Endocytosis and Intracellular Trafficking as Gateways for Nanomedicine Delivery: Opportunities and Challenges

Abstract

More than 40 nanomedicines are already in routine clinical use with a growing number following in preclinical and clinical development. The therapeutic objectives are often enhanced disease-specific targeting (with simultaneously reduced access to sites of toxicity) and, especially in the case of macromolecular biotech drugs, improving access to intracellular pharmacological target receptors. Successful navigation of the endocytic pathways is usually a prerequisite to achieve these goals. Thus a comprehensive understanding of endocytosis and intracellular trafficking pathways in both the target and bystander normal cell type(s) is essential to enable optimal nanomedicine design. It is becoming evident that endocytic pathways can become disregulated in disease and this, together with the potential changes induced during exposure to the nanocarrier itself, has the potential to significantly impact nanomedicine performance in terms of safety and efficacy. Here we overview the endomembrane trafficking pathways, discuss the methods used to determine and quantitate the intracellular fate of nanomedicines, and review the current status of lysosomotropic and endosomotropic delivery. Based on the lessons learned during more than 3 decades of clinical development, the need to use endocytosis-relevant clinical biomarkers to better select those patients most likely to benefit from nanomedicine therapy is also discussed.

Ultrasound and microbubble mediated drug delivery: Acoustic pressure as determinant for uptake via membrane pores or endocytosis

“…Favoring one of both uptake mechanism by adjusting the acoustic pressure may be exploited for drug delivery. For example, nanomedicines rely on endocytosis to be internalized, as they are too large to be taken up by passive diffusion [26]. These nanomedicines may benefit from an enhanced endocytic uptake by exposing cells to low acoustic pressures, while maintaining high viability.…”

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

“…The internalized material can either be recycled to the cell membrane or shuttled from early endosomes to the more acidic late endosomes before finally being sorted to the lysosomes, where enzymatic digestion occurs. [6,7] To further enhance the selectivity toward the cancer cells and to maximize cellular internalization, polymer-based delivery systems have been decorated with targeting ligands that bind to receptors that are overexpressed by cancer cells. [8] The folate receptor is frequently used as target since it is overexpressed in the plasma membrane of several types of cancers such as epithelial, ovarian, cervical, breast, lung, kidney, colorectal, and brain.…”

A Triple-Fluorophore-Labeled Nucleic Acid pH Nanosensor to Investigate Non-viral Gene Delivery

“…Failure to escape the endosome to the cytoplasm can result in nucleic acid degradation when the early endosome transitions to a late endosome/lysosome, typically within an hour following uptake. 17 The shift from early endocytic vesicle to late endosome and eventually lysosome results from fusion of the early endosome with other vesicles. The latter contain hydrogen pump V-ATPases and digestive enzymes that result in acidification and degradation of the nucleic acid contents of polymeric nanoparticles.…”

“…The latter contain hydrogen pump V-ATPases and digestive enzymes that result in acidification and degradation of the nucleic acid contents of polymeric nanoparticles. 17,18 To escape the endosome and avoid lysosomal degradation, polymeric nanoparticles have been designed specifically with either moieties that facilitate membrane pore formation or amine groups designed to enable them to buffer vesicle acidification and consequently escape the endosome via the hypothesized proton sponge mechanism. 18 Beginning with branched polyethylenimine (bPEI), many polymeric nanoparticles have been engineered to take advantage of endosome acidification as a means to protect their nucleic acid cargo and enable endosomal escape.…”