Theranostics is an emerging treatment approach that combines diagnostics with therapy in order to personalize treatment regimens for individual patients and decrease cancer mortality. Previously, nanoparticles entrapping conventional fluorescent dyes were developed for cancer theranostics, but fluorescent nanoparticles did not allow clinicians to significantly improve cancer treatments.
The use of fluorescent dyes that are sensitive to solvent acidity (halo-fluorochromism) and polarity (solvato-fluorochromism) may overcome the limitations of fluorescent nanoparticles and improve cancer therapy by enabling researchers to detect chemical properties within the nanoparticle core environment. The model halo- and solvato-fluorochromic dye Nile blue was attached to the core of nanoscale drug delivery systems called polymer nanoassemblies (PNAs), which were created by tethering hydrophilic polymers and hydrophobic groups to a cationic polymer scaffold. The fluorescence of empty PNAs increased by 100% at pH 5.0 compared to pH 7.4, and the fluorescence of drug-loaded PNAs increased up to 300% compared to empty PNAs. A comparison of the fluorochromic properties between PNAs with various core properties indicated that both hydrophobic pendant groups and scaffold amines contributed to the fluorochromism of PNAs.
The halo-fluorochromism of PNAs allowed investigators to minimize the detection of fluorescence signals in healthy organs such as the liver. Fluorescence imaging of halo-fluorochromic PNAs diffused into tissue mimics indicated that fluorescence of PNAs in tissues increased by 100% at pH 7.0 compared to pH 7.4. In addition, halo-fluorochromic PNAs identified the acidic perimeter surrounding metastatic tumors in orthotopic metastatic tumor models. Computational simulations of metastatic lesions verified that some halo-fluorochromic PNAs accumulate in the hypoxic/acidic regions of metastatic tumors following intravenous administration. These simulations also indicated that the accumulation of PNAs in the hypoxic regions of tumors doubles at 12 hours post-treatment compared to 1.8 hours post-treatment.
The solvato-fluorochromism of PNAs enabled the fluorescence-based measurement of drug release from the nanoassembly core during dialysis-based drug release measurements. Solvato-fluorochromic methods indicated faster drug release rates than HPLC-based methods. Mechanistic modeling of drug release indicated that solvato-fluorochromic methods were unaffected by released drugs that interfered with HPLC-based methods. However, mechanistic modeling also indicated that drug rebinding and diffusion did not account for all of the differences between drug release rates determined by solvato-fluorochromic- and HPLC-based methods. Based on this evidence, it was hypothesized that solvato-fluorochromic drug release methods measure drug diffusion from near the scaffold of PNAs in a small region of the nanoassembly core, and that this process contributes to overall drug release but does not indicate apparent drug release rates for PNAs.
In order to develop PNAs for potential clinical applications, ionizable amines were removed from the polymer scaffold to increase drug loading and sustain the release of model drugs carfilzomib and docetaxel. The removal of primary amines decreased drug diffusivity in the core of PNAs (D from 3.9*10-18 cm2/s to 0.1*10-19 cm2/s) and increased the drug release half-life (t1/2 from 4 to 26 hours). The controlled release of carfilzomib from PNAs reduced drug metabolism by 60% for up to one hour and sustained proteasome inhibition in cancer cells at 72 h post-treatment compared to free drug.
Overall, this work provides insight into the design of theranostic nanoparticles with beneficial properties for improving cancer treatment.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:pharmacy_etds-1078 |
| Date | 01 January 2017 |
| Creators | Reichel, Derek Alexander |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Pharmacy |
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