Fouad
Damiri
*ab,
Ahmed
Fatimi
*a,
Ana Cláudia Paiva
Santos
cd,
Rajender S.
Varma
e and
Mohammed
Berrada
*b
aChemical Science and Engineering Research Team (ERSIC), Department of Chemistry, Polydisciplinary Faculty of Beni Mellal (FPBM), University Sultan Moulay Slimane (USMS), Beni Mellal 23000, Morocco. E-mail: fouad.damiri@outlook.fr
bLaboratory of Biomolecules and Organic Synthesis (BIOSYNTHO), Department of Chemistry, Faculty of Sciences Ben M’Sick, University Hassan II of Casablanca, Casablanca 20000, Morocco. E-mail: a.fatimi@usms.ma
cDepartment of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Coimbra, Portugal
dREQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Coimbra, Portugal
eCentre of Excellence for Research in Sustainable Chemistry, Department of Chemistry, Federal University of São Carlos, 13565-905 São Carlos – SP, Brazil. E-mail: berrada_moh@hotmail.com
First published on 1st November 2023
Polysaccharides have found extensive utilization as biomaterials in drug delivery systems owing to their remarkable biocompatibility, simple functionalization, and inherent biological properties. Within the array of polysaccharide-based biomaterials, there is a growing fascination for self-assembled polysaccharide nanogels (NG) due to their ease of preparation and enhanced appeal across diverse biomedical appliances. Nanogel (or nanohydrogel), networks of nanoscale dimensions, are created by physically or chemically linking polymers together and have garnered immense interest as potential carriers for delivering drugs due to their favorable attributes. These include biocompatibility, high stability, the ability to adjust particle size, the capacity to load drugs, and their inherent potential to modify their surface to actively target specific cells or tissues via the attachment of ligands that can recognize corresponding receptors. Nanogels can be engineered to respond to specific stimuli, such as pH, temperature, light, or redox conditions, allowing controlled release of the encapsulated drugs. This intelligent targeting capability helps prevent drug accumulation in unintended tissues and reduces the potential side effects. Herein, an overview of nanogels is offered, comprising their methods of preparation and the design of stimulus-responsive nanogels that enable controlled release of drugs in response to specific stimuli.
Dr Ana Cláudia Paiva-Santos obtained her PhD degree in Pharmaceutical Nanotechnology in 2018. She started her pedagogical intervention as a Teaching Assistant during the PhD, and then became an Invited Assistant Professor. Since 2020 she has been an Assistant Professor at the Faculty of Pharmacy of the University of Coimbra (FFUC), where she teaches Pharmaceutical Technology and Nanotechnology. She has published >120 papers and 12 book chapters in nanotechnology and nanomedicine, and submitted one patent application, as a result of work performed with several national and international collaborations (h-index 23). She was among the World's Top 2% of Scientists in 2022 as determined by Stanford University. |
Nanohydrogels (NHs), or nanogels, are polymer networks with a size smaller than a micron and comprise hydrogel particles with a nanometer-scale space, exhibiting characteristics of both hydrogels and nanoparticles. In the realm of nanoparticles, which consists of inorganic, lipid, and polymer nanoparticles, nanogels fall into the latter category. To create nanohydrogels, one can either use polymeric precursors or carry out polymerization of monomers under heterogeneous conditions, with cross-linking being a crucial step. Nanohydrogels possess hydrophilic functionalities such as –SO3H, –OH, –CONH2–, and –CONH–, which enable them to absorb considerable quantities of biological fluids or water at the same time as preserving their organizational integrity. However, due to the existence of cross-links, nanogels expand instead of dissolving upon contact with a solvent. This remarkable characteristic makes nanogels highly promising for a wide range of applications. Numerous research studies have showcased the appropriateness of nanogels as carriers for drug delivery.4 This is attributed to their exceptional ability to accommodate a substantial quantity of drugs, maintain a high level of stability, exhibit biocompatibility, and respond to numerous environmental elements, namely ionic strength, pH, and temperature, in a superior manner relative to conventional pharmaceutical nanocarriers.
