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Sequential delivery of erlotinib and doxorubicin for enhanced triple negative Breast cancer treatment using polymeric nanoparticle.

ABSTRACT: Recent studies of signaling networks point out that an order of drugs to be administrated to the cancerous cells can be critical for optimal therapeutic outcomes of recalcitrant metastatic and drug-resistant cell types. In this study, a development of a polymeric nanoparticle system for sequential delivery is reported. The nanoparticle system can co-encapsulate and co-deliver a combination of therapeutic agents with different physicochemical properties [i.e. epidermal growth factor receptor (EGFR) inhibitor, erlotinib (Ei), and doxorubicin (Dox)]. Dox is hydrophilic and was complexed with anionic lipid, 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), via ion pairing to form a hydrophobic entity. Then it was co-encapsulated with hydrophobic Ei in a poly(L-lactide)-b-polyethylene glycol (PLA-b-PEG) nanoparticle by nanoprecipitation. The complexation of Dox with DOPA greatly helps the encapsulation of Dox, and substantially reduces the release rate of Dox. This nanoparticle system was found to burst the release of Ei with a slow and sustained profile of Dox, which is an optimal course of administration for these two drugs as previously reported. The efficacy of this sequential delivery nanoparticle system was validated in vitro and its in vivo potential applicability was substantiated by fluorescent imaging of high tumor accumulation.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC5677602 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Sequential delivery of erlotinib and doxorubicin for enhanced triple negative Breast cancer treatment using polymeric nanoparticle.

Zhou Zilan Z Kennell Carly C Jafari Mina M Lee Joo-Youp JY Ruiz-Torres Sasha J SJ Waltz Susan E SE Lee Jing-Huei JH

International journal of pharmaceutics 20170801 1-2

Recent studies of signaling networks point out that an order of drugs to be administrated to the cancerous cells can be critical for optimal therapeutic outcomes of recalcitrant metastatic and drug-resistant cell types. In this study, a development of a polymeric nanoparticle system for sequential delivery is reported. The nanoparticle system can co-encapsulate and co-deliver a combination of therapeutic agents with different physicochemical properties [i.e. epidermal growth factor receptor (EGF ...[more]

PMID: 28778627

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Project description:Biological nanoparticles, such as exosomes, offer an approach to drug delivery because of their innate ability to transport biomolecules. Exosomes are derived from cells and an integral component of cellular communication. However, the cellular cargo of human exosomes could negatively impact their use as a safe drug carrier. Additionally, exosomes have the intrinsic yet enigmatic, targeting characteristics of complex cellular communication. Hence, harnessing the natural transport abilities of exosomes for drug delivery requires predictably targeting these biological nanoparticles. This manuscript describes the use of two chemical modifications, incorporating a neuropilin receptor agonist peptide (iRGD) and a hypoxia-responsive lipid for targeting and release of an encapsulated drug from bovine milk exosomes to triple-negative breast cancer cells. Triple-negative breast cancer is a very aggressive and deadly form of malignancy with limited treatment options. Incorporation of both the iRGD peptide and hypoxia-responsive lipid into the lipid bilayer of bovine milk exosomes and encapsulation of the anticancer drug, doxorubicin, created the peptide targeted, hypoxia-responsive bovine milk exosomes, iDHRX. Initial studies confirmed the presence of iRGD peptide and the exosomes' ability to target the αvβ3 integrin, overexpressed on triple-negative breast cancer cells' surface. These modified exosomes were stable under normoxic conditions but fragmented in the reducing microenvironment created by 10 mM glutathione. In vitro cellular internalization studies in monolayer and three-dimensional (3D) spheroids of triple-negative breast cancer cells confirmed the cell-killing ability of iDHRX. Cell viability of 50% was reached at 10 μM iDHRX in the 3D spheroid models using four different triple-negative breast cancer cell lines. Overall, the tumor penetrating, hypoxia-responsive exosomes encapsulating doxorubicin would be effective in reducing triple-negative breast cancer cells' survival.

Project description:BackgroundManagement of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC.MethodsNanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses.ResultsWe demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs.ConclusionsOur study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.

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Sequential delivery of erlotinib and doxorubicin for enhanced triple negative Breast cancer treatment using polymeric nanoparticle.

Publications

Sequential delivery of erlotinib and doxorubicin for enhanced triple negative Breast cancer treatment using polymeric nanoparticle.

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