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. 2019 Oct 17;9(26):8018–8025. doi: 10.7150/thno.38587

Figure 4.

Figure 4

Use of stringent PDAC cancer models to study drug delivery using nanoparticle. With the rapid development of PDAC cancer biology, it has been possible by employing different PDAC mouse models to better understand the molecular mechanism underlying pancreatic cancer, including nanoparticle-mediated drug delivery. Trichrome staining of PANC-1 xenograft (A) and BxPC3 (B) in nude mice. While BxPC3 tumor (Kras WT) is usually regarded as stroma-rich, PANC-1 tumor (Kras mutated) contains moderate level of stroma content. With the recent success in the production of genetically engineered mouse models (GEMMs), it is theoretically possible to test nanotherapeutics in KPC model in which the conditional expression of mutant KrasG12D and Trp53R172H is governed by a pancreas-specific Cre. Without the involvement of Cre, a transcriptional and translational STOP cassette flanked by loxP sites silences the expression of mutant KrasG12D and Trp53R172H. In KPC tumor (C, adapted with permission from ref.93), substantial nuclear abnormalities occur and glands appear embedded in the tumor stroma (arrowheads) with completely random organization (arrows). However, a major pitfall using spontaneous KPC model is the variable growth characteristics of the spontaneous KPC model and the number of animal experiments that can be undertaken. Therefore, the variable tumor development and unfavorable logistics, precludes widespread use of KPC model. In order to perform robust experiment, we have established immortalized luciferase-transfected cell lines derived from spontaneous KPC tumors, and have used them to establish a surgical procedure for orthotopic tumors in immunocompetent, syngeneic B6/129 mice (D). We have confirmed that orthotopic implant in the pancreas leads to predictable tumor development within 1-2 weeks and mimic human PDAC characteristics such as local invasion of the G.I.T. and liver metastases after 3-5 weeks. Moreover, the availability of PDAC PDX model (E) allows the study of patient-specific response and personalized nanomedicine.