Smart Nanomaterials for Biomedical Applications: History
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Recent advances in nanotechnology have forced the obtaining of new materials with multiple functionalities. Due to their reduced dimensions, nanomaterials exhibit outstanding physio-chemical functionalities: increased absorption and reactivity, higher surface area, molar extinction coefficients, tunable plasmonic properties, quantum effects, and magnetic and photo properties. However, in the biomedical field, it is still difficult to use tools made of nanomaterials for better therapeutics due to their limitations (including non-biocompatible, poor photostabilities, low targeting capacity, rapid renal clearance, side effects on other organs, insufficient cellular uptake, and small blood retention), so other types with controlled abilities must be developed, called “smart” nanomaterials.

  • smart nanomaterials
  • stimuli-responsive polymers
  • biomedical applications

1. Introduction

From the oldest times, humanity has tried to mimic nature in the way that living organisms adapt their behavior to environmental conditions to improve survival. It is well known that living systems from nature can dynamically change their properties in a smart way for adapting to the surrounding environment. Some examples are given by the Mimosa pudica plant which responds to stimuli such as temperature and light by undergoing a change in leaf direction [1]; by pinecones [2], wheat awn [3], and orchid tree seedpods [4] which adopt different shapes, responding to the changing environmental humidity; and by the Venus flytrap [5] which is able to capture insects by rapidly closing its leaves, among many others [6][7]. The powerful abilities of the biological systems abovementioned in converting energy and executing multiple tasks inspired the researchers to develop “stimuli-responsive” materials with biomimetic behavior and a high potential of use in smart or intelligent devices.

To our knowledge, the first complete report of “intelligent materials” defined as “the materials that respond to environmental changes at the most optimum condition and manifest their own functions according to these changes” was made by Toshinori Takagi in April 1990 [8]. At that time, the coverage and the achievability of this concept was not comprehensible, but it was anticipated to open an unused field in science and innovation [9]. Nowadays, the term “intelligent material” is synonymous with “stimuli-responsive material” or “smart material” and has gained a growing interest in researchers’ concerns due to the development of advanced technologies and the increased need for new materials that meet the new requirements.

Richard Feynman, laureate of the Nobel Prize, was the first to introduce, in 1959, the nanotechnology concept. He had a revolutionary vision in a lecture entitled: “Why can’t we write the entire 24 volumes of the Encyclopedia Britannica on the head of a pin?” [10]. The term “nanotechnology” was used and defined in 1974, by Norio Taniguchi, as “nanotechnology mainly consists of the processing of separation, consolidation, and deformation of materials by one atom or one molecule” [11]. In 1997–1998, the perception of nanotechnology was more a “science fiction” vision, still being far from the practical applications [12], but in the early 2000s, nanomaterials were intensively studied and finally utilized in practice. As the field of biomedical engineering is developing new insights, the demand for highly functionalized biomaterials is increasing. Despite the astonishing diversity and complexity of living systems, they all share the possibility to react to environmental changes, crucial for maintaining normal functions. This need for adaptation has led to the development of smart nanomaterials, defined as materials that can react to a large variety of stimuli by adapting their own properties such as shape, surface area, size, permeability, solubility, mechanical properties, and others. Depending on the capacity of the nanomaterial to restore its initial state, the response can be reversible or not. In this specific situation, polymer-based materials have substantiated themselves as sharp choices in creating upgraded responsive frameworks on the grounds that their structure permits regulating their properties. A large variety of polymers have been obtained to respond to physical stimuli (temperature, light, ultrasound, electrical, magnetic, mechanical), chemical stimuli (pH, solvent, electrochemical), or biological stimuli (enzymes). A special type of polymer is dual or multi-stimuli-responsive, in light of the fact that it simultaneously reacts to multiple stimuli. As a rule, the polymer responsivity is directed by the science of the monomers and their distribution/concentration in the polymer chains [13].

2. Types of Stimuli

Smart nanomaterials are categorized in different groups by means of the applied stimuli. The properties of smart nanomaterials are modified by external triggers in a controlled way [14][15][16][17][18][19][20][21][22]. By considering their various properties, many kinds of smart nanomaterials are known.

2.1. Physico-Responsive Nanomaterials

Examples of physico-sensitive nanomaterials and their applications are listed in Table 1 [24][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Recent works [41-76] describe the design of phisico-responsive smart nanomaterials and their applications in the biomedical field.

Table 1. Examples of physico-responsive nanomaterials and their biomedical applications.

Nr. Crt. Stimuli Nanomaterial Application Reference
1. Temperature Poly(ethylene oxide)a-poly(propylene oxide)b-
poly(ethylene oxide)a
Oral drug delivery, wound healing [39]
2. Temperature Gold nanoparticles—Pluronic®F127-Hydroxypropyl methylcellulose
Drug delivery, photothermal platform, skin wound healing [23]
3. Temperature Poly(oligo(ethylene glycol) methacrylate –co-poly(glycidal methacrylate) copolymers/poly(lactic
acid-co-glycolic acid)
P(OEGMA-co-PGMA) copolymers/PLGA
Tissue engineering [24]
4. Temperature Collagen- or chitosan-based Drug delivery [25]
5. Temperature Poly(N-isopropylacrylamide)- poly(N,N-dimethylacrylamide)- poly(acrylic acid)
Drug delivery [26]
6. Temperature Poly(Nisopropylacrylamide-co-sulfobetaine methacrylate) nanogel
PNS nanogels
Diagnosis/chemotherapy [27]
7. Electrical Poly(3,4-ethylenedioxythiophene)-coated poly(lactic acid-co-glycolic acid) nanofiber
PEDOT-coated PLGA nanofiber
Drug delivery [28]
8. Electrical Fe3O4/Polyaniline
Antimicrobial, drug delivery [29]
9. Electrical Polyaniline/gold nanocomposite
Immunosensor detection of chronic kidney disease [30]
10. Electrical Polyaniline, poly(3,4-ethylenedioxythiophene)
Neural prostheses [31][32]
11. Electrochemical Biosynthesized gold nanoparticles/ poly(catechol)/graphene sheets/glassy carbon electrode
Bio AuNP/Pol/Gr/GCE
Biosensor, DNA mutation and acute lymphoblastic leukemia detection [33]
12. Light poly(ethylene glycol)
Switchable fluorescent probes [34]
13. Light Ruthenium-containing block copolymer
Poly-Ru nanoparticles
In vivo photodynamic therapy and photochemotherapy [35]
14. Magnetic Fe3O4/methoxy poly(ethylene glycol)-poly- (lactide) composite nanocapsules
Fe3O4/MePEG-PLA composite nanocapsules
MRI [36]
15. Magnetic Trastuzumab (Tra, a humanized monoclonal antibody that specifically recognizes HER2)- doxorubicin
poly(vinyl alcohol)/ single-component thiol-functionalized poly (methacrylic acid T-DOX
PVA/PMASH magnetic nanocapsules
Tumor therapy [37]
16. Magnetic 3D collagen hydrogel Directed neuronal regeneration [38]

2.2. Chemical-Responsive Nanomaterials

Examples of chemical-sensitive nanomaterials and their applications are listed in Table 2 [40][41][42][43][44][45][46][47][48][49][50][51]. Recent works [89][90] describe the design of chemical-responsive smart nanomaterials and their applications in the biomedical field.

Table 2. Examples of chemical-responsive nanomaterials and their biomedical applications.

