event over only a few cell diameters, 50 - 80 |im in tissues (Milenic et al. 2004)

leukemias, highly vascularized tumors, and micro-metastatic disease in which optimal access, targeting time, and appropriate disease size converge. Avenues for future work include bone marrow purging for transplant conditioning and selective vasculature tumor targeting with the ultimate goal of total tumor eradication (Bethge et al. 2003; Thorpe and Derbyshire 1997). Adjuvant therapies and combination with ß-emitters may ultimately prove viable (Hassfjell and Brechbiel 2001; Hartmann et al. 1994).

Auger emitters such as 67Ga, 195mPt, 123I, and 125I (Table 6.2) have received the least attention due to the accepted premise that their extreme cytoxicity is limited by the prerequisite for the emissions to occur within the cell nucleus (Kassis et al. 1999). Auger electrons are extremely low-energy atomic orbital electrons that are emitted as an alternative to X-ray emission following electron capture, a form of ß- decay (Kassis et al. 1987; Kassis 2004). Auger-electron therapy is a useful strategy for specific tumor cell killing originating from subcellular (nm) ranges and highly localized energy deposition (106-109 cGy) in an extremely small volume (several nm3) around the decay site (Goddu et al. 1994). Auger electron emitters produce an array of reactive radicals (e.g., OH, H, e-aq,) similar to a-emitters. The estimated absorbed dose rate at the center of a cell delivered by 99mTc, 123I, mIn, 67Ga, and 201Tl is respectively 94,21,18, 74, and 76 times higher if the radioactivity is localized within the nucleus versus being on the cell membrane (Faraggi et al. 1994). In a revealing study, the therapeutic effects of an internalizing monoclonal antibody labeled with 1251,131I, mIn, or 90Y were directly compared (Behr et al. 2000). Both Auger emitters (125I and mIn) showed better therapeutic results than the |3--emitters. In addition, a trend towards better therapeutic results with the radiometals compared to radioiodine was demonstrated. The latter finding rationalized by the fact that radio-metals attached to antibodies are residualized intracel-lularly while radioiodinated antibodies undergo lyso-somal degradation to mono- or di-iodotyrosine that is rapidly released from cells. Despite the apparent limitation posed by a nuclear localization requirement, future studies may demonstrate that Auger emitters have a significant role in chemotherapeutics (Makrigiorgos et al. 1990; Michel et al. 2003).

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