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Comparative Study
. 2018 Jun-Jul;26(5-6):505-515.
doi: 10.1080/1061186X.2017.1405424. Epub 2017 Dec 1.

Phage-derived protein-mediated targeted chemotherapy of pancreatic cancer

Tao Wang  1 , Radhika Narayanaswamy  1 , Huilan Ren  1 , James W Gillespie  2 , Valery A Petrenko  2 , Vladimir P Torchilin  1
Affiliations
Comparative Study

Phage-derived protein-mediated targeted chemotherapy of pancreatic cancer

Tao Wang et al. J Drug Target. 2018 Jun-Jul.

Abstract

Pancreatic cancer has been a life-threatening illness associated with high incidence and mortality rates. Paclitaxel (PCT) that causes mitotic arrest in cancer cells disrupting microtubule function is used for pancreatic cancer treatment. Nausea, anorexia and abdominal pain are some of the typical dose-limiting toxicity associated gastrointestinal side effects of the drug. Here, we present the use of polymeric mixed micelles to enable a targeted delivery of PCT and to provide additional advantages such as enhanced drug solubility, bioavailability and minimal dose-limiting toxicity. Also, these micelles self-assemble with pancreatic cancer cells-specific phage proteins P38, L1 and with the hydrophobic drug PCT resolving the issue of complex chemistry efforts normally needed for any conjugation. Our cytotoxicity and binding experiment results in vitro in 2 D and 3 D models suggested that the phage protein-targeted drug-loaded micelles bind and exhibit higher cell killing over the non-targeted ones.

Keywords: Cancer targeting; in vitro uptake and cytotoxicity studies; nanoparticles; paclitaxel; pancreatic cancer; pharmacokinetics; polymeric micelles; self-assembling; spheroid model; targeted drug delivery.

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Figures

Figure 1.
Figure 1.
Characterization of the Micelle Formations. (A) Critical micelle concentration (CMC) determination; (B) Size; (C) Zeta potential; (D) Drug release profiles.
Figure 2.
Figure 2.
Stability testing of phage-micelles in PBS under accelerated conditions such as shaking and elevated temperature of 37°C as opposed to normal storage at 4°C.
Figure 3.
Figure 3.
Stability testing using FBS. P38 and L1 Modified micelles had slower and lesser protein adsorption / interaction in FBS within 48h at 37 °C.
Figure 4.
Figure 4.
Cellular uptake by P38 phage micelles.
Figure 5.
Figure 5.
Cellular uptake by L1 phage micelles.
Figure 6.
Figure 6.
Fluorescence microscopy study the association of micellar nanoparticle with targeted panc-1 cells, showing improved targeted cell binding of p38 and L1 phage micelles when compared to non-modified plain micelles.
Figure 7.
Figure 7.
In vitro antitumor activity. (A) Cell viability tested on monolayer panc-1 cancer cells; (B) In vitro apoptosis-inducing ability; (C) In vitro apoptosis-inducing ability
See this image and copyright information in PMC

References

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