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Development of Halofluorochromic Polymer Nanoassemblies for the Potential Detection of Liver Metastatic Colorectal Cancer Tumors Using Experimental and Computational Approaches

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A Correction to this article was published on 16 July 2021

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Abstract

Purpose

To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes.

Methods

We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm.

Results

Dye-conjugated PNAs showed no aggregation under opsonizing conditions for 24 h and displayed low tissue diffusion and cellular uptake. Both hfPNAs and n-hfPNAs accumulated in primary and liver metastatic CRC tumors within 12 h post intravenous injection. In comparison to n-hfPNAs, hfPNAs fluoresced strongly only in the acidic tumor microenvironment (pH < 7.0) and distinguished small metastatic CRC tumors from healthy liver stroma. Computational simulations revealed that PNAs would steadily accumulate mainly in acidic (hypoxic) interstitium of metastatic tumors, independently of the vascularization degree of the tissue surrounding the lesions.

Conclusion

The combined experimental and computational data confirms that hfPNAs detecting acidic tumor tissue can be used to identify small liver metastatic CRC tumors with improved accuracy.

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Abbreviations

CRC:

Colorectal cancer

hfPNA:

Halofluorochromic PNA

hfPNA#/NB:

hfPNA with PEG-PEI scaffold labeled with NB dye

hfPNA/NB:

hfPNA labeled with NB dye

NB:

Nile blue

n-hfPNA:

Non-halofluorochromic PNA

n-hfPNA/Alexa546:

n-hfPNA labeled with Alexa546 dye

n-hfPNA/IR820:

n-hfPNA labeled with IR820 dye

PAL:

Palmitatic acid

PDX:

Patient-derived xenograft

PEG:

Poly(ethylene glycol)

PEI:

Poly(ethylene imine)

PLL:

Poly(lysine)

PNA:

Polymer nanoassembly

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Acknowledgements and Disclosures

This work was supported by the University of Kentucky Graduate School Allocated Year (GSAY) Fellowship (DR) and the National Institutes of Health grant R01CA195573 (BME and PR). HBF acknowledges partial support by the National Institutes of Health /National Cancer Institute (R15CA203605).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, KY, 40536, USA

    Derek Reichel & Younsoo Bae

  2. Department of Bioengineering, School of Engineering, University of Louisville, 2301 South Third, Louisville, KY, 40292, USA

    Louis T. Curtis, Elizabeth Ehlman & Hermann B. Frieboes

  3. Markey Cancer Center, University of Kentucky, 800 Rose, Lexington, KY, 40536, USA

    Evers, B. Mark & Piotr Rychahou

  4. Department of Surgery, College of Medicine, University of Kentucky, 741 South Limestone, Lexington, KY, 40536, USA

    Evers, B. Mark & Piotr Rychahou

  5. Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, 505 South Hancock, Louisville, KY, 40292, USA

    Hermann B. Frieboes

  6. James Graham Brown Cancer Center, University of Louisville, 529 South Jackson, Louisville, KY, 40292, USA

    Hermann B. Frieboes

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  1. Derek Reichel
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  2. Louis T. Curtis
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  3. Elizabeth Ehlman
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  4. Evers, B. Mark
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  5. Piotr Rychahou
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  6. Hermann B. Frieboes
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  7. Younsoo Bae
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Corresponding author

Correspondence to Younsoo Bae.

Additional information

Piotr Rychahou, Hermann B. Frieboes, and Younsoo Bae share joint senior authorship.

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Reichel, D., Curtis, L.T., Ehlman, E. et al. Development of Halofluorochromic Polymer Nanoassemblies for the Potential Detection of Liver Metastatic Colorectal Cancer Tumors Using Experimental and Computational Approaches. Pharm Res 34, 2385–2402 (2017). https://doi.org/10.1007/s11095-017-2245-9

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