More recently, it became evident that inhaled particles can also affect the central nervous system [ 10 , 11 ] and reproduction [ 12 ]. This seems to be by and large due to translocation of the smallest particles in the mixture, referred to as ultrafine PM or nanoparticles, into the internal organs [ 13 ]. The evidence derived from studies using ultrafine PM has also led to a rapidly growing interest in the toxicology of man-made, manufactured or engineered NPs in the last 15 years.
Interestingly, there is a significant overlap in the toxicology of ultrafine particles and engineered NPs and cross talk between these two areas can boost our understanding of the toxicology of nano-sized particles [ 14 ]. The field of particle medicine started to emerge about 50 years ago [ 15 , 16 ]. Research intensified when it became clear that nanoparticles NPs have unusual properties with exciting potential for the improvement of established and the development of novel clinical applications. Areas of high interest are imaging and diagnostics, drug delivery and anticancer therapy [ 17 — 25 ].
To date, more than a dozen anticancer nanomedicines have been approved for clinical use, and almost 40 are in clinical trials. Particular attention is currently paid to precision medicine. Here, in case of cancer treatments, the goal is to develop personalized anticancer nanomedicines, which are engineered to target, for instance, a particular type of tumour with a specific location and microvasculature pattern. Anticancer nanomedicines have various beneficial properties. These include enhanced accumulation in solid tumours with reduced off-target delivery and improved safety.
The enhanced permeability and retention EPR effect is thought to play a central role in the improved efficacy. The EPR effect is based on leaky blood vessels and impaired lymphatics in tumour tissue, which leads to enhanced extravasation of NPs into tumour tissue and reduced clearance by lymphatic drainage [ 26 — 28 ]. However, the EPR effect would only be relevant with respect to relatively large and well-vascularized tumours, and various challenges remain, including the treatment of leukaemia and metastatic disease.
Such challenges must be addressed by more specific targeting strategies. These include surface modifications of NPs with cancer cell targeting ligands, such as folate or antibodies, and magnetic targeting [ 26 , 29 — 31 ].
Specific targeting of nanomedicines may also be helpful for addressing the challenge that the EPR was effective in animal models, but it failed, so far, to perform well in human patients [ 32 , 33 ]. Surface modifications are not only important for targeting, but also for preventing clearance of nanodrugs by phagocytotic cells from the reticuloendothelial system.
This is critical for increasing the circulatory half-life of nanomedicines, and for preventing damage of non-target tissues due to activation of resident phagocytotic cells. The classical strategy for reducing interactions with the reticuloendothelial system is to modify the surface of the medical NPs with polyethylene glycol PEGylation , which hinders opsonisation binding of proteins recognised by phagocytotic cells , but may shield targeting ligands [ 34 ]. Other strategies include biomimetic coating with proteo-lipid membranes extracted from leukocytes [ 35 ], platelets [ 36 ] or other cells, and autologous cells should be used for clinical applications.
Tuning the shape and size of NP medicines is also critical. These features influence the radial drift margination of NPs in blood vessels.
Whereas small spherical NPs accumulate within the center of blood vessels, disc-like particles display enhanced lateral drift due to tumbling, and also have larger surface areas for endothelial adhesion [ 38 ]. Both are important for extravasation in tumour tissue. In addition, NP density appears to influence margination, with enhanced margination of high-density NPs. This leads to an easier distribution of low-density NPs in the body, which is associated with more rapid renal clearance [ 39 ].
Renal clearance is also strongly dependent on NP size, shape and charge, not only due to indirect effects based on margination, but also due to the properties of the renal filtration barrier. Rigid spherical NPs are not efficiently cleared by renal filtration if their hydrodynamic diameter exceeds 5. Surprisingly, large nanofiber-like materials, such as individualized carbon nanotubes with diameters and lengths of up to 20 — 30 nm and — nm, respectively, easily cross through the renal filtration barrier when aligned in the right orientation, and are cleared with similar efficiency as small molecules [ 41 , 42 ].
Tuning of renal clearance of nanomedicines must be carefully adjusted to keep the balance between maintaining therapeutic plasma levels and safe elimination from the body. During the last decades, nanomedicines with a wide range of structural features have been developed for the delivery of small molecule drugs, biologics, nucleic acids, or co-delivery of multiple compounds [ 24 , 43 ].
