In vivo pharmacokinetics,biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle

Abstract

A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC₅₀ value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93?µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the V_d, T_1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX.     

Association between HLA-G 14bp Gene Polymorphism and Serum sHLA-G Protein Concentrations in Preeclamptic Patients and Normal Pregnant Women

Background: Preeclampsia (PE) is a multisystem syndrome that is a primary source of fetal–maternal morbidity and mortality. Human leukocyte antigen-G (HLA-G) is a nonclassical Major histocompatibility complex (MHC) class-Ib molecule expressed on the extravillous trophoblast and seems to have immunomodulatory functions during pregnancy. The purpose of our study was to investigate whether HLA-G may be a vital marker in the modulation of the pregnancy.

Methods: In this case-control study, a number of 150 healthy pregnant women and 150 patients with PE had been genotyped for the 14 base-pair (bp) insertion/deletion polymorphism in exon 8 of the HLA-G gene, and the serum level of soluble HLA-G (sHLA-G) protein was measured using the enzyme-linked immunosorbent assay.

Results: Data showed that the PE syndrome was not related to the HLA-G 14 bp genotype. But, the serum level of sHLA-G in PE patients was significantly lower than that in healthy pregnant women in the third trimester (11.74 and 24.48 U/ml, respectively, p < 0.001). However, no significant association was observed between the HLA-G 14 bp genotype and serum sHLA-G level.

Conclusion: Our results demonstrate that measurement of sHLA-G protein level may be helpful as a primary diagnosis for the pathogenesis of PE. Overall, this study suggests that the association between HLA-G 14 bp polymorphism and serum sHLA-G level in different ethnic populations of PE should be taken into consideration.     

Healing potential of nanohydroxyapatite,gelatin, and fibrin-platelet glue combination as tissue engineered scaffolds in radial bone defects of rats

Different biomaterials have been used in orthopedic surgery. Evaluation of biomaterials for bone healing promotion has been a wide area of research of the orthopedic field. Sixty critical size defects of 5 mm long were bilaterally created in the radial diaphysis of 30 rats. The animals were randomly divided into six equal groups as empty defect, autograft, nanohydroxyapatite (nHA), Gelatin (Gel)-nHA, fibrin-platelet glue (FPG)-nHA, and Gel-FPG-nHA groups (n = 10 in each group). Radiographs of each forelimb were taken postoperatively on the 1st day and then at the 28th and 56th days post injury. After 56 days, the rats were euthanized and their harvested healing bone samples were evaluated by histopathology, scanning electron microscopy, and biomechanical testing.

All the treated defects demonstrated significantly superior new bone formation, remodeling, and bone tissue volume. Moreover, the defects treated with FPG-nHA showed significantly higher ultimate load, yield load, and stiffness. The Gel-FPG-nHA moderately improved bone regeneration that was not close to the autograft in some parameters, whereas FPG-nHA significantly improved bone healing closely comparable with the autograft group in most parameters. In conclusion, although all the nHA-containing scaffolds had some beneficial effects on bone regeneration, the FPG-nHA scaffold was more effective in improving the structural and functional properties of the newly formed bone and was more osteoinductive than the Gel and was comparable to the autograft. Therefore, the FPG can be regarded as a promising option to be used in conjunction with mineral scaffolds for bone tissue engineering.     

Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate

Purpose

Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine—allowing only approximate estimates of GFR—the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement.

Methods

Nephrotoxicity was analysed using ^99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with ¹⁷⁷Lu-octreotate. The mean follow-up period was 21 months (range 12–50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by ^99mTc-DTPA clearance versus serum creatinine.

Results

The alteration in GFR differed widely among the patients (mean ?2.1?±?13.1 ml/min/m² per year, relative yearly reduction ?1.8?±?18.9 %). Fifteen patients (21 %) experienced a mild (2–10 ml/min/m² per year) and 16 patients (22 %) a significant (>10 ml/min/m² per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m² per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function.

Conclusion

Serious nephrotoxicity after PRRT with ¹⁷⁷Lu-octreotate is rare (1.3 %). However, slight renal impairment (GFR loss >2 ml/min/m² per year) can frequently (43 %) be detected by ^99mTc-DTPA clearance assessments. Cumulative administered activity of ¹⁷⁷Lu-octreotate is not a major determinant of renal impairment in our study.     

Hepatic volume changes induced by radioembolization with 90Y resin microspheres. A single-centre study

Purpose

Lobar radioembolization (RE) of the liver can result in reduction in volume of the ipsilateral lobe as well as hypertrophy of the contralateral lobe. Theoretically, hypertrophy of the contralateral liver lobe after RE could increase the chance of a successful liver resection, especially in patients with limited liver function reserve. The aim of this preliminary study was to evaluate the early effects of RE with resin microspheres on the volumes of the liver lobes and spleen.

Methods

We retrospectively investigated 24 patients (12 women, 44?C78?years old) with different types of cancer and liver-dominant metastatic disease who had undergone RE of the liver with resin microspheres. Changes in the volumes of the liver lobes and spleen were quantified by CT before and about 4 to 8?weeks after treatment.

Results

Of the 24 patients, 17 suffered from metastases in both liver lobes (group A) and 7 had metastases only in the right liver lobe (group B). The patients in the group A underwent sequential treatment starting with the right liver lobe. The median administered dose was 1.75?GBq. RE was associated with a median increase in volume of the left liver lobe of 34?% (P?<?0.001) and a median decrease in volume of the right liver lobe of 11?% (P?=?0.03). The volume of the spleen showed a median increase of 17?% (P?=?0.01). Separate analysis of the two groups showed a median increases in volume of the left liver lobe of 30?% (P?=?0.001) in group A and 70?% (P?=?0.01) in group B. There was no correlation between the injected dose and the volume alteration (r?=?0.1?C0.3).

Conclusion

RE of the right liver lobe with resin microspheres caused a significant increase in the volume of the left liver lobe. This may allow liver resection in patients with metastases in the right liver lobe and a small left liver lobe.     

Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation

A multicenter analysis was conducted to evaluate the main prognostic factors driving survival after radioembolization using yttrium-90-labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole-liver (45.2%) or right-lobe (38.5%) infusions. Typically, patients were Child-Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one-quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9-15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6-38.1 months]; BCLC B, 16.9 months [95% CI, 12.8-22.8 months]; BCLC C, 10.0 months [95% CI, 7.7-10.9 months]). Consistent with this finding , survival varied significantly by ECOG status, hepatic function (Child-Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha-fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. Conclusion: This analysis provides robust evidence of the survival achieved with radioembolization, including those with advanced disease and few treatment options.