Active Targeting Significantly Outperforms Nanoparticle Size in Facilitating Tumor-Specific Uptake in Orthotopic Pancreatic Cancer

Abstract

Nanoparticles are widely studied as theranostic vehicles for cancer; however, clinical translation has been limited due to poor tumor specificity. Features that maximize tumor uptake remain controversial, particularly when using clinically relevant models. We report a systematic study that assesses two major features for the impact on tumor specificity, i.e., active vs passive targeting and nanoparticle size, to evaluate relative influences in vivo. Active targeting via the V7 peptide is superior to passive targeting for uptake by pancreatic tumors, irrespective of nanoparticle size, observed through in vivo imaging. Size has a secondary effect on uptake for actively targeted nanoparticles in which 26 nm nanoparticles outperform larger 45 and 73 nm nanoparticles. Nanoparticle size had no significant effect on uptake for passively targeted nanoparticles. Results highlight the superiority of active targeting over nanoparticle size for tumor uptake. These findings suggest a framework for optimizing similar nonaggregate nanoparticles for theranostic treatment of recalcitrant cancers.

Mesoporous Silica Nanoparticle-Based Drug Delivery Systems for the Treatment of Pancreatic Cancer: A Systematic Literature Overview

“…A recent study confirmed the importance of tumor-targeting surface modifications [84]. Utilizing V7 peptide-conjugated MSNs in an orthotopic PDAC model, MacCuaig and colleagues showed that active targeting of MSNs (i.e., including surface modifications to increase tumor cell uptake) outperforms passive targeting (i.e., no tumor targeting modifications on the MSNs) irrespective of nanoparticle size [84]. However, it is important to note that improved uptake and cytotoxicity in vitro does not always translate to similar findings in vivo, as PEGylated MSNs showed higher tumor uptake compared to PEG-transferrin-modified MSNs in one study [47].…”

“…Pioneering studies showed that surface modification by conjugation with polyethyleneimine (PEI) [37], folic acid [82], or monoclonal antibodies targeting anti-claudin4 and anti-mesothelin [83] indeed improved nanoparticle uptake by PDAC cells, whereas modification with polyethylene glycol (PEG) was shown to enhance biodistribution and circulation time in experimental animal models [40,42]. More recent studies use alternative surface modifications to target chemotherapeutics to PDAC tumors, and MSNs have been conjugated with transferrin [46,47,83], urokinase plasminogen activator [54], anti-GPC1, anti-tMUC1 [48], or V7 [84] peptides for this purpose. As envisioned, cellular uptake was increased using tumortargeting moieties compared to controls lacking a modification both in vitro [46,47,83] and in vivo [48,54,84].…”

“…More recent studies use alternative surface modifications to target chemotherapeutics to PDAC tumors, and MSNs have been conjugated with transferrin [46,47,83], urokinase plasminogen activator [54], anti-GPC1, anti-tMUC1 [48], or V7 [84] peptides for this purpose. As envisioned, cellular uptake was increased using tumortargeting moieties compared to controls lacking a modification both in vitro [46,47,83] and in vivo [48,54,84]. A recent study confirmed the importance of tumor-targeting surface modifications [84].…”

“…As envisioned, cellular uptake was increased using tumortargeting moieties compared to controls lacking a modification both in vitro [46,47,83] and in vivo [48,54,84]. A recent study confirmed the importance of tumor-targeting surface modifications [84]. Utilizing V7 peptide-conjugated MSNs in an orthotopic PDAC model, MacCuaig and colleagues showed that active targeting of MSNs (i.e., including surface modifications to increase tumor cell uptake) outperforms passive targeting (i.e., no tumor targeting modifications on the MSNs) irrespective of nanoparticle size [84].…”

“…To this end, several so-called gatekeeper systems have been developed that prevent drug release in the circulation and/or at healthy, non-tumor-bearing organ sites. The addition of pH-sensitive gatekeepers such as chitosan, disulfide bonds, and poly(D,L-lactide-co-glycolide) showed pH-specific cargo release in vitro [45,46] and in tissue-mimicking phantoms [54,84]. The reduction in tumor weight and volume upon administration to PDAC bearing mice suggests that pH-based gatekeepers also hold promise for in vivo settings [43].…”