Intracellular Cargo Delivery by an Octaarginine Transporter Adapted to Target Prostate Cancer Cells through Cell Surface Protease Activation

Goun, Elena A.; Shinde, Rajesh; Dehnert, Karen W.; Adams-Bond, Angie; Wender, Paul A.; Contag, Christopher H.; Franc, Benjamin L.

doi:10.1021/bc0503216

Cited by 67 publications

(71 citation statements)

References 39 publications

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“…The use of activatable cell-penetrating imaging probes has been advocated as a promising general strategy for the in vivo imaging of proteolytic activity, in particular in tumors (21,31). Several recent reports have asserted that tumors can be visualized via optical imaging and MRI of MMP-2/9 activity using ACPPs (21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Duijnhoven¹,

Robillard²,

Nicolay³

et al. 2011

J Nucl Med

106

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Activatable cell-penetrating peptides (ACPPs) are a new class of promising molecular imaging probes for the visualization of enzymes in vivo. The cell-penetrating function of a polycationic peptide is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a cleavable linker present between the polycationic cell-penetrating peptide and polyanionic peptide affords dissociation of both domains and enables the activated cell-penetrating peptide to enter cells. Here, we aimed to develop an ACPP sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for nuclear imaging purposes. Methods: MMP-2/9 ACPPs and nonactivatable cell-penetrating peptides (non-ACPP) were prepared by 9-fluorenylmethyloxycarbonyl solid-phase peptide synthesis and labeled with 177 Lu or 177 Lu/ 125 I for dual-isotope studies. The in vivo biodistribution of these probes was assessed in MMP-2/9-positive tumor-bearing mice (n 5 6) and healthy mice (n 5 4) using g-counting. Furthermore, a radiolabeled cell-penetrating peptide serving as a positive control was evaluated in tumorbearing mice (n 5 6). Results: Biodistribution studies showed a 5-fold-higher retention of ACPP in tumor than in muscle (P , 0.01) and a 6-fold-higher tumor retention relative to non-ACPP (P , 0.01), supporting earlier studies on fluorescently labeled ACPPs proposing activation by tumor-associated MMP-2/9. Surprisingly, however, the uptake of ACPP was significantly higher than that of non-ACPP in almost all tissues (P , 0.01). To unravel the activation process of ACPP in vivo, we developed dual-isotope ACPP analogs (dACPPs) that allowed us to discriminate between uncleaved dACPP and activated dACPP. In vivo biodistribution of dACPP indicated that the tissue-associated counts originated from activated dACPP. Interestingly, dACPP administration to healthy mice, compared with MMP-2/9-positive tumor-bearing mice, resulted in a similar dACPP biodistribution. Furthermore, a radiolabeled cell-penetrating peptide showed tumor-to-tissue ratios equal to those found for ACPP (P . 0.05). Conclusion: This study demonstrates that the tumor targeting of radiolabeled MMP-2/9 ACPPs is most likely caused by the activation in the vascular compartment rather than tumor-specific activation, as suggested earlier.The results in the present paper indicate that different and more tissue-specific enzyme-ACPP combinations are needed to unleash the full potential of the elegant ACPP concept in living animals.

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Section: Discussionmentioning

confidence: 99%

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Duijnhoven¹,

Robillard²,

Nicolay³

et al. 2011

J Nucl Med

106

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“…Upon encounter with the protease, the peptide linker is cleaved, thereby activating the transporter and allowing its entry into surrounding tissue. This tissue-specific cleavage then promotes dissociation of the transporter from its suppressing domain and subsequently the active transporter translocates the nearby tissue [16,17]. This concept has potentially wide application for targeted therapy.…”

Section: Tissue Uptakementioning

confidence: 99%

The design of guanidinium-rich transporters and their internalization mechanisms

Wender

Galliher

Goun

et al. 2008

Advanced Drug Delivery Reviews

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379

337

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The ability of a drug or probe to cross a biological barrier has historically been viewed to be a function of its intrinsic physical properties. This view has largely restricted drug design and selection to agents within a narrow log P range. Molecular transporters offer a strategy to circumvent these restrictions. In the case of guanidinium-rich transporters (GRTs), a typically highly water-soluble conjugate is found to readily pass through the non-polar membrane of a cell and for some across tissue barriers. This activity opens a field of opportunities for the use of GRTs to enable delivery of polar and nonpolar drugs or probes as well as to enhance uptake of those of intermediate polarity. The field of transporter enabled or enhanced uptake has grown dramatically in the last decade. Some GRT drug conjugates have been advanced into clinical trials. This review will provide an overview of recent work pertinent to the design and mechanism of uptake of GRTs.

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“…An example of this approach [84] is illustrated for the (d) arginine octamer (r 8 ) transporter adapted for selective uptake into cells only after proteolytic cleavage of a transporter-attenuating sequence by the prostate-specific antigen (PSA)-an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. These "activatable" octa-arginine transporters (AOT) are stable in serum, but are A C H T U N G T R E N N U N G effectively cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA.…”

Section: Targeted Cargo Delivery By Octa-arginine Transportersmentioning

confidence: 99%

Molecular Transporters: Synthesis of Oligoguanidinium Transporters and Their Application to Drug Delivery and Real‐Time Imaging

et al. 2006

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Intracellular Cargo Delivery by an Octaarginine Transporter Adapted to Target Prostate Cancer Cells through Cell Surface Protease Activation

Cited by 67 publications

References 39 publications

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

The design of guanidinium-rich transporters and their internalization mechanisms

Molecular Transporters: Synthesis of Oligoguanidinium Transporters and Their Application to Drug Delivery and Real‐Time Imaging

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