Bone site-specific delivery of siRNA

Small interfering RNAs （siRNA） have enormous potential as therapeutics to target and treat various bone disor- ders such as osteoporosis and cancer bone metastases. However, effective and specific delivery of siRNA therapeu- tics to bone and bone-specific cells in vivo is very challenging. To realize the full therapeutic potential of siRNA in treating bone disorders, a safe and efficient, tissue- and cell-specific delivery system must be developed. This review focuses on recent advances in bone site-specific delivery of siRNA at the tissue or cellular level. Bone-targeted nanoparticulate siRNA carriers and various bone-targeted moieties such as bisphosphonates, oligopeptides （Asp）8 and （AspSerSer）6, and aptamers are highlighted. Incorporation of these bone-seeking targeting moieties into siRNA carriers allows for recognition of different sub-tissue functional domains of bone and also specific cell types residing in bone tissue. It also provides a means for bone-formation surface-, bone-resorption surface-, or osteoblast- specific targeting and transportation of siRNA therapeutics. The discussion mainly focuses on systemic and local bone-specific delivery of siRNA in osteoporosis and bone metastasis preclinical models.

The clinical value of BALP on diagnosis and treatment of osteoporosis in postmenopausal women

Objective： To investigate the changes of bone-specific alkaline phosphatase （BALP） in postmenopausal women, analyze the relationship between BALP and bone mineral density, and study the effects of treatment with risedronate on BALP. Methods ： In this study, 243 women who were all at least 1 year past natural menopause were divided into two groups according to WHO standards. Group Ⅰ was 100 osteopenic patients aged from 43 to 85 （mean age, 61.2 years）. Group Ⅱ was 143 osteoporotic patients aged from 45 to 80（mean age, 62.6 yearsi. Bone mineral density（BMD） was measured by dual-energy X-ray absorptiometry （DEXA） and bone-specific alkaline phosphatase（BALP） was tested among all the patients. All the osteoporotic patients received 1-year Risedronate treatment. BALP was tested again after 3 months treatment of Risedronate for osteoporotic patients and BMD was measured after 1-year treatment. All data were processed by the application of statistical package SAS for windows V.6.12. Results： BALP was greater in the osteoporotic patients as compared with the osteopenic patients （P 〈 0.05）. There was also a significant difference of BALP in the patients before and after treatment of risedronate （P 〈 0.05）. BALP was greater in the patients who were less than 5 years past a natural menopause as compared with those who were more than 5 years past a natural menopause （P 〈 0.05）. There was no significant difference of BALP in the patients who were more than 10 years past a natural menopause. Risedronate decreased serum BALP significantly. Logistic regression analyses showed that 3-month percentage decrease in BALP was profoundly associated with the 1-year percentage increase in BMD（r = 0.696, P 〈 0.01 ）. Conclusion： BALP can predict the response in bone mass during Risedronate treatment in postmenopausal women and identify those noncompliant patients. 3-month percentage change in serum BALP was significantly correlated with the increase of BMD. Serum BALP can play a role in the monitoring of risedronate-treated postmenopausal women with osteoporosis, but it is poor to predict the treatment effects on an individual level.

Mechanisms of treatment of cancer pain with a topical Chinese herbal formula in rats

Background Pain has a substantial impact on patients＇ activities and overall quality of life, but current conventional drugs have debilitating side effects, including gastrointestinal disorders. Thus there is a pressing need for new therapies with fewer side effects to alleviate cancer pain. We recently developed a topical herbal formula Xiaotan Tongluo analgesic gel （X＇I-IL gel） based on the principles of traditional Chinese herbalism, and we have received positive feedback from bone cancer pain patients. The aim of this study was to determine the analgesic effects and explore the mechanisms of XTI-L gel in a rat model of bone cancer pain. Methods The rat model of bone cancer pain was established by inoculating Walker-256 rat carcinoma cells directly into the right tibial medullary cavity of Wistar rats. The rats were randomly assigned to three groups （n=-10 per group）： （1） sham bone cancer control （sham group）： vehicle （PBS） inoculation without carcinoma cells plus topical administration of blank gel; （2） Sham treatment control （vehicle group）： Walker-256 cell inoculation plus topical administration of blank gel; （3） XTTL gel treatment （treatment group）： Walker-256 cell inoculation plus topical administration of XTTL gel. XTTL gel treatments were applied daily for 7 days starting on day 14 following inoculation. Outcomes were assessed 21 days after inoculation by mechanical allodynia, histological staining, and by measuring concentrations of type I collagen carboxy-terminal telopeptide （ICTP） and bone-specific alkaline phosphatase （BAP） in serum. Results Fourteen days after cancer cell incubation, significant mechanical allodynia in the ipsilateral hind paw and tumor growth in proximal end of the tibia were observed in the vehicle and treatment groups but not in the sham group. At day 21, mechanical withdrawal thresholds in treatment group rats were significantly higher （（4.8557±0.8336） g） compared with those of the vehicle group （（1.8630±1.4369） g, P 〈0.05）. ICTP and BAP levels increased significantly in vehicle group rats （（101.5176±11.0694） U/L and （370.7838±12.8273） U/L, respectively） compared with those of the sham group （（11.7553±1.1885） U/L and （185.7338±3.6761） U/L, respectively; P 〈0.05）. XTTL gel decreased the level of blood serum ICTP （（41.8998±6.4970） U/L, P 〈0.05） but had little effect on blood serum BAP （（365.5338±18.5361） U/L, P 〉0.05）. Conclusion Topical use of XTTL gel may have an analgesic effect on bone cancer pain, an effect mediated by lowering of ICTP levels and inhibiting bone resorption. Chin Med J 2009; 122（17）：2027-2031