Lipid nanocarriers of a lipid-conjugated estrogenic derivative inhibit tumor growth and enhance cisplatin activity against triple-negative breast cancer: pharmacokinetic and efficacy evaluation.

نویسندگان

  • Terrick Andey
  • Godeshala Sudhakar
  • Srujan Marepally
  • Apurva Patel
  • Rajkumar Banerjee
  • Mandip Singh
چکیده

Breast cancer is the leading cause of malignancies among women globally. The triple negative breast cancer (TNBC) subtype is the most difficult to treat and accounts for 15% of all cases. Targeted therapies have been developed for TNBC but come short of clinical translation due to acquired tumor resistance. An effective therapy against TNBC must combine properties of target specificity, efficient tumor killing, and translational relevance. The objective of this study was to formulate a nontoxic, cationic, lipid-conjugated estrogenic derivative (ESC8), with demonstrated anticancer activity, for oral delivery in mice bearing triple negative breast cancer (TNBC) as xenograft tumors. The in vitro cell viability, Caco-2 permeability, and cell cycle dynamics of ESC8-treated TNBC cells were investigated. ESC8 was formulated as liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) and characterized for size, zeta potential, entrapment efficiency, size stability, and tumor biodistribution. Pharmacokinetic modeling of plasma concentration-time course data was carried out following intravenous and oral administration in Sprague-Dawley rats. In vivo efficacy investigation of ESC8-SLNC was carried out in Nu/Nu mice bearing MDA-MB-231 TNBC as xenograft tumors, and the molecular dynamics modulating tumor growth inhibition was analyzed by Western blot. In vitro ESC8 inhibited TNBC and non-TNBC cell viability with IC50 ranging from 1.81 to 3.33 μM. ESC8 was superior to tamoxifen and Cisplatin in inhibiting MDA-MB-231 cell viability; and at 2.0 μM ESC8 enhanced Cisplatin cytotoxicity 16-fold. Intravenous ESC8 (2.0 mg/kg) was eliminated at a rate of 0.048 ± 0.01 h(-1) with a half-life of 14.63 ± 2.95 h in rats. ESC8 was orally bioavailable (47.03%) as solid lipid nanoparticles (ESC8-SLN). ESC8-SLN (10 mg/kg/day, ×14 days, p.o.) inhibited breast tumor growth by 74% (P < 0.0001 vs control) in mice bearing MDA-MB-231 cells as xenografts; and when given in combination with Cisplatin (2.0 mg/kg/biweekly, ×2 weeks, IV), tumor growth was inhibited by 87% (P = 0.0002, vs ESC8-SLN; 10 mg/kg/day, ×14 days, p.o). ESC8-SLN tumor growth inhibition was associated with increased expression of p21 and Caspase-9; as well as by inhibition of EGFR, Slug, p-Akt1, Vimentin, NFkβ, and IKKγ. These results show the promise of ESC8 as an oral adjuvant or neoadjuvant against triple negative breast cancer.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Polysaccharide from Sepia esculenta ink and cisplatin inhibit synergistically proliferation and metastasis of triple-negative breast cancer MDA-MB-231 cells

Objective(s): This paper aims to investigate synergistic inhibition of polysaccharide from Sepia esculenta ink (SIP), a newly isolated marine polysaccharide in our laboratory, on breast cancer MDA-MB-231 cells exposed to cisplatin. Materials and Methods: Cell viability of MDA-MB-231 cells was determined by CCK 8 assay. Median-effect concentration was analyzed using Chou-Talalay method that was ...

متن کامل

Signaling and Regulation A Lipid-Modified Estrogen Derivative that Treats Breast Cancer Independent of Estrogen Receptor Expression through Simultaneous Induction of Autophagy and Apoptosis

It is a challenge to develop a universal single drug that can treat breast cancer at singleor multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer–specific, estrogen-based drugs are being developed that cannot act against multistaged breast cancer complications owing to the cells differential estrogen receptor (ER) expression statu...

متن کامل

Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer

BACKGROUND Cervical cancer is a major world health problem for women. Currently, cancer research focuses on improving therapy for cervical cancer using various treatment options such as co-delivery of chemotherapeutic agents by nanocarriers. PURPOSE The aim of this study was to develop trans-activating transcriptional activator (TAT)-modified solid lipid nanoparticles (SLNs) for co-delivery o...

متن کامل

Gene Expression Changes in Pomegranate Peel Extract-Treated Triple-Negative Breast Cancer Cells

Background: Triple-negative breast cancer (TNBC) is treated with highly aggressive non-targeted chemotherapies.&nbsp;Safer and more effective therapeutic approaches than those currently in use are needed. Natural pomegranate peel extract (PPE) has recently been found to inhibit breast cancer progression; however, its mechanisms of action remain unclear. We hypothesized that transcriptional chan...

متن کامل

A lipid-modified estrogen derivative that treats breast cancer independent of estrogen receptor expression through simultaneous induction of autophagy and apoptosis.

It is a challenge to develop a universal single drug that can treat breast cancer at single- or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific, estrogen-based drugs are being developed that cannot act against multistaged breast cancer complications owing to the cells differential estrogen receptor (ER) expression sta...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular pharmaceutics

دوره 12 4  شماره 

صفحات  -

تاریخ انتشار 2015