Extensive research endeavors have focused on investigating stimulus-responsive nanogels in the past decade, resulting in their noteworthy impact on the advancement of drug transport systems (Fig. 1). Nanogels have emerged as targeted nanocarriers that enable precise and controlled release of drugs, thereby improving drug stability in the field of nanomedicine. These nanohydrogels, composed of hydrophilic polymeric systems with a size range below one micron, serve as efficient vehicles for drug delivery. Most nanogels reported previously, however, are not biodegradable, and their synthesis often entails the use of surfactants.5 They possess viscoelastic characteristics and are formed through either non-covalent interactions or covalent bonding between polymer chains. When exposed to an aqueous medium, nanohydrogels tend to absorb water. While their internal structure resembles hydrogels and polyelectrolyte microgels, nanogels differ primarily in size and the kind of reaction deployed in their synthesis. Nanohydrogels possess distinctive qualities that make them ideal for various applications. They exhibit biocompatibility, ensuring compatibility with living systems, and offer exceptional stability.6 Moreover, their particle size can be easily adjusted as needed. Additionally, nanohydrogels are capable of responding to external factors like temperature, pH, light, and ionic strength, thus enhancing their versatility. These exceptional attributes make nanogels well-suited for diverse uses, such as tissue engineering, biomedical implants, gene therapy, and the delivery of medications.7
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Fig. 1 A visual representation of nanogels responding to specific stimuli and their application in delivering therapeutic substances (created with https://BioRender.com). |
Polysaccharides are sourced from several natural sources, like animals, plants, microbes, and algae.4,8,9 Consequently, nanogels (NG) constructed from biocompatible and biodegradable polymers show immense potential for utilization in drug delivery systems (DDS).4 Moreover, polysaccharide-derived NGs offer excellent biocompatibility, functionality, adjustable size, ample surface area for bioconjugation, and an inner network that allows for precise regulation of the integration and release of bioactive compounds.10 Biopolymeric nanocarriers are created using natural polymers, like cellulose,11 chitosan,12 sodium alginate,13 and hyaluronic acid,14 as well as synthetic polymers, namely polylactic acid (PLA),15 polyacrylamide (PAA),16 poly(lactide-co-glycolide) (PLGA),17 and polyglycolic acid (PGA),18 dendrimers,19 among others.
Intelligent stimuli-responsive polysaccharide nanohydrogels for drug delivery have garnered significant consideration recently. These nanohydrogels, comprising biocompatible and biodegradable polysaccharides, offer promising potential for enhancing drug delivery systems. Herein, a comprehensive overview is offered for the synthesis, characterization, and applications of these intelligent nanohydrogels, besides an exploration of their response to different stimuli like temperature, pH, enzymes, and external triggers.20 Furthermore, the benefits, obstructions, and potential future advancements of utilizing these nanohydrogels in the field of drug delivery are discussed. The advancements in this field are highlighted by exploring the progress made in intelligent stimuli-responsive nanohydrogels derived from polysaccharides, with the ultimate goal of facilitating the growth of these nanohydrogels for effective drug delivery applications.21,22
Nevertheless, the evaluation also highlighted their usage in the transportation of drugs and genes, photodynamic treatment, biological imaging, and biological sensing, with the primary emphasis being on the various types of responsive nanogels, especially those triggered by redox reactions, temperature changes, pH, and light. Simultaneously, it addressed the challenges that need to be circumvented to achieve successful cancer therapy (Fig. 1).
Polymer | Nanogel system | Therapeutics | Ref. |
---|---|---|---|
Chitosan | CTS-g-PHEMA-maleic acid | Doxorubicin (DOX) | 24 |
Chitosan/poly(N-isopropylacrylamide) | Gold nanoparticles (AuNPs) | 25 | |
Trimethyl chitosan (TMC)/poly(2-hydroxyethyl methacrylate) (PHEMA) | Melatonin | 12 | |
Cellulose | Methacrylated monocarboxylic sugarcane bagasse cellulose (MAMC-SBC)/N-isopropylacrylamide (NIPAM) | Doxorubicin (DOX) | 11 |
Carboxymethyl nanocellulose (CMNC)/lysozyme | Acyclovir, carbamazepine, and furosemide | 26 | |
(CDs/DCMC-Gel)-FA | Curcumin (CUR)/doxorubicin (DOX) | 27 | |
Starch | Carboxymethyl starch-lysozyme | Epigallocatechin gallate (EGCG) | 28 |
Starch nanocrystals/gum Arabic | Hydroxyurea | 29 | |
Fe3O4-g-(PNIPAAm-co-PMA)@starch | Doxorubicin (DOX) | 30 | |
