Jansen David R, Krijger Gerard C, Kolar Zvonimir I, Zonnenberg Bernard A, Zeevaart Jan Rijn
Radiochemistry, Department of Applied Chemistry, Necsa (South African Nuclear Energy Corporation Ltd.), P.O. Box 582, Pretoria 0001, South Africa.
Curr Drug Discov Technol. 2010 Dec;7(4):233-46. doi: 10.2174/157016310793360675.
The severe pain associated with many disorders affecting bone account for a large proportion of cases of patient morbidity, due to the encumbrance of mobility and therefore, compromised quality of life. Skeletal metastasis is one such condition, which generally complicates the treatment of the primary cancers such as that of the breast, prostate and lung - causing intense pain and eventually even mortality. This paper presents examples of various approaches explored and proposed in the ongoing search to identify better radiopharmaceuticals for the treatment of bone disorders such as metastases. The primary objective of these developments is to alleviate the debilitating pain commonly associated with bone lesions. The efficacy of a radiotherapeutic agent intended for the treatment of diseased bone is particularly dependent on the radiation dose to the tumor cells and on the extent to which suppression of bone marrow or other critical organs can be avoided. Therefore, the design rationale requires careful consideration of the choice radionuclide and especially ensuring that the drug selectively targets the lesion or tumor site. The options pursued include the use of radioisotopes with an intrinsic affinity for bone, such as (89)Sr or (223)Ra, or the design of bone-seeking ligands, such as phosphonates, to selectively deliver the radionuclide to the target, e.g. [(153)Sm]Sm-EDTMP. A combination of the above may too be possible, where the bone seeking ligand facilitates the selective accumulation of a radionuclide, which by itself is also bone homing. In terms of therapeutic application radionuclides with various decay modes are proposed, including beta (-) emitters: (153)Sm, (89)Sr, (186)Re, (188)Re, (32)P, (177)Lu and (170)Tm; alpha (α) emitters: (223)Ra and (225)Ra; and Auger or conversion electron emitter: (117)mSn. From a purely diagnostic perspective, the radioisotopes used for imaging include the well known photon emitting (99)mTc, and positron emitters (18)F and (68)Ga. The current status in the development and application of internal radiotherapy for the palliative treatment of bone pain will be discussed, summarizing the progress made and challenges encountered in the process to realizing an effective drug candidate.
许多影响骨骼的疾病所伴随的剧痛，在患者发病案例中占很大比例，这是由于行动不便，进而导致生活质量下降。骨转移就是这样一种情况，它通常会使乳腺癌、前列腺癌和肺癌等原发性癌症的治疗变得复杂，引发剧痛，甚至最终导致死亡。本文列举了在持续寻找用于治疗骨转移等骨骼疾病的更好放射性药物过程中探索和提出的各种方法。这些研发的主要目标是减轻通常与骨病变相关的使人衰弱的疼痛。用于治疗患病骨骼的放射治疗剂的疗效尤其取决于对肿瘤细胞的辐射剂量，以及避免抑制骨髓或其他关键器官的程度。因此，设计原理需要仔细考虑放射性核素的选择，尤其要确保药物能选择性地靶向病变或肿瘤部位。所采用的方法包括使用对骨骼具有内在亲和力的放射性同位素，如（89）锶或（223）镭，或设计亲骨配体，如膦酸盐，以选择性地将放射性核素输送到靶点，例如[（153）钐]钐 - 乙二胺四甲基膦酸。上述方法的组合也有可能实现，即亲骨配体促进放射性核素的选择性积累，而该放射性核素本身也具有亲骨特性。在治疗应用方面，提出了具有各种衰变模式的放射性核素，包括β（-）发射体：（153）钐、（89）锶、（186）铼、（188）铼、（32）磷、（177）镥和（170）铥；α发射体：（223）镭和（225）镭；以及俄歇电子或内转换电子发射体：（117）m锡。从纯粹的诊断角度来看，用于成像的放射性同位素包括众所周知的发射光子的（99）m锝，以及正电子发射体（18）氟和（68）镓。将讨论用于骨痛姑息治疗的内放射治疗的研发和应用现状，总结在实现有效候选药物过程中取得的进展和遇到的挑战。
