Enhancing Accumulation and Penetration of HPMA Copolymer–Doxorubicin Conjugates in 2D and 3D Prostate Cancer Cells via iRGD Conjugation with an MMP-2 Cleavable Spacer

Peng, Zheng Hong; Kopeček, Jindřich

doi:10.1021/jacs.5b00922

Cited by 142 publications

(88 citation statements)

References 38 publications

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“…In addition to the size‐transition discussed above,[13,33b,123] other strategies have also been explored to improve tumor penetration ability of nanomedicines, including functionalizing nanomedicines with tumor penetrating peptides and modulating tumor extracellular matrix . Tumor‐homing and ‐penetrating cyclic peptide iRGD, tLyP‐1, PFVYLI (PFV) have been shown to enhance the tumor accumulation and penetration of nanomedicines, particularly tumor penetrating peptides containing a cryptic (R/K)XX(R/K) CendR element that must be C‐terminally exposed to trigger neuropilin‐1 (NRP‐1) binding, cellular internalization and malignant tissue penetration …”

Section: Approaches To Achieve the 3s Transitionsmentioning

confidence: 99%

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization

et al. 2017

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Current cancer nanomedicines can only mitigate adverse effects but fail to enhance therapeutic efficacies of anticancer drugs. Rational design of next-generation cancer nanomedicines should aim to enhance their therapeutic efficacies. Taking this into account, this review first analyzes the typical cancer-drug-delivery process of an intravenously administered nanomedicine and concludes that the delivery involves a five-step CAPIR cascade and that high efficiency at every step is critical to guarantee high overall therapeutic efficiency. Further analysis shows that the nanoproperties needed in each step for a nanomedicine to maximize its efficiency are different and even opposing in different steps, particularly what the authors call the PEG, surface-charge, size and stability dilemmas. To resolve those dilemmas in order to integrate all needed nanoproperties into one nanomedicine, stability, surface and size nanoproperty transitions (3S transitions for short) are proposed and the reported strategies to realize these transitions are comprehensively summarized. Examples of nanomedicines capable of the 3S transitions are discussed, as are future research directions to design high-performance cancer nanomedicines and their clinical translations.

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Section: Approaches To Achieve the 3s Transitionsmentioning

confidence: 99%

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization

et al. 2017

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“…Since that publication there have been additional studies that have utilized the iRGD peptide with the chemotherapeutic agent doxorubicin (DOX) in cancer biology research. Follow-up studies by Peng et al reported that in an in vitro model of prostate cancer iRGD improved the penetrance of DOX into tumor cell lines (Peng and Kopeček, 2015). However, this improvement was only observed in a DOX/iRGD conjugated form.…”

Section: Introductionmentioning

confidence: 99%

Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs

Mantis

Kandela

Aird

2017

eLife

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In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs“ (Sugahara et al., 2010). Here we report the results of those experiments. We found that coadministration with iRGD peptide did not have an impact on permeability of the chemotherapeutic agent doxorubicin (DOX) in a xenograft model of prostate cancer, whereas the original study reported that it increased the penetrance of this cancer drug (Figure 2B; Sugahara et al., 2010). Further, in mice bearing orthotopic 22Rv1 human prostate tumors, we did not find a statistically significant difference in tumor weight for mice treated with DOX and iRGD compared to DOX alone, whereas the original study reported a decrease in tumor weight when DOX was coadministered with iRGD (Figure 2C; Sugahara et al., 2010). In addition, we did not find a statistically significant difference in TUNEL staining in tumor tissue between mice treated with DOX and iRGD compared to DOX alone, while the original study reported an increase in TUNEL positive staining with iRGD coadministration (Figure 2D; Sugahara et al., 2010). Similar to the original study (Supplemental Figure 9A; Sugahara et al., 2010), we did not observe an impact on mouse body weight with DOX and iRGD treatment. Finally, we report meta-analyses for each result.DOI: http://dx.doi.org/10.7554/eLife.17584.001

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“…Tumor homing of the disulfide-bridged cyclic iRGD peptide follows the consecutive steps: the RGD sequence binds to αv integrins on tumor endothelium, then iRGD undergoes a proteolytic cleavage to expose the CendR motif (R/KXXR/K) that triggers neuropilin-1 (NRP-1)-mediated internalization into cells [20, 21]. These distinct attributes of iRGD have been utilized to improve the tumor targeting and internalization of imaging agents and drugs [22-29]. …”

Section: Introductionmentioning

confidence: 99%

Activatable iRGD-based peptide monolith: Targeting, internalization, and fluorescence activation for precise tumor imaging

Cho

Lee

Park

et al. 2016

Journal of Controlled Release

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A disulfide-bridged cyclic RGD peptide, named iRGD (internalizing RGD, c(CRGDK/RGPD/EC)), is known to facilitate tumor targeting as well as tissue penetration. After the RGD motif-induced targeting on αv integrins expressed near tumor tissue, iRGD encounters proteolytic cleavage to expose the CendR motif that promotes penetration into cancer cells via the interaction with neuropilin-1. Based on these proteolytic cleavage and internalization mechanism, we designed an iRGD-based monolithic imaging probe that integrates multiple functions (cancer-specific targeting, internalization and fluorescence activation) within a small peptide framework. To provide the capability of activatable fluorescence signaling, we conjugated a fluorescent dye to the N-terminal of iRGD, which was linked to the internalizing sequence (CendR motif), and a quencher to the opposite C-terminal. It turned out that fluorescence activation of the dye/quencher-conjugated monolithic peptide probe requires dual (reductive and proteolytic) cleavages on both disulfide and amide bond of iRGD peptide. Furthermore, the cleavage of the iRGD peptide leading to fluorescence recovery was indeed operative depending on the tumor-related angiogenic receptors (αvβ3 integrin and neuropilin-1) in vitro as well as in vivo. Compared to an ‘always fluorescent’ iRGD control probe without quencher conjugation, the dye/quencher-conjugated activatable monolithic peptide probe visualized tumor regions more precisely with lower background noise after intravenous injection, owing to the multifunctional responses specific to tumor microenvironment. All these results, along with minimal in vitro and in vivo toxicity profiles, suggest potential of the iRGD-based activatable monolithic peptide probe as a promising imaging agent for precise tumor diagnosis.

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Enhancing Accumulation and Penetration of HPMA Copolymer–Doxorubicin Conjugates in 2D and 3D Prostate Cancer Cells via iRGD Conjugation with an MMP-2 Cleavable Spacer

Cited by 142 publications

References 38 publications

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization

Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs

Activatable iRGD-based peptide monolith: Targeting, internalization, and fluorescence activation for precise tumor imaging

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