Alginate | Alginate/chitosan (ACC) | Mupirocin | 31 |
Sodium alginate-chitosan (AO/CHPCS) | Berberine (BBR) | 32 | |
Alginate | Doxorubicin (DOX) | 33 | |
Dextran | Dextran (Dex-CHO)/cystamine dihydrochloride (Cys) | Doxorubicin (DOX) | 34 |
SPI-SA-DX | Curcumin | 35 | |
(Fe3O4@Dex) | — | 36 | |
Pectin | Lysozyme-pectin | Methotrexate (MTX) | 37 |
ALG-g-PHPMA@Et | Etoposide (Et) | 38 | |
Ovalbumin-pullulan | Curcumin (Cur) | 39 | |
Hyaluronic acid | Maleoyl-chitosan/poly(aspartic acid) | Amoxicillin (Amox) | 40 |
(Ce6HANG/DOX) | Doxorubicin (DOX) | 41 | |
(Lf-DOX/PBNG) | Doxorubicin (DOX) | 42 | |
Carragenan | (CG or κ-carrageenan) | Rivastigmine tartrate (RIV) | 43 |
KCAR-NGs | Amoxicillin and iodixanol | 44 | |
PN-NG@ION PAA-g-κC HG | Levodopa (L-DOPA) | 45 | |
Heparin | HEP | Doxorubicin (DOX) | 46 |
Heparin–Pluronic (Hep–Pr) | Paclitaxel and DNase | 47 | |
HP403 | Cisplatin/curcumin | 48 | |
Gellan gum | Gellan–cholesterol | Prednisolone (Pred) | 49 |
Gellan–prednisolone | |||
Chitosan–gellan gum | Curcumin (Cur) | 50 | |
Gellan gum (GG)/chitosan (CS) | Polymyxin B (PMB) | 51 | |
Xanthan gum | Cassava starch (CS)/xanthan gum (XG) | — | 52 |
Polyethylene glycol/xanthan gum-co-poly(acrylic acid) | Venlafaxine | 53 | |
Xanthan gum (XG)/poly(AA) | Amoxicillin | 54 |
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Fig. 2 Illustration of various synthetic approaches, natural as well as synthetic polymers and crosslinkers employed in the fabrication of stimuli-responsive polymer nanogels. Reproduced from ref. 23 with permission from Elsevier, copyright 2020. |
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Fig. 3 Classification of polysaccharides based on their sources of origin. Reproduced from ref. 4 with permission from Elsevier, copyright 2023. |
Natural polymers are favored over synthetic counterparts due to their readily available nature, susceptibility to chemical alterations, renewability, cost-effectiveness, non-toxicity, stability, hydrophilicity, biocompatibility, and biodegradability (Fig. 4). In contrast, synthetic polymers are relatively expensive and pose environmental and toxicity concerns, along with lengthy and involved synthetic processes.
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Fig. 4 The categorization of common polysaccharides that are widely deployed in the drug delivery field. |
Yao and colleagues60 introduced an innovative nanogel/gel that exploited chitosan (CS) as a foundation for the oral delivery of myricetin (Myr); CS/β-glycerol phosphate (β-GP) nanogels loaded with Myr of particle sizes ranging from 100 to 300 nm.
In their study, Pan et al.11 created multi-responsive nanogels by utilizing a modified form of cellulose obtained from sugarcane bagasse (SBC). They deployed cystamine bisacrylamide (CBA) as a crosslinking agent and performed an in situ aqueous copolymerization (free radical) of methacrylated monocarboxylic sugarcane bagasse cellulose (MAMC-SBC) and N-isopropylacrylamide (NIPAM). This synthesis process resulted in the formation of nanogels that exhibit responsiveness to changes in redox conditions, pH levels, and temperature.
Sousa et al.67 conducted a co-encapsulation synthesis to merge oncocalyxone A (onco A) and magnetite nanoparticles (Fe3O4@citrate) with modified surfaces, forming a unified nanostructure. The nanocapsules obtained displayed a core–shell structure and possessed an average diameter of 143 nm.
In this context, Suhail et al.71 have created a network of nanogels using polymers to achieve a continuous release of caffeine. To attain this, they employed a free-radical polymerization method to fabricate alginate-based nanogels. To crosslink the alginate polymer, the monomer 2-acrylamido-2-methylpropanesulfonic acid was employed, along with the crosslinker N′,N′-methylene bisacrylamide. Several analyses were performed on the synthesized nanogels, encompassing assessments of the sol–gel fraction, polymer volume fraction, swelling behavior, drug loading capacity, and drug discharge characteristics.
In their study, Yu et al.34 focused on the generation of dextran-based nanogels termed Dex-SS via a straightforward method that involved the formation of Schiff base bonds containing disulfide between polyaldehyde dextran and cystamine. This process occurred within a water-in-oil inverse microemulsion. The researchers analyzed the morphology of the treated nanogels using SEM imaging and investigated the degradation behavior of these nanogels under both acidic and reductive (GSH) conditions. To achieve controlled drug release, they covalently linked doxorubicin (DOX) to the dextran nanogels through Schiff base connections. As a result, the drug release profiles exhibited sensitivity to both pH and GSH, enabling a dual-responsive drug release mechanism.
