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Liposome-Mediated Radiotherapeutics Within Avascular Tumor Spheroids: Comparative Dosimetry Study for Various Radionuclides, Liposome Systems, and a Targeting Antibody

¹ Department of Medical Physics, University of Ioannina Medical School, Ioannina, Greece
² Centre for Drug Delivery Research, The School of Pharmacy, University of London, London, United Kingdom
³ Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York
⁴ Department of Radiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland

Absorbed dose profiles within tumor spheroids simulating avascular micrometastases have been calculated for a variety of liposome- and antibody-radionuclide combinations to assess the anticipated therapeutic efficacy based on the intratumoral distribution of the carrier systems within the spheroid model. Methods: Experiments studying the targeting and diffusion capability of the most clinically relevant liposome systems and the anti-PSMA (prostate-specific membrane antigen) antibody J591 within spheroids of the prostate cancer cell line LNCaP (diameter, 150–200 µm) have been performed. The intratumoral biodistribution data were then used as the input to obtain absorbed dose profiles within the tumor spheroid mass. The dosimetric analysis was performed for a variety of medium- and high-energy ß-emitting radionuclides (³²P, ⁹⁰Y, ¹⁸⁸Re, ⁶⁷Cu, ¹³¹I) and 2 low-energy Auger or conversion electron emitters (¹²³I, ¹²⁵I) following the point-kernel convolution method in the continuous slowing-down approximation. Results: Relative absorbed dose distribution calculations as a function of the distance from the rim of the spheroids are presented. For all liposome systems studied, the SUV-DMPC-chol (small unilamellar vesicle-dimyristoyl-phosphatidylcholine-cholesterol) was most efficient in penetrating deeper within the spheroids. For the ß-emitters it delivered its maximum absorbed dose (D_max) at 40- to 50-µm depth, exhibiting an almost flat absorbed dose profile beyond that point, as is evident by the high absorbed dose value at the center of the spheroid (D_core), D_core/D_max > 0.9; the respective values for the J591 antibody were 20 µm and 0.85. The Auger or conversion emitters resulted in the most heterogeneous absorbed dose distribution; the ratio D_core/D_max fell to 0.4 for the SUV-DMPC-chol and to 0.4–0.5 for the antibody. In general, a 2- to 10-fold "cross-fire"-related increase of the core absorbed dose was observed. For liposomes exhibiting high binding capacity (3ß-[N-(N',N']-dimethylaminoethane)carbamoyl]cholesterol [DC-chol]), however, the low-energy emitters deliver up to a 40% higher D_max relative to the ß-emitters. The surface characteristics of liposomes appear to have a noticeable influence on the absorbed dose profiles. The use of neutral (DMPC-chol) versus cationic (DC-chol) lipids resulted in up to a 10-fold increase of D_core/D_max depending on the radionuclide. Changing the cationic lipid used to N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate also had a notable influence (up to a 6-fold increase), whereas the effect of fusogenic lipids (dioleoylphosphatidylcholine) was found to be much smaller. Conclusion: It is possible to engineer liposome systems that are particularly effective in delivering an almost uniform absorbed dose profile at the central region of micrometastatic tumors, provided that conjugates with the appropriate radionuclides are constructed. In view of the passive means of diffusion of liposomes within solid tumors, it is suggested that they may effectively complement an antibody-based therapeutic regime against micrometastatic tumors, leading to cytotoxic absorbed dose levels throughout the entire tumor volume—thus, hindering tumor recurrence.

Key Words: radiotherapeutics • dosimetry • liposome systems • radiotherapy • radionuclides • spheroids

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