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Targeted delivery of paclitaxel to EphA2-expressing cancer cells.

ABSTRACT: YSA is an EphA2-targeting peptide that effectively delivers anticancer agents to prostate cancer tumors. Here, we report on how we increased the drug-like properties of this delivery system.By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo.dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared with vehicle or paclitaxel treatments.This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anticancer agents to a variety of tumor types.

SUBMITTER: Wang S

PROVIDER: S-EPMC3537892 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Targeted delivery of paclitaxel to EphA2-expressing cancer cells.

Wang Si S Noberini Roberta R Stebbins John L JL Das Swadesh S Zhang Ziming Z Wu Bainan B Mitra Sayantan S Billet Sandrine S Fernandez Ana A Bhowmick Neil A NA Kitada Shinichi S Pasquale Elena B EB Fisher Paul B PB Pellecchia Maurizio M

Clinical cancer research : an official journal of the American Association for Cancer Research 20121115 1

<h4>Purpose</h4>YSA is an EphA2-targeting peptide that effectively delivers anticancer agents to prostate cancer tumors. Here, we report on how we increased the drug-like properties of this delivery system.<h4>Experimental design</h4>By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. ...[more]

PMID: 23155185

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Project description:BackgroundOsteosarcoma (OS) is the most common bone tumour in children and adolescents. Despite aggressive therapy regimens, treatment outcomes are unsatisfactory. Targeted delivery of drugs can provide higher effective doses at the site of the tumour, ultimately improving the efficacy of existing therapy. Identification of suitable receptors for drug targeting is an essential step in the design of targeted therapy for OS.MethodsWe conducted a comparative analysis of the surface proteome of human OS cells and osteoblasts using cell surface biotinylation combined with nano-liquid chromatography - tandem mass spectrometry-based proteomics to identify surface proteins specifically upregulated on OS cells. This approach generated an extensive data set from which we selected a candidate to study for its suitability as receptor for targeted treatment delivery to OS. First, surface expression of the ephrin type-A receptor 2 (EPHA2) receptor was confirmed using FACS analysis. Ephrin type-A receptor 2 expression in human tumour tissue was tested using immunohistochemistry. Receptor targeting and internalisation studies were conducted to assess intracellular uptake of targeted modalities via EPHA2. Finally, tissue micro arrays containing cores of human OS tissue were stained using immunohistochemistry and EPHA2 staining was correlated to clinical outcome measures.ResultsUsing mass spectrometry, a total of 2841 proteins were identified of which 156 were surface proteins significantly upregulated on OS cells compared with human primary osteoblasts. Ephrin type-A receptor 2 was highly upregulated and the most abundant surface protein on OS cells. In addition, EPHA2 was expressed in a vast majority of human OS samples. Ephrin type-A receptor 2 effectively mediates internalisation of targeted adenoviral vectors into OS cells. Patients with EPHA2-positive tumours showed a trend toward inferior overall survival.ConclusionThe results presented here suggest that the EPHA2 receptor can be considered an attractive candidate receptor for targeted delivery of therapeutics to OS.

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Targeted delivery of paclitaxel to EphA2-expressing cancer cells.

Publications

Targeted delivery of paclitaxel to EphA2-expressing cancer cells.

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