In 2016, Zhou et al.77 created protein/polysaccharide complexes that have captured significant attention due to their potential uses in the food industry, biomedicine, and pharmaceutics. In their research, they focused on developing new nanogels, measuring less than 60 nm, by utilizing a straightforward process involving the complexation of low-density lipoprotein (LDL) from egg yolk with pectin, induced by changes in pH and temperature. The team conducted a detailed examination of the nanostructure of egg yolk LDL under varying pH conditions and thoroughly investigated its interaction with pectin.
Luan et al.79 have developed nanogels capable of undergoing degradation in the presence of acidic environments and were synthesized in an aqueous medium using a surfactant-free polymerization technique, employing 2,2-dimethacroyloxy-1-ethoxypropane (DMAEP) as a cross-linker that is sensitive to pH changes. Through the adjustment of cross-linking degrees, nanogels with diverse properties were produced. The researchers successfully loaded the anti-cancer drug doxorubicin (DOX) into the nanogels, achieving drug-loading contents (DLC) ranging from 7.67% to 12.15%. Importantly, when subjected to acidic conditions, the nanogels demonstrated an accelerated release of DOX.
Rahmani et al.43 developed pH-responsive nanogels that incorporate rivastigmine as a representative drug model. The nanogels were created by the graft polymerizing method, deploying acrylamide and sodium acrylate monomers onto chitosan (CS) and kappa-carrageenan (CG or κ-carrageenan) structures. The synthesis procedure involved the utilization of N,N′-methylenebisacrylamide (MBA) as a cross-linker, along with ammonium persulfate and nitrogen-doped carbon dots (N-CDs) as initiators. Various techniques such as FTIR, FE-SEM, EDX, XRD, and TGA were employed to characterize the nanogels. The swelling performance of the nanogels was affected by factors like monomer content, MBA content, the quantity of CS or CG, and the pH conditions during synthesis. Notably, the nanogels demonstrated notable responsiveness to pH in drug release experiments, with a drug release of less than 61% observed under simulated gastric conditions (pH 1.2) and ∼95% under imitation intestinal conditions (pH 7.4).
Nguyen et al.48 developed a nanogel called HP403, which is a combination of amphiphilic heparin and poloxamer P403. The researchers explored a nanogel that possesses the capacity to co-encapsulate cisplatin hydrate (CisOH) and curcuminoid (Cur) through distinct loading mechanisms. Comprehensive analysis of the HP403 nanogels and HP403@CisOH@Cur nanogels was conducted by the researchers using multiple techniques such as FT-IR spectroscopy, 1H-NMR spectroscopy, DLS, and TEM. Through these analyses, it was established that the nanogels maintained their stability effectively and displayed a spherical structure. The drug release process indicated that Cur and CisOH were released at a faster rate under acidic conditions (pH 5.5) compared to under a neutral pH, thus affirming that the nanogels were effective in delivering the loaded compounds to tumor sites.
D'Arrigo et al.49 created and characterized nanohydrogels that self-assemble using sonicated chains of gellan gum. They achieved this by chemically linking prednisolone (Pred), an anti-inflammatory drug with limited water solubility, to the carboxylic groups of gellan (Ge-Pred); Ge-Pred played a crucial role as the hydrophobic element accountable for the self-assembly mechanism. The researchers employed 1H-NMR to analyze the Ge-Pred compound, while the cytotoxicity of Ge-Pred on cells was determined using the MTS assay. The self-aggregation characteristics of Ge-Pred in water were examined using the pyrene fluorescence technique, and the resulting nanohydrogels (NHs) were generated through bath sonication in an aqueous medium. Subsequently, these NHs were analyzed utilizing ζ-potential measurements and dynamic light scattering (DLS). The nanohydrogels exhibited an average size of ∼300 nm and demonstrated negative ζ-potential values. The research findings demonstrated that Ge-Pred nanohydrogels were compatible with cells, facilitating the drug's bioavailability. As a result, these nanohydrogels present a promising and innovative carrier for delivering prednisolone.
Ferreira et al.85 conducted a study to investigate the potential anti-tumor effects of polymeric nanocapsules (NC (PhSe)2) loaded with (PhSe)2 on a melanoma cell line called SK-Mel-103, known for its resistance. Additionally, they developed a xanthan gum-based hydrogel for the topical application of NC (PhSe)2. In the in vitro evaluation, the researchers exposed the cells to different concentrations (ranging from 0.7 to 200 μM) of either free (PhSe)2 or NC (PhSe)2. After 48 hours, they conducted the MTT assay to assess cell viability, measured propidium iodide uptake (a marker for necrosis), and evaluated nitrite levels. The hydrogels were prepared by incorporating xanthan gum into the suspension of NC (PhSe)2 or the (PhSe)2 solutions to increase their viscosity. The researchers conducted various characterization tests on the hydrogels, including determination of their average diameter, pH, polydispersity index, spreadability, drug content, and rheological profiles. Additionally, they evaluated the in vitro permeation of the hydrogels through human skin.