Since the s, polymeric micelle-based nanomedicines for drug delivery have been approved for clinical applications. Polymeric micelles consist of amphiphilic block copolymers that self-assemble into a core-shell structure.
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The hydrophobic core can be loaded with hydrophobic small molecule drugs or biologics, whereas the hydrophilic shell can be further modified by PEGylation or with targeting ligands. Until now, polymeric micelles or other types of NPs, which did not have any anticancer activity themselves, were used as vehicles for the delivery of anticancer agents. An exciting more recent development are micellar nanocomplexes MNCs for anticancer protein drug delivery, which have anticancer activity themselves also in the absence of the anticancer protein [ 46 ].
The MNCs were based on derivatives of the green tea catechin - -epigallocatechinO-gallate, which has known anticancer activity. After loading of the MNCs with the anticancer protein drug Herceptin, synergistic anticancer activity of the MNCs and Herceptin has been observed, which resulted in enhanced antitumor activity in vitro and in vivo compared to Herceptin alone [ 46 ]. In addition, prolonged plasma half-life and enhanced accumulation in the tumour tissue of the MNCs compared to the protein drug alone were demonstrated [ 46 ].
The most important goal for the future is to achieve personalized treatments by designing precision nanomedicines. Crucial for achieving this goal is an improved understanding of the interactions between NPs and biological structures and tissues. This will help to guide the development of smart strategies for manipulating NP surface chemistries, which is required for reducing unspecific interactions and for increasing targeting of tumors with specific, individual properties.
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Important will be also the tuning of the size and shape of nanomedicines based on the understanding of how these features influence interactions in normal and disease states. Addressing the variability between patients as a function of age, gender, ethnicity, their individual disease state and other patient-specific factors will be essential to guide the design of NPs for precision nanomedicine and to achieve personalized treatments.
Deposition of inhaled NPs is governed by their diffusivity in the air leading to a rather homogeneous deposition density on the epithelium of the various regions of the respiratory tract. In other words, two thirds of the deposited 20 nm sized NP will be cleared rapidly within 24 hours by mucociliary action within the ciliated conducting airways and one third will be long-term retained in the lung periphery. Below that size, increasing fractions deposit in the airways of the head and thorax according to their increasing diffusivity with decreasing size, such that less NP reach the distal alveolar region see Fig.
In this short summary a few consequences on the biokinetics fate will be discussed for insoluble NP. Artwork by Mark Miller, reproduced with permission from [ 14 ]. All percentages are relative to the contemporary lung burden. The low NP recovery becomes plausible since NPs deposit rather uniform on the surface of an alveolus by diffusion. Indeed, macrophages on the epithelial surface will rapidly phagocytize all NP which happen to be deposited close to where a macrophage happens to reside, while distant NP are not recognized due to the weak opsonizing signal of NPs.
As discussed in our previous paper [ 59 ], numerous authors provided evidence that epithelial type 1 cells EC1 can endocytose NP at the epithelial surface and eventually exocytose those towards the baso-lateral side at the end of the last century, including the review of Lehnert [ 61 ] and papers by Adamson and Bowden [ 62 — 64 ]. More recently, Thorley and co-workers [ 65 ] provided evidence for prominent NP uptake by EC1 while they ruled out uptake by alveolar epithelial type 2 cells EC2 and the passage of NPs by paracellular transport was also discounted.
They stated that NP uptake occurs preferentially by diffusive processes into the cytoplasm which allows for exocytosis and transport across the basal membrane into the interstitium, as supported by in vivo studies. According to [ 68 , 69 ] the cytoplasmic leaflets of EC1 provide the largest portion of their surface area on the basal membrane which separates the adjacent vascular endothelial cells to allow unhindered gas exchange.
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Once there, NP may be phagocytized by interstitial macrophages IM , fibroblasts, etc. Referring to [ 61 , 70 ] there is a large population of IM such that the role of IM in phagocytizing NPs and long-term retention in the septal interstitial spaces appears plausible.
