Albumin-Binding Lutetium-177-Labeled LLP2A Derivatives as Theranostics for Melanoma.

Very late antigen-4 (VLA-4) is a transmembrane integrin protein that is highly expressed in aggressive forms of metastatic melanoma. A small-molecule peptidomimetic, LLP2A, was found to have a low pM affinity binding to VLA-4. Because LLP2A itself does not inhibit cancer cell proliferation and survival, it is an ideal candidate for the imaging and delivery of therapeutic payloads. An analog of [177Lu]Lu-labeled-LLP2A was previously investigated as a therapeutic agent in melanoma tumor-bearing mice, resulting in only a modest improvement in tumor growth inhibition, likely due to rapid clearance of the agent from the tumor. To improve the pharmacokinetic profile, DOTAGA-PEG4-LLP2A with a 4-(p-iodophenyl)butyric acid (pIBA) albumin binding moiety was synthesized. We demonstrate the feasibility of this albumin binding strategy by comparing in vitro cell binding assays and in vivo biodistribution performance of [177Lu]Lu-DOTAGA-PEG4-LLP2A ([177Lu]Lu-1) to the albumin binding [177Lu]Lu-DOTAGA-pIBA-PEG4-LLP2A ([177Lu]Lu-2). In vitro cell binding assay results for [177Lu]Lu-1 and [177Lu]Lu-2 showed Kd values of 0.40 ± 0.07 and 1.75 ± 0.40 nM, with similar Bmax values of 200 ± 6 and 315 ± 15 fmol/mg, respectively. In vivo biodistribution data for both tracers exhibited specific uptake in the tumor, spleen, thymus, and bone due to endogenous expression of VLA-4. Compound [177Lu]Lu-2 exhibited a much longer blood circulation time compared to [177Lu]Lu-1. The tumor uptake for [177Lu]Lu-1 was highest at 1 h (∼15%ID/g) and that for [177Lu]Lu-2 was highest at 4 h (∼23%ID/g). Significant clearance of [177Lu]Lu-1 from the tumor occurs at 24 h (<5%ID/g) while[177Lu]Lu-2 is retained for greater than 96 h (∼10%ID/g). An efficacy study showed that melanoma tumor-bearing mice receiving compound [177Lu]Lu-2 given in two fractions (2 × 14.8 MBq, 14 days apart) had a greater median survival time than mice administered a single 29.6 MBq dose of compound [177Lu]Lu-1, while a single 29.6 MBq dose of [177Lu]Lu-2 imparted hematopoietic toxicity. The in vitro and in vivo data show addition of pIBA to [177Lu]Lu-DOTAGA-PEG4-LLP2A slows blood clearance for a higher tumor uptake, and there is potential of [177Lu]Lu-2 as a theranostic in fractionated administered doses.

Coronary sequelae of Kawasaki disease treated with rotational atherectomy and drug coated balloon: A case report.

INTRODUCTION: Kawasaki disease (KD) is an acute vasculitis syndrome that mainly affects children and is the first cause of acquired heart disease. Coronary artery lesion is the most serious complication of KD. Only two previous studies have reported similar cases, but we reported patient was younger and had a longer follow-up. PATIENT CONCERNS: We reported a case of coronary sequelae of KD treated with rotational atherectomy and drug coated balloon (DCB). During the week after surgery, the patient complained of a slight chest pain intermittently, but no longer appeared after that. DIAGNOSIS: We diagnosed by electrocardiogram and angiography. Angiography showed that the anterior descending branch (LAD) proximal stenosis was 95%, the right coronary artery (RCA) middle stenosis was 99%, and the calcification was severe. INTERVENTIONS: We treat the patient with rotational atherectomy using a 1.25 mm burr, pre-dilatation of the stenosis lesion with a 3.5 mm × 15 mm non-compliant balloon was achieved. Then 3.5 mm × 15 mm drug eluting balloon was inflated at 10 atm for 60 seconds. OUTCOMES: After the 6-month follow-up (from October 2018 to March 2019), the symptom of angina disappeared. Coronary angiography 6 months later showed no apparent progression of vessel narrowing. CONCLUSION: The present case suggests that rotational atherectomy followed by DCB dilation could be an alternative revascularization therapy of choice in coronary KD sequelae complicated with atherosclerosis.

Prevalence and distribution of hypertension and related risk factors in Jilin Province, China 2015: a cross-sectional study.

OBJECTIVE: This study aimed to investigate the prevalence and distribution of hypertension and its related factors in Jilin province, China. DESIGN: A cross-sectional study in four cities and four rural counties in Jilin as part of a national Chinese study. PARTICIPANTS AND SETTING: A total of 15 206 participants who were ≥15 years old and were selected using a stratified multistage random sampling method. MAIN OUTCOME MEASURES: The prevalence of hypertension. RESULTS: The prevalence of hypertension in Jilin province was 24.7%. Moreover, the prevalence of hypertension increased with age in both sexes, and was higher in men than in women. The modifiable factors that were associated with hypertension were body mass index, smoking and alcohol drinking. The risk factors identified are similar to those in southern China, except smoking, which has no association with hypertension prevalence in the South. CONCLUSIONS: Age, sex, body mass index, smoking and alcohol drinking were risk factors of hypertension. Control of these related risk factors, especially smoking, may be helpful in the treatment and management of hypertension in Jilin province.