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Fig. 5 The process of delivering drugs using acid-sensitive nanogels. Reproduced from ref. 86 with permission from Elsevier, copyright 2023. |
The pH-responsive degradation of hydrogels is responsible for the targeted discharge of cargo. Zheng et al.87 have developed a hybrid hydrogel that combines micelles and nanocomposites for applications in skin cancer treatment and bacterial extermination, both in vitro and in vivo. They designed a responsive hydrogel system that can respond to multiple stimuli, leading to enhanced photothermal and chemodynamic therapy (CDT). The hydrogel was created by incorporating MoS2@MnFe2O4 nanocomposites into a cross-linked network consisting of chitosan-grafted-dihydrocaffeic acid (CS–DA) and aldehyde Pluronic F127 (F127-CHO) micelles laden with glucose oxidase (GOx). The hydrogel network contained dynamic Schiff-based imine bonds, which allowed for pH responsiveness and controlled degradation of the gel. The hydrogel exhibited a loading capacity of 0.5666 mg g−1 for GOx, and ∼60% of GOx was released over 15 days under a slightly acidic pH of 6.8. Upon release, the GOx enzymatically reacted with glucose, resulting in the generation of hydrogen peroxide and increased acidity in the environment. This acidity allowed iron atoms to participate in the Fenton reaction, producing reactive hydroxyl radicals that induced cell death. The combination of chemodynamic therapy (CDT) with local hyperthermia effectively suppressed tumor growth, achieving a suppression rate of 98.8% in vitro and 97.6% in vivo.
pH-Responsive nanogels find extensive application in drug delivery, and they can be synthesized using both synthetic and natural polymers. Natural polymers like cellulose, chitosan, hyaluronic acid, and dextrin, among others, are highly preferred due to their favorable attributes such as biocompatibility, biodegradability, and non-toxic nature.
In a study conducted by Rahmani et al.,88 a new nanocomposite was created using pH-responsive chitosan (CS), nitrogen-doped carbon quantum dots (NCQDs), and montmorillonite (MMT) (Fig. 6). This nanocomposite was loaded with doxorubicin (DOX) and introduced into a double emulsion system to achieve a controlled and prolonged release of the drug. The incorporation of nitrogen-doped carbon quantum dots (NCQDs) into the CS–MMT hydrogel resulted in notable enhancements in loading and entrapment efficiencies. Additionally, the presence of NCQDs nanoparticles in the CS–MMT hydrogel enabled an extended and pH-responsive release of doxorubicin (DOX) for a duration of 96 hours, surpassing the release profile demonstrated by CS–MMT–DOX nanocarriers at pH 5.4. The release of DOX was precisely controlled and followed the Korsmeyer–Peppas model at pH 5.4, ensuring reduced side effects. On the other hand, no diffusion of DOX was observed at pH 7.4, indicating the potential to minimize the undesirable effects.
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Fig. 6 (A) A structural depiction of a hydrogel nanocomposite consisting of cross-linked chitosan (CS), nanocrystalline quantum dots (NCQDs), montmorillonite (MMT) and the drug doxorubicin (DOX) shown as a diagram. (B) An image obtained through field-emission scanning electron microscopy (FESEM) showing the CS–MMT–NCQDs nanocarrier loaded with DOX. (C) The release pattern of DOX from the CS–MMT–NCQDs nanocarrier and CS–MMT without NCQDs in vitro at pH 5.4 and pH 7.4, both at 37 °C, using the dialysis protocol; release profiles measured at specific time intervals. Reproduced from ref. 88 with permission from Wiley, copyright 2022. |
An alternative method of developing pH-responsive nanogels involves utilizing polymer components that contain amino functionalities, known as cationic polymers. These polymers have the ability to ionize (protonate) and form NH3+ when exposed to an acidic environment. This ionization process leads to enhanced electrostatic repulsion, triggering a volume-phase transition or swelling of the nanogels. The swelling phenomenon is of paramount importance in the controlled release and regulation of drugs. Furthermore, nanogels with a positive charge have a heightened affinity for negatively charged cell membranes, facilitating their rapid internalization by cells.
