Nanomaterials have demonstrated the potential to revolutionize the way in which neoplasms are diagnosed and treated. Some efficient treatments relying on organic nanomaterials are already in the market while the even more promising ones based on noble metals are still on the bench scale. In particular, the intrinsic features of nanomaterials offer the possibility of the development of synergistic non-invasive treatments, by designing unique theranostic agents.

Despite the giant number of proposed nanoplatforms for development of healthcare products in the last decade, almost all have led to failure before the clinical stage. This is related to lack of sufficient knowledge of the regulatory and industrial requirements by researchers and the lack of available standard regulatory frameworks [1]. The pipeline for the development of a nanomaterial for healthcare is composed by its in silico/in vitro investigations, pre-clinical and manufacturing validation, and to clinical pilot and phase II/III validations. It is worth to notice that only the most promising nanomaterials can pass to the costly pre-clinical and following assessments. For a better understanding on the validation steps, we would like to suggest to readers the story of the first approved nanomaterial for healthcare application, Doxil [2].

Chiefly, a nanomaterial has to work efficiently and safely to attract industrial interests. It has to meet good manufacturing practice (GMP) standards, be ready to be scalable (up to 1 kg in the pre-clinical phase), be more efficient compared to the standard of care, adhere to regulatory analytical requirements, be stable, be reproducible, be controlled (all impurities, surfactants, and other involved molecules known and quantified), be simple (the more complex is the material the higher the risks of pre-clinical failure), be flexible and transferable [1, 3]. As recently reported, also a complete set of absorption/distribution/metabolism/excretion (ADME) investigations has to be fully provided in a couple of animal models, such as mice and rabbits [4, 5]. For a complete discussion on the parameters for quality and safety evaluation of nanomaterials for biomedical applications, we suggest the readers to other recent works [1, 5–7].

Nowadays, more than 40 nanomaterials have been approved for healthcare applications (organic or metal-oxide materials), but there is still a lack of specific general protocols for their preclinical assessment [6, 8, 9]. Global regulatory trends are yet to be defined. As alternative, safety/toxicology for small molecules have been frequently adapted to evaluate the behaviors of nanomaterials [7, 10]. Nevertheless, the standard development program applied to small molecules cannot be applied to nanotheranostics [10]. Indeed, nanomaterials are complex 3D-constructs comprising multiple components with preferred spatial arrangements [1, 11]. Due to this complexity, there is a general agreement to allow specific regulatory framework for each new nanomaterial on a product-by-product basis [8, 12]. This is consistent with the recently published protocol of regulatory agencies [12]. This evaluation strategy is due to the various characterization methods, physicochemical properties, and biological interactions of the involved nanomaterials [12]. Nevertheless, international cooperation and harmonized strategies between regulatory agencies are desirable in order to produce standard evaluation guidelines and boost this promising and fast-growing field. Remarkably, a profound knowledge of nanomaterials and characterization methods is needed in order to avoid unpredicted effects on patients, such as potential immune reactivity [7]. It is worth to remembering here that in the nano-range, small size/shape-changes result in dramatic change of behaviours [8]. Thus, standardized quality control protocols and assays have to be developed and validated in order to effectively monitor and characterize both the physicochemical features of nanomaterials (such as size, dispersion, morphology and charge) and to assess their performance, pharmacokinetics, specific cellular uptake, interaction with immune cells and organisms [6–8].

It should be noted that strong interactions between experimental and computational scientists would be highly desirable. Indeed, such interactions could greatly enhance the predictive accuracy of the investigations and speed-up the development process.

