Synthesis and biological evaluation of a peptide–paclitaxel conjugate which targets the integrin αvβ6

Li, Shunzi; Gray, Bethany Powell; McGuire, Michael J.; Brown, Kathlynn C.

doi:10.1016/j.bmc.2011.07.046

Cited by 25 publications

(19 citation statements)

References 43 publications

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“…The crude product was purified by flash chromatography using EtP:AcoEt = 2:3 as eluent to obtain the final pure product as white powder with 46% yield. 1 H NMR, 400 MHz, CDCl 3 21 . 13 C-NMR, 100 MHz, CDCl 3 , δ: 9.59; 14.77; 20.80; 22.14; 22.67; 26.77; 32.47; 33.29; 35.48; 43.13; 45.54; 52.36; 58.49; 71.74; 72.09; 74.47; 75.12; 75.60; 79.14; 81.02; 84.45 (24C, Caliph.)…”

Section: Methodsmentioning

confidence: 99%

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Brunetti

Pillozzi

Falciani

et al. 2015

Sci Rep

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Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity.

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Section: Methodsmentioning

confidence: 99%

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Brunetti

Pillozzi

Falciani

et al. 2015

Sci Rep

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“…Therefore, smarter conjugate strategies linking PTX and trastuzumab should be exploited for improved performance of targeted delivery and tumor‐selective action of the drug. Furthermore, the 2′‐hydroxyl group of PTX should be intact after release from the conjugate to properly interfere with tubulin ,. Consequently, a linker that is stable enough in human plasma but hydrolyzed within cancer cells releasing PTX without liker residues should be applied.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Feasibility Evaluation of a new Trastuzumab Conjugate Integrated with Paclitaxel and ⁸⁹Zr for Theranostic Application Against HER2‐Expressing Breast Cancers

et al. 2019

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The preparation and in vitro evaluation of a theranostic conjugate composed of trastuzumab, paclitaxel (PTX), and deferoxamine (DFO)‐chelated 89Zr have been reported. These comounds have potential applications against HER2 receptor positive breast cancers. We conjugated DFO and PTX to trastuzumab by exploiting simple conjugation chemistry. The conjugate (DFO‐trastuzumab‐PTX) showed excellent radiolabeling efficiency with 89Zr and the labeled conjugate had high in vitro stability in human serum. Furthermore, DFO‐trastuzumab‐PTX displayed comparable cytotoxicity with PTX and 89Zr‐DFO‐trastuzumab‐PTX exhibited HER2 receptor‐mediated binding on HER2‐positive MDA‐MB‐231 breast cancer cells. The results of our in vitro study indicate high potential of 89Zr‐DFO‐trastuzumab‐PTX to be utilized in the theranostic application against HER2‐postive breast cancers.

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“…Small ligands with high affinity are also predicted to have high accumulation and retention in tumors and better distribution throughout the tumor tissue [33]. The H2009.1 peptide can easily be modified for direct conjugation to different chemotherapeutics, and a H2009.1 tetrameric peptide-paclitaxel conjugate shows promising results in vivo , inhibiting tumor growth to the same extent as free paclitaxel, despite a >30-fold lower toxicity in vitro [74]. …”

Section: Discussionmentioning

confidence: 99%

A Liposomal Drug Platform Overrides Peptide Ligand Targeting to a Cancer Biomarker, Irrespective of Ligand Affinity or Density

2013

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One method for improving cancer treatment is the use of nanoparticle drugs functionalized with targeting ligands that recognize receptors expressed selectively by tumor cells. In theory such targeting ligands should specifically deliver the nanoparticle drug to the tumor, increasing drug concentration in the tumor and delivering the drug to its site of action within the tumor tissue. However, the leaky vasculature of tumors combined with a poor lymphatic system allows the passive accumulation, and subsequent retention, of nanosized materials in tumors. Furthermore, a large nanoparticle size may impede tumor penetration. As such, the role of active targeting in nanoparticle delivery is controversial, and it is difficult to predict how a targeted nanoparticle drug will behave in vivo. Here we report in vivo studies for αvβ6-specific H2009.1 peptide targeted liposomal doxorubicin, which increased liposomal delivery and toxicity to lung cancer cells in vitro. We systematically varied ligand affinity, ligand density, ligand stability, liposome dosage, and tumor models to assess the role of active targeting of liposomes to αvβ6. In direct contrast to the in vitro results, we demonstrate no difference in in vivo targeting or efficacy for H2009.1 tetrameric peptide liposomal doxorubicin, compared to control peptide and no peptide liposomes. Examining liposome accumulation and distribution within the tumor demonstrates that the liposome, and not the H2009.1 peptide, drives tumor accumulation, and that both targeted H2009.1 and untargeted liposomes remain in perivascular regions, with little tumor penetration. Thus H2009.1 targeted liposomes fail to improve drug efficacy because the liposome drug platform prevents the H2009.1 peptide from both actively targeting the tumor and binding to tumor cells throughout the tumor tissue. Therefore, using a high affinity and high specificity ligand targeting an over-expressed tumor biomarker does not guarantee enhanced efficacy of a liposomal drug. These results highlight the complexity of in vivo targeting.

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Synthesis and biological evaluation of a peptide–paclitaxel conjugate which targets the integrin αvβ6

Cited by 25 publications

References 43 publications

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Synthesis and Feasibility Evaluation of a new Trastuzumab Conjugate Integrated with Paclitaxel and ⁸⁹Zr for Theranostic Application Against HER2‐Expressing Breast Cancers

A Liposomal Drug Platform Overrides Peptide Ligand Targeting to a Cancer Biomarker, Irrespective of Ligand Affinity or Density

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Synthesis and biological evaluation of a peptide–paclitaxel conjugate which targets the integrin αvβ6

Cited by 25 publications

References 43 publications

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

Synthesis and Feasibility Evaluation of a new Trastuzumab Conjugate Integrated with Paclitaxel and 89Zr for Theranostic Application Against HER2‐Expressing Breast Cancers

A Liposomal Drug Platform Overrides Peptide Ligand Targeting to a Cancer Biomarker, Irrespective of Ligand Affinity or Density

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Synthesis and Feasibility Evaluation of a new Trastuzumab Conjugate Integrated with Paclitaxel and ⁸⁹Zr for Theranostic Application Against HER2‐Expressing Breast Cancers