Rong et al. conducted a study,89 deploying an injectable composite hydrogel that was obtained by combining hydroxypropyl chitosan (HPCS) and oxidized hyaluronic acid (OHA) through the formation of imine bonds (Fig. 7); functional substances could be delivered using this hydrogel. To enhance its properties, mesoporous polydopamine (MPDA) nanoparticles were integrated into the gel, serving both as an effective photothermal agent and a reservoir for the drug doxorubicin (DOX). This combination allows for effective photothermal conversion and controlled discharge of the drug. In addition, to tackle inflammation resulting from photothermal therapy (PTT), the scientists introduced the curcumin–cyclodextrin host–guest inclusion complex (CUR@NH2-CD) into the hydrogel. In vivo experiments demonstrated that the composite hydrogel effectively inhibited the growth of Hepa1-6 tumors, benefiting from the synergistic effects of MPDA's photothermal properties, DOX's chemotherapy, and CUR's anti-inflammatory activity. These findings indicate that the composite hydrogel has significant potential for comprehensive tumor therapy.
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Fig. 7 (A) A diagram depicting the conceptual framework of the hydrogel composite intended for tumor treatment utilizing near-infrared (NIR) irradiation. (B) Various analyses were conducted to assess the characteristics of the materials, including the X-ray photoelectron spectroscopy (XPS) wide-scan spectrum, Fourier-transform infrared (FTIR) spectra, size distribution assessment, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images, nitrogen (N2) sorption isotherm measurement, doxorubicin (DOX) adsorption capacity evaluation, and determination of the corresponding pore size distribution of the MPDA. (C) The process of gelation of the resultant hydrogel, the Fourier-transform infrared (FTIR) spectra of the hydroxypropyl cellulose sulfate (HPCS), octylphosphonic acid (OHA), and the respective hydrogel, the storage modulus (G′) and loss modulus (G′′) of the hydrogel with a gradient composition, as determined through strain sweep and frequency sweep experiments, the images showcasing the self-healing and injecting procedures of the hydrogel, and the scanning electron microscopy (SEM) images of the freeze-dried hydrogel. Reproduced from ref. 89 with permission from Elsevier, copyright 2023. |
The role of thermoresponsive nanogels as nanocarriers relies on the properties of responsive moieties/polymers, which exhibit a lower critical solution temperature (LCST). At temperatures below the LCST, nanogels maintain sufficient hydration in a water-based environment and form hydrogen bonds with water molecules. However, as the temperature rises above the LCST, nanogels undergo a volume-phase transition, becoming more hydrophobic. This results in the shrinkage of the nanogel structure, enabling the release of drug molecules. The transition is triggered by a reduction in the hydrophilic interactions between the polymer and water molecules, leading to an increase in intra- and inter-hydrophobic interactions among the polymer molecules. The precise lower critical solution temperature (LCST) of a thermosensitive polymer is dictated by its structure and composition, and it can be altered by manipulating the composition of the nanogel. Although PNiPAAm is frequently utilized in nanogel synthesis due to its LCST range of 30–35 °C, its potential toxicity and lack of biodegradability restrict its application as a nanocarrier. To overcome these limitations, efforts have been made to enhance the biodegradability and biocompatibility of nanogels by integrating copolymerization or grafting techniques with biodegradable polymers like cellulose, chitosan, hyaluronic acid, dextran, and similar materials.
Nanogels with temperature responsiveness, derived from hyaluronic acid (HA) and grafted with PNIPAM, have exhibited enhanced drug loading capacity and improved bioavailability when nanogels are utilized for curcumin, which is a hydrophobic anti-cancer medication. The synthesis of HA nanogels grafted with PNIPAM was accomplished using the sonification method, yielding nanogels with a narrow size distribution ranging from 100 to 300 nm and a polydispersity index (PDI) of 0.2. Premature dispensation of the drug payload prior to reaching the intended target sites is a significant challenge in drug delivery systems. To address this issue, the development of nanogels with a hollow-shell structure has been explored, which have the ability to efficiently uptake, store, and subsequently release the cargo, providing a solution to the aforementioned challenge.
Luckanagul et al.90 have developed intelligent material platforms for the delivery of curcumin, via the deployment of nanoscale hydrogel particles derived from the natural polymer chitosan (Fig. 8). In this investigation, chitosan was employed as the fundamental material and subjected to a chemical grafting process with poly-(N-isopropylacrylamide) (pNIPAM) using an EDC/NHS coupling reaction. The resulting conjugated products were analyzed and characterized using TGA and 1H NMR techniques. By employing a sonication method, chitosan-grafted pNIPAM (CS-g-pN) nanogels were prepared, and the loading of curcumin into these nanogels was accomplished through an incubation process. Various analytical techniques, including DLS, TEM, fluorescent spectroscopy, and confocal microscopy, were utilized to investigate the size, morphology, curcumin loading capacity, and cellular uptake of the nanogels, respectively. To evaluate the safety of the CS-g-pN nanogel particles, the CellTiter-Blue® cell viability assay was conducted on NIH-3T3 and HeLa cells. Additionally, an MTT assay was performed on HepG2, Caco-2, MDA-231, and HT-29 cells to assess the cytotoxic effects. The findings indicated that CS-g-pN nanogel particles with submicron sizes could be easily formed by assembling CS-g-pN with a modification degree ranging from 3% to 60%, and the resulting nanogels efficiently encapsulated curcumin. The thermoresponsive properties of the different CS-g-pN nanogel formulations varied based on the density and length of the grafted pNIPAM. Moreover, the CS-g-pN nanogel preparations displayed no toxicity towards HeLa cells or NIH-3T3. Each curcumin-loaded CS-g-pN nanogel formulation was taken up by NIH-3T3 cell lines and exhibited cytotoxicity against the tested cell lines in a dose-dependent manner.