While some organic nanomaterials have reached the agencies approbation, metal nanomaterials still demonstrate a major issue: the persistence. Persistence and accumulation in organism after the medical action is the major concern that has hampered their clinical translation. Indeed, the first concept for agencies approbation of therapeutics relies on the complete excretion of all the components of the agent after the desired action in an optimal time frame [1]. Leaving residues in patients is not acceptable [1]. In this book, besides a profound presentation of the behaviors of materials at the nanoscale and their real or promising biomedical applications, we have comprehensively discussed this key-question and the approach to unlock the features of metal nanomaterials for healthcare. Indeed, persistence is the first concept to address while developing a novel nanotheranostics, before the consideration of other concepts such as “4S parameters” (size, shape, surface properties and mechanical stiffness of nanomaterials), vascular residence, tumor accumulation and phagocytic sequestration [5, 13]. Clearance of nanomaterials from kidneys has been demonstrated to be the most practical pathway to avoid undesirable toxic effects. The possibility to employ this excretion pathway while maintaining desirable theranostic moieties is related to the design of all-in-one biodegradable nanoplatforms. The most groundbreaking advancement for their development is the recently introduced ultrasmall-in-nano approach [14]. Disassembling nanomaterials would be the key-technology to overcome the concern of safe medical-employment of noble metal nanoparticles opening new horizons in medicine, and paving the way for new paradigms in the next generation of theranostics. Despite the field is very young, personalized and effective treatments of diseases based on noble metal nanoparticles may be no longer a dream, but a real possibility in the very next future.

References

1. Eaton, M. A. W., Levy, L., and Fontaine, O. M. A. Delivering nanomedicines to patients: A practical guide. Nanomedicine Nanotechnology, Biol. Med. 11, 983–992, 2015.

2. Barenholz, Y. (Chezy). Doxil^® — The first FDA-approved nanodrug: Lessons learned. J. Control. Release 160, 117–134, 2012.

3. Alkilany, A. M., and Murphy, C. J. Toxicity and cellular uptake of gold nanoparticles: what we have learned so far? J. Nanoparticle Res. 12, 2313–2333, 2010.

4. Dawidczyk, C. M., Kim, C., Park, J. H., Russell, L. M., Lee, K. H., Pomper, M. G., and Searson, P. C. State-of-the-art in design rules for drug delivery platforms: Lessons learned from FDA-approved nanomedicines. J. Control. Release 187, 133–144, 2014.

5. Anchordoquy, T. J., Barenholz, Y., Boraschi, D., Chorny, M., Decuzzi, P., Dobrovolskaia, M. A., Farhangrazi, Z. S., Farrell, D., Gabizon, A., Ghandehari, H., Godin, B., La-Beck, N. M., Ljubimova, J., Moghimi, S. M., Pagliaro, L., Park, J.-H., Peer, D., Ruoslahti, E., Serkova, N. J., and Simberg, D. Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions. ACS Nano 11, 12–18, 2017.

6. Anselmo, A. C., and Mitragotri, S. Nanoparticles in the clinic. Bioeng. Transl. Med. 1, 10–29, 2016.

7. Sainz, V., Conniot, J., Matos, A. I., Peres, C., Zupanoio, E., Moura, L., Silva, L. C., Florindo, H. F., and Gaspar, R. S. Regulatory aspects on nanomedicines. Biochem. Biophys. Res. Commun. 468, 504–510, 2015.

8. Sandoval, B. (MacDonald). Perspectives on FDA’s Regulation of Nanotechnology: Emerging Challenges and Potential Solutions. Compr. Rev. Food Sci. Food Saf. 8, 375–393, 2009.

9. Desai, N. Challenges in Development of Nanoparticle-Based Therapeutics. AAPS J. 14, 282–295, 2012.

10. Schellekens, H., Stegemann, S., Weinstein, V., de Vlieger, J. S. B., Flühmann, B., Mühlebach, S., Gaspar, R., Shah, V. P., and Crommelin, D. J. A. How to Regulate Nonbiological Complex Drugs (NBCD) and Their Follow-on Versions: Points to Consider. AAPS J. 16, 15–21, 2014.

11. Voliani, V., Gemmi, M., Francés-Soriano, L., González-Béjar, M., and Pérez-Prieto, J. Texture and Phase Recognition Analysis of β-NaYF 4 Nanocrystals. J. Phys. Chem. C 118, 11404–11408, 2014.

12. Malinoski, F. J. The nanomedicines alliance: an industry perspective on nanomedicines. Nanomedicine Nanotechnology, Biol. Med. 10, 1819–1820, 2014.

13. Sun, T., Zhang, Y. S., Pang, B., Hyun, D. C., Yang, M., and Xia, Y. Engineered Nanoparticles for Drug Delivery in Cancer Therapy. Angew. Chemie Int. Ed. 53, 12320–12364, 2014.

14. Cassano, D., Pocoví-Martínez, S., and Voliani, V. Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to Clinics. Bioconjug. Chem. accepted, 2017. acs. bioconjchem.7b00664.