GE11 Modified PLGA/TPGS Nanoparticles Targeting Delivery of Salinomycin to Breast Cancer Cells
Abstract:
Salinomycin (Sal) is a potent inhibitor with effective anti-breast cancer properties in clinical therapy. The occurrence of various side effect of Sal greatly limits its application. The epidermal growth factor receptor (EGFR) family is a family of receptors highly expressed in most breast cancer cells. GE11 is a dodecapeptide which shows excellent EGFR affinity. A series of nanoparticles derivatives with GE11 peptide conjugated PLGA/TPGS were synthesized. Nanoprecipitation method was used to prepare the Sal loaded nanoparticles at the optimized concentration. The characterization, targeting efficacy, and antitumor activity were detected both in vitro and in vivo. Encapsulation of Sal in GE11 modified PLGA/TPGS nanoparticles shows an improved therapy efficacy and lower systemic side effect. This represents the delivery system a promising strategy to enhance the therapeutic effect against EGFR highly expressed breast cancer.
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Introduction:
Breast cancer is the second most common cancer among female globally. Effective treatments for breast cancer with early-stage include surgical resection and concurrent chemoradiotherapy, which can lead to a 5-year survival of ≤ 75%. About 50% of breast cancer patients eventually cause tumor recurrence and/or metastasis, which hampers the long-lasting and effective therapy.
The chemotherapeutic drug of Salinomycin (Sal), which isolated from Streptomyces albus, has been reported to eliminate various tumors, such as liver cancer, breast cancer, and lung cancer. Significantly, more and more evidence established that the Sal inhibits the breast cancer stem cells via blocking the Wnt/β-catenin pathway both in vitro and in vivo.Therefore, the Sal is regarding as a potentially effective agent for treatment of breast cancer. However, Sal possesses poor aqueous solubility and un-substantial cancer cells cytotoxicity.These disadvantages induce the limitation of the Sal application on breast cancer therapy. Direct delivery of Sal to the breast cancer cells would be a valuable breakthrough for its clinical application.
Targeted nanoparticles have developed to be excellent drug delivery systems due to their promising performance and unique characteristics, such as improving the inapplicable properties of drugs or pharmacokinetic properties.In addition, the chemotherapeutic drugs could accumulate at the solid tumor site owing to the enhanced permeability and retention (EPR) effect, leading to the clinical benefit with decreased side effects.The biodegradable polymers and biocompatible liposomes are the widely used categories in nanomedicine. The liposomes are the spherical lipid carriers with single or multiple bilayers and favorable in feasible surface modification and long circulation time in vivo. However, the prepared liposomes are restricted by uncontrollable drug release, instability, and insufficient drug loading. While the combination of polymer-lipid hybrid nanoparticles could dissolve the limitations, some researchers developed these nanoparticles as powerful drug delivery systems on the treatments of cancers. PLGA, poly lactic-co-glycolic acid, is characterized by long-lasting drugs release from many days to many weeks and easy medicated with many approaches such as surface embellish, novel synthesized, and polyporous. In addition, PLGA shows advanced biocompatibility in vivo with a rigid structure. TPGS, D-α-Tocopheryl polyethylene glycol 1000 succinate, is a water-soluble derivative of natural vitamin E which can be used as solvent, stabilizer, and emulsifier for PLGA modification. These modifications can cause the size of PLGA nanoparticles be smaller and the drug encapsulation efficiency be higher. Moreover, both the PLGA and TPGS are approved by US food and drug administration (FDA) as safe pharmaceutical excipients. Some researchers have used PLGA/TPGS particles to deliver drugs for improving chemotherapy about multi-drug resistant breast cancer.
Epidermal growth factor receptor (EGFR) is greatly overexpressed on the surface of various human malignancies and regarding as a valuable target for cancer therapy include breast cancer. A screened small peptide GE11 by the phage display was demonstrated to have high affinity against EGFR significantly upregulated cancer cells. The affinity between GE11 and EGFR is significantly high (kd = 22 nM).GE11 has only 12 amino acids (YHWYGYTPQNVI) and is much smaller than the EFGR’s ligand EGF. This small peptide targets only to one region of EGFR. These characters make it a prospecting targeting candidate for EGFR-targeted therapy of breast cancer.
In present study, we designed and synthesized Sal-loaded nanoparticles (NPs) functionalized with GE11 targeting peptide to achieve the efficient delivery of Sal to breast cancer cells. The chemotherapeutic drugs Sal were successfully encapsulated in NPs via the 1-step nanoprecipitation process.NPs-Sal-GE11 was further prepared by binding anti-EGFR peptide with NP-Sal by a maleimide-thiol reaction. The physicochemical characterization, targeting efficacy, and antitumor activity of the Sal-NPs-GE11 against breast cancer cells were evaluated in this work.