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. 2023 Jun 27;24(13):10704.
doi: 10.3390/ijms241310704.

Preclinical Assessment of ADAM9-Responsive Mesoporous Silica Nanoparticles for the Treatment of Pancreatic Cancer

Etienne J Slapak  1   2   3 , Mouad El Mandili  1   2 , Marieke S Ten Brink  1 , Alexander Kros  4 , Maarten F Bijlsma  1   2   3 , C Arnold Spek  1   3
Affiliations

Preclinical Assessment of ADAM9-Responsive Mesoporous Silica Nanoparticles for the Treatment of Pancreatic Cancer

Etienne J Slapak et al. Int J Mol Sci. .

Abstract

Pancreatic adenocarcinoma (PDAC) remains largely refractory to chemotherapeutic treatment regimens and, consequently, has the worst survival rate of all cancers. The low efficacy of current treatments results largely from toxicity-dependent dose limitations and premature cessation of therapy. Recently, targeted delivery approaches that may reduce off-target toxicities have been developed. In this paper, we present a preclinical evaluation of a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSNs) functionalized with a protease linker that is specifically cleaved by PDAC cells. Our previous work demonstrated that ADAM9 is a PDAC-enriched protease and that paclitaxel-loaded ADAM9-responsive MSNs effectively kill PDAC cells in vitro. Here, we show that paclitaxel-loaded ADAM9-MSNs result in off-target cytotoxicity in clinically relevant models, which spurred the development of optimized ADAM9-responsive MSNs (OPT-MSNs). We found that these OPT-MSNs still efficiently kill PDAC cells but, as opposed to free paclitaxel, do not induce death in neuronal or bone marrow cells. In line with these in vitro data, paclitaxel-loaded OPT-MSNs showed reduced organ damage and leukopenia in a preclinical PDAC xenograft model. However, no antitumor response was observed upon OPT-MSN administration in vivo. The poor in vivo antitumor activity of OPT-MSNs despite efficient antitumor effects in vitro highlights that although MSN-based tumor-targeting strategies may hold therapeutic potential, clinical translation does not seem as straightforward as anticipated.

Keywords: MSN; PDAC; antitumor; drug delivery; leukopenia; neurotoxicity; targeted therapy.

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Conflict of interest statement

M.F.B. has received research funding from Celgene, Lead Pharma, and Frame Therapeutics and acted as a consultant to Servier and Olympus. Neither of these organizations were involved in the design of this study nor the drafting of the manuscript.

Figures

Figure 1
Figure 1
Paclitaxel-loaded ADAM9-MSNs evoke neurotoxicity and bone marrow toxicity in preclinical models in vitro. IC50 curve in PANC-1 (A) and SH-SY5Y (C) cells after 72 h of free paclitaxel administration (data modified from a previous publication [9]). Cytotoxicity of paclitaxel-loaded ADAM9-MSNs in PANC-1 (B) and SH-SY5Y (D) cells after 72 h. Data are shown as the mean of one representative experiment with n = 6. Results are normalized to untreated controls. Microscopic images resembling diverse bone-marrow-derived colonies from representative colony-forming assays (E). Cytotoxicity of free paclitaxel and paclitaxel-loaded ADAM9-MSNs on bone marrow cells from colony-forming assays after 7 days. Data are shown as the mean of one representative experiment with n = 3. Levels of significance: ** p < 0.01 and *** p < 0.001.
Figure 2
Figure 2
MSNs with a modified ADAM9 linker have increased PDAC specificity and reduced general toxicity. (A) Expression levels of proteases capable of cleaving the ADAM9 linker. Data were extracted from publicly available gene expression datasets (GSE36133, GSE57083, GSE46903, and E-MTAB-783). (B) Molecular structure of modified ADAM9 linker (OPT linker). (C) Transmission electron microscopic images of peptide–biotin-coupled MSNs. (D) Fourier transform infrared spectra of MSNs, several modified intermediates, and final products OPT and uncleavable OPT-MSNs. (E) Cytotoxicity of paclitaxel-loaded OPT and uncleavable OPT-MSNs in PANC-1 cells after 72 h (n = 12). (F) Cytotoxicity of paclitaxel-loaded OPT-MSNs in Capan-2 cells (n = 12) and SH-SY5Y cells ((G), n = 12) after 72 h and in bone marrow cells ((H), n = 3) after 7 days. Data are normalized to untreated controls. Levels of significance: ns = not significant, * p < 0.05 and **** p < 0.0001.
Figure 3
Figure 3
Intravenous injection of fluorescent MSNs results in significant tumor accumulation in vivo. (A) Determination of optimal dose administration in vivo. (B) In vivo biodistribution of fluorescent MSNs after repeated administration. Measurements were performed in technical replicates. Levels of significance: *** p < 0.001 and **** p < 0.0001.
Figure 4
Figure 4
Paclitaxel-loaded OPT-MSNs reduce neutropenia and organ damage but show no antitumor effect in vivo. (A) Toxicity of paclitaxel-loaded OPT-MSNs in KP2 cells 72 h after administration (n = 12). (B) Weight of mice during the experiment. (C) Tumor volume (mm3) plotted over time. Data analysis was complicated by the fast-growing nature and ulcerative properties of KP2 cells, causing the sacrificing of 16 mice before the end of the experiment because they met the criteria set as humane end points. Both ulceration and reaching a tumor size of >1.5 cm3 led to the killing of eight mice, and two mice reached both humane end points simultaneously. (D) Blood leukocyte counts at sacrifice. Plasma LDH (E), ALAT (F), and creatinine (G) levels as measured by HPLC following standardized clinical guidelines of the AUMC. Levels of significance: * p < 0.05 and *** p < 0.001.
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