For gradual re-entrainment back onto the epithelium, Lehnert [ 61 ] reviewed the pathway of IM onto the epithelium. Surprisingly, NPs are cleared with a similar clearance rate dynamics via this macrophage-mediated transport indicating re-entrainment of the NPs from the interstitial spaces back on top of the epithelium for subsequent LT-MC towards the larynx and into the gastro-intestinal-tract GIT [ 55 , 56 ]. NP passage through BALT at bronchioles-alveolar duct junctions back onto the bronchiolar epithelium [ 63 ] [ 77 ] cannot be excluded; however, BALT may play an important immunogenic role for fluid absorbed from the alveolar surface, but the reverse flow onto the epithelial surface was postulated in the literature but has not been proven so far [ 68 , 69 ].
As a result, LT-MC is the most prominent long-term clearance mechanism for insoluble NPs from the peripheral lung of rodents. In fact, although the NP are retained in the septal interstitial spaces close to blood vessels, only rather small fractions are translocated via this pathway into circulation leading to subsequent accumulation in secondary organs and tissues which, however, depends strongly on the physicochemical properties of the NPs. For example, four different materials iridium Ir , elemental carbon EC , TiO 2 , and gold Au , which were inhaled as freshly generated nm NP aerosols during a single 1—2 h exposure by healthy, adult, female Wistar—Kyoto rats; the translocation percentages normalized to the alveolar NP deposition of IrNP 7.
Retention in secondary organs was followed up to six months after the inhalation of the IrNP aerosol showing no detectable clearance [ 55 , 58 ]. During chronic exposure to insoluble NP, continuous accumulation is likely to occur in secondary organs. This may play a modulating role in adverse cardio-vascular health effects which have been observed in epidemiologic studies after exposure to ambient fine and ultrafine particles [ 80 ].
Systemically circulating NPs may accumulate in secondary organs and tissues by two particle clearance pathways, i NP translocation across the air-blood-barrier ABB either directly into blood circulation or via the thoracic lymph duct and ii NP absorption across the GIT walls, again either directly into blood circulation or via the thoracic lymph duct, of those NP which were eliminated from the lungs towards the larynx and swallowed into the GIT.
The latter clearance pathway has a fast component of those NP deposited on the epithelium of the conducting airways which are cleared rapidly by mucociliary action MCC followed by a slow component of those NP from the peripheral lungs eliminated by LT-MC towards the larynx. The contribution of both pathways towards secondary organs was quantitatively investigated for the first time in a series of studies in which identical nm-sized TiO 2 NP were applied to rats either as a single bolus via intratracheal IT instillation or via gavage oral ingestion or via intravenous injection.
Their biokinetics were determined quantitatively in the entire organism during the next 28 days [ 81 — 83 ]. The biokinetics data obtained from the gavage study were used to estimate the absorbed TiO 2 NP fractions across the gut walls after IT-instillation which had been cleared from the lungs via the larynx into the GIT. In Fig. The integral absorbed TiO 2 NP ratios increase with time up to 0.
Ratios in liver, kidneys and the various tissues of the carcass stay below 0. These data show that accumulation in secondary organs and tissues is predominantly determined by ABB-translocated TiO 2 NP which, however, occurs mainly during the first few days after IT-instillation see Fig. Yet, with increasing retention time the gut-absorbed NP fractions become more and more important. The ratios R i represent the fractions of TiO 2 2NP present in liver, spleen, kidneys and carcass without organs and the integral sum of all absorbed fractions determined after IT-instillation that have been absorbed through the GIT relative to the sum of gut-absorbed and ABB-translocated TiO 2 NP after 1, 7 and 28 days.
Results of numerous studies, in vitro and in vivo , have revealed that engineered NPs and ambient ultrafine particles UFPs, e. In order to characterize appropriately the associated risk as a function of hazard and exposure, exposure-dose-response relationships have to be established. With respect to inhalation as the main route of exposure - involving acute, subchronic or chronic rodent studies - a minimum of three exposure concentrations plus sham-exposed controls should be used [ 84 ].
The experimental design should include detailed aerosol characterization and biokinetic data. Essential for the evaluation of the results of inhalation studies is to determine the retained dose lung burden at the end of exposure to establish dose-response relationships.