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Fig. 8 The schematic representation of assembly and drug release of CS-g-pN nanogels. Reproduced from ref. 90 with permission from Elsevier, copyright 2018. |
Metawea and his colleagues91 conducted research on the development of poly(N-isopropylacrylamide) (PNIPAM) due to its versatility for chemical modifications, allowing adjustment of its thermoresponsive properties and incorporation of additional stimulus responsiveness (Fig. 9). The main goal of this study was to create a delivery system for resveratrol (RSV), a natural polyphenol with limited bioavailability in breast cancer treatment, that is both targeted and responsive to stimuli. To achieve this, PNIPAM-maltodextrin nanohydrogels (PNIPAM-MD NGs) were synthesized and decorated with folic acid (FA).
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Fig. 9 An illustration of the novel thermo-/pH-responsive nanohydrogels composed of folic acid-poly(N-isopropylacrylamide-maltodextrin) for targeted therapy of breast cancer using resveratrol. Reproduced from ref. 91 with permission from Elsevier, copyright 2023. |
Yang et al.92 developed methacrylated hyaluronic acid (HA) nanogels that respond to enzymes for delivering anti-cancer drugs (DOX) to various cancer cells, like NIH3T3, A549, and H22 (Fig. 10). The HA nanogels were synthesized using radical copolymerization with the incorporation of a crosslinker called di(ethylene glycol) diacrylate (DEGDA), which contained enzyme-cleavable ester bonds. The researchers observed the disintegration or breakdown of the enzyme-sensitive nanogel networks by monitoring the change in light scattering intensity (It/I0) of the HA nanogels when exposed to hyaluronidase (Haase) and lipase enzymes. This demonstrated that the nanogels could respond to specific enzymes. The researchers conducted evaluations of the nanogels both in vitro and in vivo to assess their suitability for drug delivery applications.
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Fig. 10 (A) The synthesis pathway for producing HA nanogels is depicted. (B) The hydrodynamic diameter distribution of the HA nanogels is performed using DLS, TEM and SEM images of the HA nanogels, scale bar representing 200 nm with the impact of pH on the particle size and zeta potential of the HA nanogels. The FT-IR spectrum illustrates the comparison between MAHA (black), DEGDA (red), and the HA nanogels (blue). (C) The in vitro release profiles of DOX from the nanogels are evaluated in PBS at pH 5.0 and pH 7.4, at 37 °C, with and without hyaluronidase, lipase, and two other enzymes, respectively. (D) In vivo near-infrared (NIR) fluorescence imaging of H22 tumor-bearing mice after intravenous injection of NIR-797 labeled HA nanogels, and NIR fluorescence intensity of the tumor being measured at different time intervals in mice treated with HA nanogels. Reproduced from ref. 92 with permission from Elsevier, copyright 2015. |
Gao et al.93 created a specific nanogel system for treating breast cancer by combining CD44 and biotin receptors, wherein they were loaded with paclitaxel (PTX/Bio-NG). After fabrication using enzyme-sensitive hyaluronic acid, nanogels exhibited a spherical shape with an average particle size of 149.1 ± 1.6 nm (Fig. 11). They demonstrated high entrapment efficiency (90.17 ± 0.52%) and drug loading (15.28± 0.10%). When exposed to hyaluronidase and/or lipase enzymes, the PTX/Bio-NG formulation displayed rapid drug release. Cellular studies verified that the internalization of Bio-NG by 4T1 cells occurred via both the CD44 receptor and the biotin-specific receptor. PTX/Bio-NG, in comparison to PTX-loaded nanogels lacking biotin (PTX/NG), exhibited improved cytotoxicity against breast cancer cells (4T1 cells). Pharmacokinetic analysis conducted in rats demonstrated higher AUC0-t values and lower clearance rates for PTX/NG (6.24 times and 15.96%, respectively) as well as PTX/Bio-NG (6.66 times and 14.89%, respectively) when compared to the control group (Taxol). In vivo studies performed on Balb/c mice with 4T1 tumors demonstrated the excellent therapeutic efficacy of PTX/Bio-NG, indicating its potential as a promising candidate for breast cancer treatment.
