1. Introduction
The term “nanoparticles” (NPs) refers to various types of particulate materials with one dimension of a size smaller than 100 nm [1,2]. They are increasingly popular for use as drug delivery systems to overcome classical problems faced by most drugs such as low solubility [3,4], low bioavailability [5,6], non-specificity [7,8], and/or toxicity [9,10]. Therefore, each year there is an increasing trend of NP-based therapies being approved by governmental medicine regulatory agencies such as the US Food and Drug Administration (FDA) [11,12] or the European Medicines Agency (EMA) [13,14]. However, even though many NP systems were designed to evade drug delivery-related problems, some types of NPs face unexpected challenges in vivo which can potentially lower their therapeutic effectiveness [15,16].
The term “nano-bio-interactions” is used to describe the various ways in which NPs interact with the body. These interactions can be categorized based on the organs which the NPs interact with, such as NP-liver interactions [17], NP-kidney interactions [18], NP-brain interactions [19], NP-tumor interactions [20], and other non-specific NP interactions [21]. When NPs are injected, the first interaction occurs when serum proteins circulating in the blood attach themselves onto the surface of the NP, forming what is known as a protein corona [22,23]. The characteristics of the corona formed will depend on the physical and chemical characteristics of the NP, such as its size, charge, and shape, which are discussed in more detail below.
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The particles then circulate around the body in the bloodstream. Their biodistribution and other nano-bio-interactions are affected by their protein corona [24,25]. In some cases, the corona configuration can cause most of the NPs to be sequestered by the reticuloendothelial system (RES). This leads to their biodistribution mainly accumulating in the liver and spleen [26,27], which could lower their therapeutic effectiveness. To overcome this, scientists employ strategies such as conjugation of polyethylene glycol (PEG) to the NP surface. PEG helps reduce the formation of the protein corona, hence giving them a “stealth” effect to evade the RES and prolong their circulation time in vivo [22,26,28,29]. Another strategy to prevent the adsorption of proteins onto NP surfaces is to conjugate the surfaces of the particles with zwitterions [30].
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After overcoming NP-liver interactions and those with other RES organs, subsequent obstacles are NP-kidney interactions [21]. It is well-known that, in general, NPs sized larger than 8 nm cannot be cleared out by the kidneys into the urine, as they are too large [31]. This is because large particles are generally unable to penetrate the glomerular filtration barrier (GFB) of the kidneys. The GFB functions as a sieve that normally only lets water and small solutes pass through [32,33]. Thus, it was assumed that “large” NPs could easily avoid clearance by the kidneys. Despite this assumption, there are reports of large NPs being found in the urine of lab mice [34,35,36,37]. There are even instances of particles being detected in cellular structures of the kidneys which are located beyond the GFB [35,38,39,40]. This is strange because normally NPs are degraded by the body [41,42].
Certain publications indicated that it is possible for some large NPs, even ones sized 100-200 nm [36,40], to escape degradation and then bypass the GFB. However, the cellular and molecular mechanisms of how these phenomena occur remain somewhat unknown. In this review, we attempt to gather known publications that show that “large” NPs can bypass the GFB. Large NPs, in this case, mean “NPs with a diameter of more than 8 nm”. Small particles with diameters of less than 8 nm are not considered because they easily cross the GFB. In addition, a summary of the physicochemical characteristics of large NPs is provided. This is done to examine which factors possibly impart the ability of large particles to be cleared into the urine.
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