Nr. Crt. Stimuli Nanomaterial Application Reference.
1. pH Ppoly (ethylene glycol)-Ag nanoparticle
Antibacterial, wound healing [40]
2. pH Hybrid ultra-pH-sensitive (HyUPS) nanotransistor
HyUPS nanotransistors
Receptor-mediated endocytosis in tumor cells [41]
3. pH Layered double hydroxides-zinc (II) phthalocyanine containing octasulfonate nanohybrid
LDH-ZnPcS8 nanohybrid
Theranostics [42]
4. pH Melanin-like nanoparticles Photoacoustic imaging of tumors [43]
5. pH polylactic acid-Resveratrol
Drug delivery [44]
6. pH Poly(carboxybetaine methacrylate)-nanodiamonds
Theranostics [45]
7. Redox Poly (ethylene glycol)-Pluronic F68-nanoscale covalent organic frameworks
Cancer therapy [46]
8. Redox Hyaluronic acid–chitosan–lipoic acid nanoparticles
Breast cancer therapy [47]
9. Redox Folate redox-responsive chitosan nanoparticles
Anticancer drug delivery [48]
10. Redox Poly (ethylene glycol) conjugated to paclitaxel via disulfide linkage
Prodrug for breast cancer cells [49]
11. Redox Prodrug/AgNPs hybrid nanoparticles Drug delivery [50]
12. Redox P[(2-((2- ((camptothecin)-oxy)ethyl)disulfanyl)ethylmethacrylate) -co- (2-(D-galactose)methylmethacryl-ate)] and silver nanoparticles
P(MACPTS-co-MAGP)@AgNPs nanoparticles
Drug release [51]

2.3. Biological-Responsive Nanomaterials

Examples of biological-sensitive nanomaterials and their applications are listed in Table 3 [52][53][54][55][56][57][58][59][60][61][62]. Recent works describe the design of biological-responsive smart nanomaterials and their applications in the biomedical field.

Table 3. Examples of biological-responsive nanomaterials and their biomedical applications.

Nr. Crt. Stimuli Nanomaterial Application Reference.
1. Glucose Acetalated dextran nanoparticles
Ac-Dex Nps
Glycemic control [52]
2. Glucose Boronic acid-derived polymers Drug delivery [53]
3. Glucose Glycidyl methacrylated dextran/Concanavalin A
Dex-GMA/Con A
ConA micro/nanospheres
Insulin treatment [54]
4. Glucose Chitosan-g-polyethylene glycol monomethyl ether nanocomplex
CS-g-(mPEG) NP
Oral insulin delivery [55]
5. Glucose Hyaluronic Acid (HA)-coated calcium carbonate NPs Oral insulin delivery [56]
6. Glucose Chitosan/poly(gamma-glutamic acid) nanoparticles Oral insulin delivery [57]
7. Glucose Carboxymethyl chitosan-phenylboronic acid-Lvaline nanoparticles
Oral administration of insulin [58]
8. Enzyme Nanoplatform formed from Ti substrates modified with
layer-by layer mesoporous silica nanoparticles-silver nanoparticles
LBL@MSN-Ag nanoparticles
Tissue growth in vivo and, simultaneously, treat implant-associated bacterial infection [59]
9. Enzyme Adenosine triphosphate coated with silver nanoparticles
ATP-Ag nanoparticles
Participate in signal transduction and protein activity [60]
10. Enzyme Activatable low-molecular weight protamine—poly(ethylene glycol) poly(ε-caprolactone) nanoparticles—loaded with paclitaxel
Glioblastoma therapy [61]
11. Enzyme Layer-by-layer assembly of poly(2-oxazoline)-based materials Therapeutic delivery [62]

2.4. Dual and Multi-Responsive Nanomaterials

A step forward for biomedical applications is attained when the smart nanomaterials are simultaneously sensitive to more stimuli. The nanomaterials which are sensitive to a few sorts of stimuli are the key for expanding the efficacy of drug delivery and for supporting the diagnosis by monitoring a few physiological changes at once.

The development of nanomaterials with both diagnostic and therapeutic properties is the most powerful technological frontier for moving forward to nanotheranostics. The demand for these technologies is based on the advantage of multiple functions such as multimodal imaging, synergistic therapies, and targeting. The working system of nanotheranostics depends on biological, chemical, and physical triggers considering the activation of the diagnostic and/or the therapeutic properties only at the infected site. In this era of the “war on cancer”, the dual and multi-stimuli-responsive methodology is undeniably appropriate for theranostics as some properties can provide diagnostics, while others could initiate therapy and curing. Consequently, multi-stimuli-sensitive polymers are drawing in expanding consideration for their advantages in the biomedical field.