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Fig. 11 (A) Synthetic schemes for MHA, CHOL-NH2, and CMHA. (B) Schematic illustration showcasing the preparation of PTX/Bio-NG and its in vivo drug transport process. (C) The appearance of PTX/NG and PTX/Bio-NG, along with a TEM image of PTX/NG. (D) Performing in vivo imaging on 4T1 tumor-bearing mice using DiR-loaded formulations. Reproduced from ref. 93 with permission from Elsevier, copyright 2022. |
El Shaarani et al.96 performed a study involving the synthesis of various glucose-responsive nanogels using 4-(1,6-dioxo-2,5-diaza-7-oxamyl) phenylboronic acid (DDOPBA) and N-isopropylacrylamide (NIPAM) (Fig. 12). To serve as the crosslinker, they employed dextran-grafted maleic acid (Dex-MA). The nanogels, referred to as P(NIPAM-co-Dex-co-DDOPBA)s, underwent characterization through various methods, including DLS, TEM, 1H NMR, and X-ray photoelectron spectroscopy (XPS). The incorporation of DDOPBA, which contains an electron-withdrawing group, resulted in significant sensitivity to glucose at physiological pH due to its unique properties. Furthermore, the hydrophilic Dex-MA played a role in modulating the temperature sensitivity of the nanogels near physiological temperatures. The nanogels demonstrated excellent capacity for insulin loading and exhibited a high encapsulation efficiency. In in vitro experiments, the release of insulin from the loaded system was found to be contingent on the concentration of glucose under physiological pH and temperature conditions. This glucose-dependent response allowed for controlled insulin release based on glucose levels. Overall, the study successfully synthesized and characterized glucose-responsive nanogels with desirable properties for drug delivery applications.
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Fig. 12 Schematic illustration of glucose-responsive nanogel. Reproduced from ref. 96 with permission from Elsevier, copyright 2020. |
Zhang et al.42 developed a novel therapeutic strategy, involving lactoferrin (Lf) and phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels for the treatment of glioma (Fig. 13), and the nanogels were crosslinked using a disulfide-bond crosslinker. This platform, referred to as Lf-DOX/PBNG, is specifically designed to deliver doxorubicin hydrochloride (DOX). The spherical Lf-DOX/PBNG nanogels are endowed with optimized physicochemical properties and exhibit rapid release of DOX under high concentrations of glutathione, which serves as a reduction-sensitive trigger. In cellular investigations, Lf-DOX/PBNG demonstrated enhanced cytotoxicity, increased cellular uptake efficiency, and significantly improved permeability in the brain when compared to neat DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf-modified DOX-loaded nanogels (Lf-DOX/NG). Pharmacokinetic analysis indicated that the area under the curve for DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20, and 4.32 times, respectively, in comparison to the DOX solution. Biodistribution studies confirmed that Lf-DOX/PBNG accumulated in the brain at levels 12.37 and 4.67 times higher than neat DOX solution and DOX/PBNG, respectively. These findings emphasize the potential of Lf-DOX/PBNG as an exceptionally effective targeting system for glioma therapy.
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Fig. 13 A schematic illustration of Lf-DOX/PBNG for improving BBB penetration and glioma targeting of DOX through receptor-mediated endocytosis. Reproduced from ref. 42 with permission from Elsevier, copyright 2022. |
Extensive research has been conducted on nanoparticles and nanogels that respond to light, during the exploration of their potential applications in targeted drug delivery, diagnostics, and monitoring the progress of healing. These nanocarriers, being sensitive to light, facilitate the transportation of drugs to specific locations through passive, active, and internalization mechanisms. Phototherapy commonly utilizes ultraviolet (UV), visible, and near-infrared (NIR) light. UV light, with a wavelength range of 100–380 nm, has been widely researched for its ability to trigger drug release due to its high sensitivity and energy, which can induce structural changes in materials. However, UV light has limitations such as poor tissue penetrability and phototoxicity, which restrict its use in biomedical applications. On the contrary, visible and infrared lights possess an enhanced capability to penetrate deep tissues as they experience minimal attenuation. The material's reaction to light is contingent upon various factors, including wavelength, intensity/energy, polarity, and length of exposure. While near-infrared light offers advantages in terms of tissue penetration, its limited energy hampers its efficacy in drug transport systems.
The use of light as a trigger for drug transport offers several benefits, including non-invasiveness, precise control over timing and location, and user-friendliness. