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.
|Number of pages||18|
|State||Published - Nov 1 2017|
Bibliographical noteFunding Information:
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).
© 2017, Springer Science+Business Media, LLC.
- computational tumor simulation
- nanoparticle distribution simulation
- tissue acidity
- tumor microenvironment
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Organic Chemistry
- Pharmacology (medical)