与肿瘤有关的氨基酸代谢缺陷及其相关药物的应用

氨基酸代谢是生命活动的基础。在肿瘤组织的恶性转化中,由于肿瘤细胞动力学的改变,导致机体氨基酸代谢缺陷的发生。随着代谢组学的发展,氨基酸及相关衍生药物在肿瘤物诊断及治疗中有着广泛的运用,文章概述了与肿瘤有关的氨基酸代谢缺陷的发生,以及氨基酸衍生药物和氨基酸放射标记物在肿瘤诊断和治疗中的应用,为其在医药领域中进一步地发展提供参考依据。     

Synthesis of a Novel l-Methyl-Methionine–ICG-Der-02 Fluorescent Probe for In Vivo Near Infrared Imaging of Tumors

Purpose

A novel near infrared fluorescent probe, l-methyl-methionine (Met)?CICG-Der-02, was synthesized and characterized for in vivo imaging of tumors and early diagnosis of cancers.

Method

Met was conjugated with ICG-Der-02 dye through the amide bond function by ethyl-3-(3-dimethyllaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide catalysis chemistry. Met?CICG-Der-02 probe uptake was evaluated on PC3, MDA-MB-231, and human embryonic lung fibroblast cell lines. The dynamics of Met?CICG-Der-02 was investigated in athymic nude mice prior to evaluation of the probe targeting capability in prostate and breast cancer models.

Results

Met?CICG-Der-02 was successfully synthesized. Cell experiments demonstrated excellent cellular uptake of Met?CICG-Der-02 on cancer cell lines without cytotoxicity. Optical imaging showed a distinguishable fluorescence signal in the tumor area at 2?h while maximal tumor-to-normal tissue contrast ratio was at 12?h Met?CICG-Der-02 post-injection. Additionally, dynamic study of the probe indicated intestinal and liver?Ckidney clearance pathways.

Conclusion

Met?CICG-Der-02 probe is a promising optical imaging agent for tumor diagnosis, especially in their early stage.     

In vivo NIR imaging with PbS quantum dots entrapped in biodegradable micelles

In this article, we firstly synthesized oil-soluble PbS quantum dots (QDs) emitting in the near-infrared (NIR) spectral range through a two-phase method, which exhibit a conveniently tunable photoluminescence (PL) emission (from ~750 to 872 nm) with a narrow PL bandwidth, as well as a high (up to 40%) PL quantum yield (QY). Next, the as-prepared oil-soluble NIR PbS QDs were applied to the in vivo imaging of tumors by entrapping in biodegradable micelles (N-succinyl-N'-octyl nanomicelles, SOC) which had hydrophobic inner cores. Transmission electron microscope results show well dispersed spherical shaped QDs-loaded SOC micelles with 100 nm diameter. The QY of PbS QDs entrapped into SOC has no significant change compared to free QDs. Besides, both in vitro and in vivo acute toxicity results demonstrated that the QDs-loaded micelles have low cytotoxicity. Furthermore, in vivo imaging of PbS QDs-loaded SOC injected intravenously into tumor-bearing nude mice showed the NIR QDs-loaded micelles can accumulate in the tumor tissue due to the enhanced permeability and retention effect of SOC micelles. These results confirm that the as-prepared PbS QDs could be used as fluorescence probes to study the biodistribution of nanocarriers and their intracellular pathways, as well as their passive targeted behavior to tumors in preclinical research.     

Novel mutation in a family with WNT1-related osteoporosis

Osteogenesis imperfecta (OI) is an inherited disorder with osteoporosis and recurrent fractures. Children presenting with recurrent fractures and bowing of limbs have severe form of the disorder. Patients carrying homozygous WNT1 mutations have more frequent fractures while heterozygous carriers of the mutation in WNT1 gene are also found to have early onset osteoporosis. We identified a family with novel WNT1 mutation. The index case, a 6 month old child presented with fractures from early infancy. Next generation sequencing (NGS)done for the child didn't show any variations in other OI genes including COL1A1, COL1A2, SERPINH1, CRTAP, LEPRE1, PP1B, 1F1TM5 and BMP1 genes. Sanger sequencing showed 41bp deletion in splice region following exon 1 of WNT1 gene in homozygous state. The mutation was found to be likely pathogenic on bioinformatic analysis. To further characterize the significance of the mutation we studied his mother who is 30 year old with blue sclera and history of backache but no fractures. Her DXA scan of lumber spine showed osteoporosis and she was heterozygous for the mutation. The child's DXA scan showed T-score of ?6.4?at lumbar spine level. Father also has history of backache and was carrier for the same deletion variant. The child was given 3 doses of zoledronate and did not have any further fractures. Thus, we conclude that this novel variant identified in the child with OI is likely cause for the disease and possibly zoledronate has a role in prevention of fractures in this case.