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Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.

ABSTRACT: Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (∼5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.

SUBMITTER: Mittapalli RK

PROVIDER: S-EPMC8391070 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.

Mittapalli Rajendar K RK Liu Xinli X Adkins Chris E CE Nounou Mohamed I MI Bohn Kaci A KA Terrell Tori B TB Qhattal Hussaini S HS Geldenhuys Werner J WJ Palmieri Diane D Steeg Patricia S PS Smith Quentin R QR Lockman Paul R PR

Molecular cancer therapeutics 20130903 11

Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (∼5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up i ...[more]

PMID: 24002934

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Project description:Background60-70% of patients who die from breast cancer have lung metastases. However, there is a lack of readily available tools for accurate risk stratification in patients with breast cancer lung metastases (BCLM). Therefore, a web-based dynamic nomogram was developed for BCLM to quickly, accurately, and intuitively assess overall and cancer-specific survival rates.MethodsPatients diagnosed with BCLM between 2004 and 2016 were extracted from the Surveillance, Epidemiology, and Final Results (SEER) database. After excluding incomplete data, all patients were randomly assigned to training and validation cohorts (2:1). Patients' basic clinical information, detailed pathological staging and treatment information, and sociological information were included in further analysis. Nomograms were constructed following the evaluations of the Cox regression model and verified using the concordance index (C-index), calibration curves, time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Web-based dynamic nomograms were published online.Results3916 breast cancer patients with lung metastases were identified from the SEER database. Based on multivariate Cox regression analysis, overall survival (OS) and cancer-specific survival (CSS) are significantly correlated with 13 variables: age, marital status, race, grade, T stage, surgery, chemotherapy, bone metastatic, brain metastatic, liver metastatic, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). These are included in the construction of the nomogram of OS and CSS. The time-dependent receiver operating characteristic curve, decision curve analysis, consistency index, and calibration curve prove the distinct advantages of the nomogram.ConclusionsOur web-based dynamic nomogram effectively integrates patient molecular subtype and sociodemographic characteristics with clinical characteristics and guidance and can be easily used. ER-Negative should receive attention in diagnosing and treating BCLM.

Dataset Information

Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.

Publications

Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.

Similar Datasets

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