科研之友
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摘要
Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with alpha-particle emitters. This is mostly due to the alpha-particles' relatively short range (<= 100 mm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of alpha-particles against solid tumors, we designed non-targeted, non-internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly-diffusive forms of the encapsulated alpha-particle generator Actinium-225 (Ac-225) resulting in more homogeneous distributions of the alpha-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 mu m-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing Ac-225-loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of alpha-particle emitters, independent of cell-targeting.
- 出版日期2017-6