Multi-stimuli-sensitive polymeric nanoparticles were developed as emerging targeting drug delivery systems. External stimuli such as temperature and pH facilitate the emergence of nanoparticles, while stimuli such as light, the magnetic field, the temperature, and ultrasonic are intended to control drug delivery. Examples of multi-sensitive nanomaterials and their applications are listed in Table 4 [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77].Recent works [143-150] describe the design of multi-responsive smart nanomaterials and their applications in the biomedical field.

Nr. Crt. Stimuli Nanomaterial Application Ref.
1. pH/redox/temperature N,N0 -bis(acryloyl)cystamine, Poly(N-isopropylacrylamide), 2-hydroxyethylmethacrylate, Methacrylic acid, a disulfide bond contained cross-linker, and doxorubicin
Drug delivery [63]
2. Ultrasound/pH Poly(ethylene oxide, 2-(diethylamino)ethyl methacrylate, (2-tetrahydrofuranyloxy)ethyl methacrylate
Drug release [64]
3. Temperature/magnetic field Poly(N-isopropylacrylamide)- Magnetic nanoparticles
The isolation of diagnostic targets that can be used in point-of-care devices [65]
4. Light/pH rGO-PDA nanosheets Drug delivery, phototherapy [66]
5. pH/magnetic field Magnetic nanoparticles
Targeting, drug delivery, MRI [67]
6. Temperature/pH Poly(N-isopropylacrylamide)
Drug release [68]
7. pH/light/enzyme Copper sulfide nanoparticles
Theranostics [69]
8. pH/redox Thiol-modified polylysine- indocyanine green/ poly(ethylene glycol) nanoparticles
Photothermal and photodynamic therapy [70]
9. pH/redox Poly (ethylene glycol) –polylacticacid-thioketal groups-Paclitaxel-(Maleimide thioether) Chlorin e6
mPEG-PLA-TKI-PTX nanoparticles and Ce6-(SS-mal-)-Ce6 (PNPCe6)
Chemotherapy, drug release [71]
10. pH/redox Histidine -4 polyamidoamine dendrimer -Disulfide bonds- (poly (ethylene glycol)- Transferrin
(His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) nanocarrier
Anticancer drug delivery [72]
11. pH/redox Lipoic acid ethylenediamine- Polyethylene glycol diglycidyl ether- Llysine
poly(LAE-co-PGDE-co-Lys) core-crosslinked nano aggregate
Anticancer drug delivery [73]
12. pH/redox Paclitaxel- poly(6-O-methacryloyl-d-galactopyranose)- gemcitabine/ N-acetyl-d-glucosamine(NAG)-poly(styrene-alt-maleic anhydride)-b-polystyrene
Anticancer drug delivery [74]
13. UV light/redox/pH Six-arm star-shaped amphiphilic copolymer with poly (caprolactone) -bpoly (acrylic acid) -b-poly (poly (ethylene glycol) methyl ether methacrylate) Anticancer drug delivery [75]
14. pH/temperature Poly(NIPAM)nanogel @ Fe3O4 NPs/poly(acrylic acid) -graft—κ—carrageenan Drug delivery [76]
15. Redox/pH/temperature Nanogels based on alginate and cystamine Anticancer drug delivery [77]

3. Advances in Plasmonic Nanomaterials

A special class of smart nanomaterials is derived from plasmonic nanoparticles used in innovative sensitive tools for diagnostics and therapeutics. The collective electronic (plasmon) resonances of noble/coinage metal nanoparticles enable a strong optical response essential in applications such as photocatalysis, sensing, photothermal heating, and enhanced fluorescence. Biomedical applications rely on plasmonic nanoparticles’ properties to absorb or scatter light at near-infrared wavelengths, transmissive in the human body [78]. A large number of applications misuse the extraordinary properties of metals to support electromagnetic waves at their surfaces, through the oscillation of their conduction electrons known as surface plasmons. The local dielectric environment, size, structure, shape, and composition determine the surface plasmon polariton modes enabling nanostructures to focus and direct light down to the nanoscale. The ability of plasmonic nanostructures to strongly interact with light at wavelengths that significantly exceed their dimensions led to the appearance of the nanoplasmoic field [79]. Consequently, most recent strategies for the design and manufacture of plasmonic nanostructures for accurately controlling light have opened new entryways for the applications that were recently perceived as impossible.

