Abstract
Major developments in nanomedicines, such as nanoparticles (NPs), nanosomes, and conjugates, have revolutionized drug delivery capabilities over the past four decades. Although nanocarrier agents provide numerous advantages (e.g., greater solubility and duration of systemic exposure) compared to their small-molecule counterparts, there is considerable inter-patient variability seen in the systemic disposition, tumor delivery and overall pharmacological effects (i.e., anti-tumor efficacy and unwanted toxicity) of NP agents. This review aims to provide a summary of fundamental factors that affect the disposition of NPs in the treatment of cancer and why they should be evaluated during preclinical and clinical development. Furthermore, this chapter will highlight some of the translational challenges associated with elements of NPs and how these issues can only be addressed by detailed and novel pharmacology studies.
Highlights
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Classical NP agents have been shown to be effective in pre-clinical studies due to their ability to increase the solubility of certain anticancer agents and structure which allows for sustained efficacious concentrations over a longer period of time when compared to traditional small-molecule drugs [2,3]
The results suggest that tumor-specific differences in the microenvironment, such as microvessel density (MVD), impacts
Summary
Once a tumor begins to grow, its interaction with non-malignant cells leads to the development of the tumor microenvironment. A similar effect was seen when scavenger receptors were removed from the cell surface This suggests that the smaller colloids could have a near-complete inhibition of cellular uptake if clathrin-mediated endocytosis and scavenger receptors were the only pathways of ingestion. When this theory was tested in RAW264.7 cells (which lack scavenger receptors) and incubated in the presence of chlorpromazine, a similar difference in the 30 nm gold colloid uptake was observed This would suggest that scavenger receptors may not be involved in the clathrin-mediated phagocytic pathways [42]. A recent study by Sindhwani et al evaluated the role of alternative processes to passive diffusion using U87-MG, 4T1, PDX, and MMTV-PyMT mouse models either before or after whole mouse fixation [79] This would, in theory, mean that NPs circulated after fixation could only enter the tumor via passive transport (due to existing gaps between cells), whereas mice undergoing fixation after NP administration could have NPs enter the tumor space by either passive or active mechanisms. While additional studies are necessary to clarify these results and determine which active mechanisms are predominating, this new information of NP uptake could lead to new strategies to enhance the delivery efficiency of NPs to tumors
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