molecules Review Polymeric Nanoparticles: Production, Characterization, Toxicology and Ecotoxicology Aleksandra Zieli ´nska 1,2 , Filipa Carreiró 1, Ana M. Oliveira 1, Andreia Neves 1,Bárbara Pires 1, D. Nagasamy Venkatesh 3 , Alessandra Durazzo 4 , Massimo Lucarini 4, Piotr Eder 5 , Amélia M. Silva 6,7 , Antonello Santini 8,* and Eliana B. Souto 1,9,* 1 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; [email protected] (A.Z.); fi[email protected] (F.C.); [email protected] (A.M.O.); [email protected] (A.N.); [email protected] (B.P.) 2 Institute of Human Genetics, Polish Academy of Sciences, Strzeszy´nska32, 60-479 Pozna´n,Poland 3 JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty 643 001, Tamil Nadu, India; nagasamyvenkatesh@rediffmail.com 4 CREA-Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy; [email protected] (A.D.); [email protected] (M.L.) 5 Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Przybyszewskiego 49, 60–355 Pozna´n,Poland; [email protected] 6 Department of Biology and Environment, University of Tras-os-Montes e Alto Douro, UTAD, Quinta de Prados, 5001-801 Vila Real, Portugal; [email protected] 7 Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB-UTAD), Quinta de Prados, 5001-801 Vila Real, Portugal 8 Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy 9 CEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal * Correspondence: [email protected] (A.S.); ebsouto@ff.uc.pt (E.B.S.) Academic Editor: Magnus Willander Received: 8 June 2020; Accepted: 13 August 2020; Published: 15 August 2020 Abstract: Polymeric nanoparticles (NPs) are particles within the size range from 1 to 1000 nm and can be loaded with active compounds entrapped within or surface-adsorbed onto the polymeric core. The term “nanoparticle” stands for both nanocapsules and nanospheres, which are distinguished by the morphological structure. Polymeric NPs have shown great potential for targeted delivery of drugs for the treatment of several diseases. In this review, we discuss the most commonly used methods for the production and characterization of polymeric NPs, the association efficiency of the active compound to the polymeric core, and the in vitro release mechanisms. As the safety of nanoparticles is a high priority, we also discuss the toxicology and ecotoxicology of nanoparticles to humans and to the environment. Keywords: polymeric nanoparticles; nanocapsules; nanospheres; therapeutic potential; targeted drug delivery; toxicology; ecotoxicology. 1. Introduction Polymeric nanoparticles (NPs) have attracted considerable interest over recent years due to their properties resulting from their small size [1–3]. Advantages of polymeric NPs as drug carriers include their potential use for controlled release, the ability to protect drug and other molecules with biological activity against the environment, improve their bioavailability and therapeutic index [1,4]. The term “nanoparticle” comprises both nanocapsules and nanospheres, which differ with respect to their morphology [5]. Nanocapsules are composed of an oily core in which the drug is usually Molecules 2020, 25, 3731; doi:10.3390/molecules25163731 www.mdpi.com/journal/molecules Molecules 2020, 25, 3731 2 of 20 Moleculesdissolved, 2020, 25, surroundedx FOR PEER REVIEW by a polymeric shell which controls the release profile of the drug from2 of the 21 core. Nanospheres are based on a continuous polymeric network in which the drug can be retained inside or core. Nanospheres are based on a continuous polymeric network in which the drug can be retained adsorbed onto their surface [5–7]. These two types of polymeric NPs recognized as a reservoir system inside or adsorbed onto their surface [5–7]. These two types of polymeric NPs recognized as a (nanocapsule), and matrix system (nanosphere) [8] are shown in Figure1. Examples of drugs /bioactive reservoir system (nanocapsule), and matrix system (nanosphere) [8] are shown in Figure 1. ingredients loaded in polymeric nanoparticles are depicted in Table1. Examples of drugs/bioactive ingredients loaded in polymeric nanoparticles are depicted in Table 1. Figure 1. Schematic representation of the structure of nanocapsules and nanospheres (arrow stands for Figurethe 1. presence Schematic of drugrepresentation/bioactive withinof the structure the nanoparticles). of nanocapsules and nanospheres (arrow stands for the presence of drug/bioactive within the nanoparticles). Table 1. Examples of drugs/bioactive ingredients loaded in polymeric nanoparticles. Table 1. Examples of drugs/bioactive ingredients loaded in polymeric