Facile and efficient access to Androsten-17-(1',3',4')-pyrazoles and Androst-17ß-(1',3',4')-pyrazoles via Vilsmeier reagents, and their antiproliferative activity evaluation in vitro.

In this work, twenty-seven novel steroidal pyrazole derivatives were designed and effectively synthesized with two different commercially available staring material, Isopregnanolone 1 and 5,16-Pregnadienolone 7, via the key intermediates, 17ß-(4'-formyl)pyrazolylandrost-3ß-yl formate and 17-(4'-formyl)pyrazolylandrost- 5,16-dienes-3ß-yl formate, which were obtained from the cyclization of steroidal phenylhydrazone with Vilsmeier reagent catalyzed by phosphorous oxychloride followed by hydrolysis, then Borch reduction to afford the target derivatives under mild conditions. Structures of these compounds were identified by 1H NMR, 13C NMR and high resolution mass spectrometry. Based on our previous work, the cytotoxicity of these derivatives were evaluated by the SRB method against 293T cell lines and three cancer cell lines: A549, Hela and MCF-7. The results indicated that compounds 5b-d, and 11a-e exhibited moderate to high cytotoxic activities with IC50 values ranging from 0.62 to 7.51 µM. Among the eight hybrids, compound 11b, with an ethyl amino and a dien-pregn moieties showed the highest potency, with an IC50 values of 0.87 µM and 0.53 µM for 293T cell lines and Hela cell lines, respectively. Some structure-activity relationships among the groups of the twenty-seven derivatives are discussed and identify several determinants important for the activity of these compounds. What's more, further molecular mechanism studies suggested that 11b one of the most potent derivatives caused Hela cell lines apoptosis and arrested the cell cycle at S phase in a concentration dependent manner.

Design, synthesis and cytotoxic activity of a novel series of steroidal phenylpyrazoles.

Thirty novel steroidal pyrazole derivatives were designed and synthesized via a highly efficient route from pregnenolone (1) as starting material. The key intermediates 3a-c were obtained under Vilsmeier conditions, and the subsequent hydrolysis, acetylation or Borch reduction afforded thirty target compounds. These compounds were mainly characterized by (1)H NMR, (13)C NMR, DEPT135°. The structure of compound 3a was also confirmed by X-ray single crystal diffraction. The cytotoxicity of these compounds was evaluated by the SRB method against four cancer cell lines, including A549, Hela, MCF-7 and HepG2, and the results indicated that compounds 5a, 6a, 7a and 8a exhibited significant cytotoxicity with IC50 values ranging from 0.91 to 5.44 µM. Most importantly, compound 5a exhibited excellent cytotoxicity against A549 with an IC50 value of 0.91 µM. On the basis of our research the structure-activity relationships (SAR) of these compounds were discussed. This work provides some important hints for further structural modification of steroids towards developing novel and highly effective anticancer drugs.

Synthesis and insecticidal activity of ß-dihydroagarofuran ether analogues.

BACKGROUND: 1ß, 2ß, 4α, 6α, 8ß, 9α, 12-hepthydroxyl-ß-dihydroagarofuran is the main skeleton of ß-dihydroagarofuran sesquiterpenoids, which exhibit excellent insecticidal activity. To study further the structure-activity relationship of ß-dihydroagarofuran sesquiterpenoids towards finding novel botanical pesticides, two series of new structurally modified ether analogues were designed and synthesised, and their insecticidal activities were evaluated. RESULTS: Twenty-two ether derivatives were synthesised using 1ß, 2ß, 4α, 6α, 8ß, 9α, 12-hepthydroxyl-ß-dihydroagarofuran as starting material. Bioassay results indicated that most of the derivatives, particularly compounds 5.1.2, 5.1.3, 5.1.7, 5.2.3, 5.2.6 and 5.2.7, exhibited significant insecticidal activity against the third-instar larvae of the oriental armyworm Mythimna separata. Most importantly, compound 5.2.7 showed the lowest LD50 value of 29.2 µg g(-1) among these synthesised compounds, which provides some important hints for further design, synthesis and structural modification of ß-dihydroagarofuran sesquiterpenoids towards developing novel botanical insecticides. CONCLUSION: The structure-activity relationship illustrated that the moiety at the 1-position affected the insecticidal activity significantly, and that specifically the derivatives with two or three carbon atoms at the 1-position showed promising insecticidal activity, with mortality over 60%, while those with o-F-Bn and p-F-Bn at the 6-position showed similar activity.