Recent studies have shown that by targeting gold nanoparticles to the cell nucleus region, the nuclear stiffness is enhanced, slowing down the migration and invasion speed of cancer cells and suppressing metastasis [80]. Further, gold nanoparticles exhibit high contrast in photothermal therapeutic treatments, as well as photoacoustic, optical coherence, and X-ray CT imaging. Conjugates of gold nanoparticles present augmented binding affinity, long circulatory half-life, size-enhanced tumor uptake, increased targeting selectivity, high biocompatibility, and rapid transport kinetics. If all those properties are put together in a highly multifunctional platform, one can obtain an increasingly selective and potent oncologic treatment [81].

As diagnosis is the key in the screening and treatment of human diseases, modern-day researchers developed sensitive tools for real-time and accurate tracking of the treatment effect. In a recent paper, the authors obtained a core–shell structure MPs@ SiO2@Pd–Au with a crystalline magnetic core, amorphous silica interaction layer, and Pd–Au shell for medulloblastoma diagnosis and radiotherapy evaluation. Owing to the plasmonic and alloying effects, MPs@SiO2@Pd–Au may contribute to efficient electron transfer and high surface stability under laser irradiation during the laser desorption/ionization process [82]. Other authors described the design of a plasmonic gold nano-island (pGold) chip assay for enhanced diagnosis and monitoring of myocardial infarction [83]. A multifunctional platinum nanoreactor intended for point-of-care metabolic analysis, visual detection, and mass spectrometry fingerprinting for in vitro pancreatic cancer diagnostics was designed using controlled core–shell structured Fe3O4@SiO2@Pt particles [84]. Another work describing the application of laser desorption/ionization mass spectrometry in large-scale clinical in vitro cervical cancer diagnosis utilized a plasmonic chip with Au nanoparticles deposited on a dopamine bubble layer [85].

An increasing interest was paid to the field of thermoplasmonics, defined as plasmonic nanoparticles remotely controlled by light to release heat on the nanoscale volumes. The capability of using plasmonic materials as photothermal agents is based on a combination of properties such as the high density of free electrons, the absence of thermobleaching, resonances that enhance light–matter interaction, and low losses for noble metals. Those materials are best choices in applications requiring spatially confined heating, such as in nanosurgery and photoacoustic and photothermal imaging [86]. Recent works described the capability of gold nanorods to convert NIR radiation into heat for antibacterial application without affecting cells’ viability and proliferation [87] and of keratin-coated gold nanoparticles to kill the brain cancer cells by photothermal therapy [88]. The photothermal therapy induced by the presence of gold nanoparticles in a system capable to develop immunotherapy represents a major breakthrough in the fight against malignant solid tumors. This synergistic new approach was comprehensively described moving from in vivo studies to clinical trial applications in patients suffering from solid tumors. Although those systems hold great promise in nanomedicine, there are still risks involved, such as the wrong cells being targeted, unknown long-term side effects, and unwanted immune reaction systems. For this reason, the combination of hyperthermia with chemotherapeutic activity or cancer immunotherapy demonstrated improved care of oncological patients [89].

The properties of Au and Ag nanoparticles have inspired the field of plasmonic nanoparticles in the last two decades, but recently, non-noble metals have been the subject of quickly expanding interest as less expensive, more practical alternatives. Colloidal nanocrystals functionalized with silica have been utilized for plasmon-driven photocatalysis and surface-enhanced Raman spectroscopy at visible and near-infrared wavelengths due to their enhanced stability in water and efficient broadband photothermal heating [90].

This entry is adapted from the peer-reviewed paper 10.3390/nano11020396


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