Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to Clinics

Abstract

Currently, nanomaterials are of widespread use in daily commercial products. However, the most-promising and potentially impacting application is in the medical field. In particular, nanosized noble metals hold the promise of shifting the current medical paradigms for the detection and therapy of neoplasms thanks to the: (i) localized surface plasmon resonances (LSPRs), (ii) high electron density, and (iii) suitability for straightforward development of all-in-one nanoplatforms. Nonetheless, there is still no clinically approved noble metal nanomaterial for cancer therapy and diagnostics. The clinical translation of noble metal nanoparticles (NPs) is mainly prevented by the issue of persistence in organism after the medical action. Such persistence increases the likelihood of toxicity and the interference with common medical diagnoses. Size reduction to ultrasmall nanoparticles (USNPs) is a suitable approach to promoting metal excretion by the renal pathway. However, most of the functionalities of NPs are lost or severely altered in USNPs, jeopardizing clinical applications. A ground-breaking advance to jointly combine the appealing behaviors of NPs with metal excretion relies on the ultrasmall-in-nano approach for the design of all-in-one degradable nanoplatforms composed of USNPs. Such nanoarchitectures might lead to the delivery of a novel paradigm for nanotechnology, enabling the translation of noble metal nanomaterials to clinics to treat carcinomas in a less-invasive and more-efficient manner. This Review covers the recent progresses related to this exciting approach. The most-significant nanoarchitectures designed with the ultrasmall-in-nano approach are discussed, and perspectives on these nanoarchitectures are provided.

Biodegradable Ultrasmall‐in‐Nano Gold Architectures: Mid‐Period In Vivo Distribution and Excretion Assessment

“…In average, the daily excretion of gold was 1–5 µg d −1 (maximum urine volume: 2 mL d −1 ) for a cumulative amount of 31.8 µg in 10 d (≈16% of the % ID). Thus, by taking into account this encouraging result on a mid‐term period together with the validation of daily metal excretion, our foresight regarding a potential complete metal excretion in a longer timeframe is supported, in particular if compared to recent literature …”

“…In particular, the amount of gold in kidneys remains stable during 10 d while increasing the urine, suggesting that gold USNPs pass through the renal pathway without accumulation in these excretory organs. The ability of gold USNPs to be excreted after the biodegradation of NAs by the renal pathway is of particular interest, as the only passive and fast way of elimination of materials in organisms . For the sake of completeness, gold biodistribution was also evaluated in other areas of the body such as lungs, brain, and blood, collecting negligible amount of metal (Figure S9, Supporting Information).…”

“…Indeed, leaving residues of therapeutics in patients is not acceptable, as one of the key‐question of regulatory agencies is related to the excretion rate of nanomaterials after the designed action . Noble metal nanoparticles (NPs) are not biodegradable, resulting in their long‐term persistence within excretion system organs, such as liver . On the other hand, NPs are of increasing interest for the advancement of cancer treatments, as demonstrated in many animal models, due to their intrinsic multi‐functionalities related to high electron density and peculiar interaction with electromagnetic waves .…”

“…As a first attempt to reduce the metal persistence, the hydrodynamic diameter (HD) of NPs was decreased to ultrasmall range (<6 nm, ultrasmall nanoparticles, USNPs) . Unluckily, despite the interesting excretion rate of USNPs by the renal pathway, the clearance is usually excessively fast and, in this size regime, many significant features for cancer theranostics including localized surface plasmon resonances (LSPRs) are altered, hindering a number of applications …”

“…Furthermore, the extreme versatility and reproducibility of the synthetic protocol was discussed and the remarkable biocompatibility of NAs was assessed in relevant Zebrafish models . Overall, NAs result as appealing candidates for the translation of metal nanotheranostic to clinics …”