Hazard Assessment of Polymeric Nanobiomaterials for Drug Delivery: What Can We Learn From Literature So Far

Abstract

The physicochemical properties of nanobiomaterials, such as their small size and high surface area ratio, make them attractive, novel drug-carriers, with increased cellular interaction and increased permeation through several biological barriers. However, these same properties hinder any extrapolation of knowledge from the toxicity of their raw material. Though, as suggested by the Safe-by-Design (SbD) concept, the hazard assessment should be the starting point for the formulation development. This may enable us to select the most promising candidates of polymeric nanobiomaterials for safe drug-delivery in an early phase of innovation. Nowadays the majority of reports on polymeric nanomaterials are focused in optimizing the nanocarrier features, such as size, physical stability and drug loading efficacy, and in performing preliminary cytocompatibility testing and proving effectiveness of the drug loaded formulation, using the most diverse cell lines. Toxicological studies exploring the biological effects of the polymeric nanomaterials, particularly regarding immune system interaction are often disregarded. The objective of this review is to illustrate what is known about the biological effects of polymeric nanomaterials and to see if trends in toxicity and general links between physicochemical properties of nanobiomaterials and their effects may be derived. For that, data on chitosan, polylactic acid (PLA), polyhydroxyalkanoate (PHA), poly(lactic-co-glycolic acid) (PLGA) and policaprolactone (PCL) nanomaterials will be evaluated regarding acute and repeated dose toxicity, inflammation, oxidative stress, genotoxicity, toxicity on reproduction and hemocompatibility. We further intend to identify the analytical and biological tests described in the literature used to assess polymeric nanomaterials toxicity, to evaluate and interpret the available results and to expose the obstacles and challenges related to the nanomaterial testing. At the present time, considering all the information collected, the hazard assessment and thus also the SbD of polymeric nanomaterials is still dependent on a case-by-case evaluation. The identified obstacles prevent the identification of toxicity trends and the generation of an assertive toxicity database. In the future, in vitro and in vivo harmonized toxicity studies using unloaded polymeric nanomaterials, extensively characterized regarding their intrinsic and extrinsic properties should allow to generate such database. Such a database would enable us to apply the SbD approach more efficiently.

Chitosan Nanoparticles: Shedding Light on Immunotoxicity and Hemocompatibility

“…In fact, all authors mentioned used similar DDA Chit (75-85%) and no pattern could be observed. Moreover, those results are also affected by other variables, such as the different cellular models and testing conditions, namely concentrations, used by each author, as previously reviewed elsewhere (Jesus et al, 2019). Furthermore, none of the studies mentioned used RAW 264.7 cells, which hinders the comparison with the results herein presented.…”

“…These contradictions and ambiguity may be due to differences in the used Chit polymers or in vitro methodology, namely the cellular model, NP concentration and incubation period. Moreover, it has been observed that most of the studies do not properly characterize, or at least do not report, both the polymer and the derived NPs, nor use or report adequate controls to screen NP interferences or monitor the presence of endotoxin contamination (Jesus et al, 2019). Notably, in the context of Safe-by-Design (SbD) of new polymeric NPs for drug delivery, it is necessary to rely on assertive results of immunotoxicity and hemocompatibility, obtained with properly characterized polymeric NPs.…”

A Methodological Safe-by-Design Approach for the Development of Nanomedicines

“…This may be a result of the lack of standardized assays, which lead to a high variation in reported studies (Hofmann-Amtenbrink et al, 2015). Also some studies have no proper characterization and lack appropriate controls specific to the nanoscale (Jesus et al, 2019), which makes comparisons between toxicity outcomes difficult. Therefore, experimental studies are still needed.…”

Multifunctional Nanocarriers for Lung Drug Delivery

“…In fact, the superiority of nanosystems has been demonstrated in certain applications of the respiratory field, as will be described in the following sections of the review. The nanocarriers permit drug protection, provide a greater ability to interact with the tissues and cells, owing to the high surface area, often allowing specific targeting and/or controlled drug release [38]. However, the proposal of nanocarriers must not be blind, and it is important to note that some applications may take greater benefit from the use of microcarriers, for example if the therapeutic target is phagocytic cells such as macrophages.…”