Intraperitoneal injection is not always a suitable alternative to intravenous injection for radiotherapy

Cancer Biother Radiopharm. 2013; 28(4): 757-762

Dou S, Smith M, Wang Y, Rusckowski M, Liu G.

Department of Radiology, University of Massachusetts Medical School , Worcester, Massachusetts.

 

ABSTRACT

Intraperitoneal (IP) injection is frequently reported to be as effective as intravenous (IV) injection. Because it allows administering a larger volume with more radioactivity, we have investigated this route and the possibility of using it to circumvent the volume constraint we earlier experienced with pretargeting radiotherapy. Using 99mTc as the label, the pharmacokinetics (PK) of the cMORF effector (a DNA analogue) was evaluated after IP or IV injection in normal mice by necropsy and SPECT/CT imaging. In another experiment, nude mice bearing tumors were used and they received MORF-CC49 pretargeting antibody IV 2 days earlier than the labeled cMORF IV or IP. Tumor accumulations of cMORF were measured at 6 hours after its injections. The absorbed radiation doses for 188Re or 90Y pretargeting were estimated using the 99mTc data and a self-absorbed model. Although the absorbed radiation doses to other organs were comparable, the dose to intestines after IP injection was 30-fold higher than IV injection due to the slow entry into the circulation. It had reached such a level as high as the dose to the kidneys that cleared the radioactivity and usually were at the highest level. Nevertheless, the slow entry did not reduce or increase the tumor accumulation. In conclusion, using IP in place of IV led to an unacceptably high absorbed radiation dose to the intestines although the tumor accumulation was not compromised. This effect may be applicable to other radiotherapeutic agents as well.

PMID: 23469942

 

SUPPLEMENTARY

Injection is the primary means of drug administration for systematic tumor therapy. Although intravenous (IV) injection is the prevailing injection route, others may be preferable sometimes. We developed a need for more radioactivity in our study of systematic targeted radiotherapy in a mouse model. Because IP allows a larger volume and was frequently reported to be as effective as IV in both mouse model and human, this injection route was considered as an alternative to IV. However, we observed a high level of mortality in a pilot study at elevated level of radioactivity. Therefore, we examined the absorbed radiation dose exposed to the intraperitoneal organs due to the longer stay of the radioactivity in the peritoneal cavity. The absorption process of the cavity radioactivity was qualitatively visualized using a gamma camera in Fig 1.                       Guozheng Liu-fig1Fig 1. Whole body images of normal mice after IP or IV injection of 99mTc-cMORF. The maximum voxel brightness for each is set such that after decay correction it is at the same value.

 

Because there was no convenient method in the literature to quantitatively measure the free radioactivity in the cavity, we developed a dilution method. Directly drawing the fluid left in the cavity was not possible especially at the later stage because of the small volume. After euthanization of a mouse, 2 mL isotonic phosphate buffer saline (PBS) solution was injected into the cavity to dilute the radioactivity and thereafter 0.2 mL was sampled. Another 2 mL of the isotonic solution was injected and another 0.2 mL was sampled. With the two volumes of 2 mL and the other two of 0.2 mL, the cavity activity and the volume of cavity fluid could be calculated from the radioactivity concentration C1 in the first 0.2 mL and the other C2 in the second 0.2 mL. Measurement of the pooled multiple washes provided identical radioactivity value.Guozheng Liu-fig2Enabling a method to quantitatively determine the absorption process of the radioactivity allowed us to calculate the area under the cavity radioactivity curve. Absorption of the cavity radioactivity took about 200 min. The radiation dose to the intestinal wall following IP injection due to the cavity radioactivity was over 30-fold above that by IV injection. Even this could be an underestimate. Any organ surface directly exposing to the cavity fluid or the channels for the radioactivity to enter the circulation would analogously experience similar increased absorbed radiation exposure. The increased exposure was likely to be the cause of animal death, though toxicological evidences were yet to be known.

The absorption process of the cavity radioactivity greatly stretched the area under the blood curve (AUC) as compared to that by IV. However, the AUC value did not change (AUCIP/AUCIV= 0.96), suggesting an unchanged bioavailability. Based on a model we proposed previously [1, 2], if the binding sites were more than sufficient, an unchanged bioavailability would lead to an unchanged tumor accumulation. The prediction was confirmed in mice with pretargeted tumors that specifically accumulated radioactivity.

In summary, we developed a dilution method to measure the radioactivity in the peritoneal cavity. With this method, we determined that the IP injection induced increased absorbed radiation dose to the cavity organs and would not offer any benefit to tumor accumulation and tumor therapy as well if the tumors were not located in the cavity.

 

References

1. Liu G, He J, Dou S, et al. Further investigations of morpholino pretargeting in mice — establishing quantitative relations in tumor. Eur J Nucl Med Mol Imaging 2005;32:1115-1123.

2. Liu G, Hnatowich DJ. A semiempirical model of tumor pretargeting. Bioconjug Chem 2008;19:2095-2014.

Acknowledgments

This work was supported by the grants of CA94994, DK82894, and DK 94199 from the National Institutes of Health. We thank Dr. Donald J Hnatowich from the Department of Radiology, University of Massachusetts Medical School, Worcester, MA, for his help in the discussion of this research.

 

Contact:

Guozheng Liu, Ph D

Associate Professor of Radiology

Co-Director of Biomarker Development Group

Department of Radiology

University of Massachusetts Medical School

55 Lake Ave North, Worcester, MA 01655

Phone: (508)856-1958

FAX: (508)-856-6363

e-mail: Guozheng.Liu@umassmed.edu

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