Dose‐Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin‐Coated PGMA Nanoparticles

Abstract

The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery.

Targeting iron metabolism in drug discovery and delivery

“…Targeting TfR1 using drugs and drug delivery systems functionalized with transferrin, antibodies, antibody-derivatives, or TfR-targeted peptides, is a commonly employed and arguably the best-known strategy, as illustrated by its usage as a prototypical system for mechanistic studies of active targeting to cancer cells228. An impressive amount of different TfR-targeted delivery systems have been designed and evaluated for cancer therapy by exploiting the increased expression of TfR in some tumours, and this strategy has shown preclinical benefit when using a low-dose regimen229. At least three TfR-targeted systems are currently under clinical development (Table 3)(MBP-426, Mebiopharm; SGT-53, SGT-94, SynerGene Therapeutics)230,231.…”

Fluorescamine Labeling for Assessment of Protein Conformational Change and Binding Affinity in Protein–Nanoparticle Interaction

“…4,11–13 Transferrin adsorbed by the polystyrene and poly(glycidyl methacrylate) ENMs could actively target the breast or prostate cancer cells overexpressing transferrin receptor. 8,14,15 However, serum albumin could reduce the targeting capability of such ENMs if co-existing in the surrounding environment, 16 probably because albumin displaces transferrin off the ENM surface or interferes with receptor binding by covering up the binding sites on transferrin. Besides the type and affinity of the adsorbed proteins, changes to protein conformation upon adsorption could alter the biological responses to ENMs.…”

Recent Advances in Targeted Tumor Chemotherapy Based on Smart Nanomedicines

“…In contrast to free DTX that showed low cytotoxicity at a high DTX concentration, improved cytotoxicity of Tf‐modified DTX nanomedicine was observed as a result of the targeting effect and enhanced stability in cell medium . As aforementioned, drug delivery mediated by positive targeting initially relies on the passive targeting, which suggests that the positive and passive drug delivery mechanisms are interrelated. Adopting Tf as the positive targeting group ( Figure ), Singh et al found both the passive targeting and positive targeting exhibited dose‐dependent therapeutic distinction .…”

“…Positive targeting (i.e., active targeting) serving as a complementary paradigm for passive targeting has been widely established for tumor chemotherapy. Generally, positive targeting initially depends on the passive accumulation of nanomedicines in tumors . Positive targeting relies on the presence of certain tumor biomarkers or unique tumor microenvironment.…”