nanoparticles. Formulated Type of Polymeric Applications Type of Polymers Ref. Drug/Bioactive Nanoparticles/Method Purpose Formulated Type of Polymeric Applications Type of Polymers Ref. Drug/Bioactive Nanoparticles/Methodnanospheres; Purpose C-6-loaded polymeric core-shell nanospheres; NPs (polymeric core-multilayer drug delivery, PCL, PLA, PLGA Coumarin-6 (C-6) C-6-loadedpolyelectrolyte polymeric shell NPs), theranostics, or [9] core-shellobtained NPs by (polymeric prepared by the bioimaging drug delivery, spontaneouscore-multilayer emulsification PCL, PLA, PLGA Coumarin-6 (C-6) theranostics, or [9] polyelectrolytesolvent evaporation shell NPs), method nanospheres; bioimaging PLGA Rapamycin obtainedRapamycin-loaded by prepared polysorbate by anti-glioma activity [10] the80-coated spontaneous PLGA NPs emulsificationnanospheres; solvent Hyperforin-loadednanospheres; AcDex-based NPs formulated via single anti-inflammatory AcDex Hyperforin Rapamycin-loaded [11] PLGA Rapamycin emulsion/solvent anti-gliomaactivity activity [10] polysorbateevaporationusing 80-coated ethyl acetate PLGAand NPs water nanospheres; diabetic retinopathy, neovascular Hyperforin-loadednanospheres; PLGA Fenofibrate (Feno) age-related macular [12] AcDex-basedPLGA-Feno NPs NPs anti-inflammatorydegeneration (ocular AcDex Hyperforin formulated via single neovascularization) [11] activity emulsion/solventnanocapsules; anti-leishmanial Amphotericin B PCL-NCs loaded with Amp B, (Leishmania biopolymer of PCL evaporationusing ethyl [13] (Amp B) obtained by nanoprecipitation infections), acetate andmethod water anti-fungal diabetic retinopathy, neovascular Fenofibrate nanospheres; PLGA age-related macular [12] (Feno) PLGA-Feno NPs degeneration (ocular neovascularization) biopolymer of PCL Amphotericin B nanocapsules; anti-leishmanial [13] Molecules 2020, 25, 3731 3 of 20 Table 1. Cont. Formulated Type of Polymeric Applications Type of Polymers Ref. Drug/Bioactive Nanoparticles/Method Purpose anionic copolymers nanocapsules; based on methacrylic FF-loaded-Eudragit L 100 NCs, undefined oral acic and methyl Fenofibrate (FF) [14] obtained by nanoprecipitation delivery methacrylate (Eudragit method L 100) in situ tissue nanocapsules; regeneration and ciprofloxacin-loaded PLGA NCs, PLGA, PCL Ciprofloxacin accelerated healing, [15] obtained by nanoprecipitation anti-inflammatory method activity nanocapsules; antibacterial activity, PLGA Curcumin (Cur) [16,17] Cur-loaded PLGA NCs pancreatic cancer colloidal nanocapsules; F108: PEG-PPG-PEG Curcumin (Cur) anticancer [18] Cur-loaded PEG-PPG-PEG NCs colloidal nanocapsules; severe combined PEG Pegademase bovine Pegademase bovine-loaded PEG immunodeficiency [17,19] NCs disease lung cancers in nanocapsules; combinationwith PCL-PEG-PCL Paclitaxel (PTX) [20] PTX-loaded PCL-PEG-PCL NCs chrono-modulatedche motherapy breast, pancreatic nanocapsules; PLGA-PEG Paclitaxel (PTX) andovarian and [20] PTX-loaded PLGA-PEG NCs brain cancers Eudragit® RS100, Eudragit® L100-55, EO based-nanoparticles by antioxidant/ Essential Oils [21] Eudragit® EPO, PCL, nanoprecipitation method antimicrobial polylactide, PLGA Cymbopogon martini nanocapsules; antioxidant, PCL [22] Roxb. (Palmarosa oil) Palmarosa oil-loaded PCL NCs antimicrobial nanocapsules; Thymus vulgaris L. Eudragit® L100-55 Thyme oil-loaded Eudragit® antioxidant [23] (Thyme oil) L100-55 NCs nanocapsules; Citrus bergamia Risso. Eudragit® RS100 Bergamot oi-loaded Eudragit® antimicrobial [24] (Bergamot oil) RS100 NCs nanocapsules; Citrus sinensis L. Eudragit® RS100 Orange oil-loaded Eudragit® antimicrobial [24] (Orange oil) RS100 nanocapsules; Rosmarinus officinalis Eudragit® EPO Rosemary oil-loaded Eudragit® antioxidant [25] L. (Rosemary oil) EPO NCs nanocapsules; Lavandula dentata L. Eudragit® EPO Lavender oil-loaded Eudragit® antioxidant [25] (Lavender oil) EPO NCs nanocapsules; antioxidant, PCL Geraniol [22] Geraniol-loaded PCL NCs antimicrobial Abbreviations: AcDex—acetalated dextran; F108—poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide); NCs—nanocapsules; NPs—nanoparticles; PCL—poly("-caprolactone); PEG—poly(ethylene glycol); PLA—poly(lactic acid); PLGA—poly(lactide-co-glycolide). 2. Methods for Production of Polymeric Nanoparticles Depending on the type of drug to be loaded in the polymeric NPs and their requirements for a particular administration route, different methods can be used for the production of the particles [26]. In general, two main strategies are employed, namely, the dispersion of preformed polymers or the polymerization of monomers [27,28]. Table2 lists the most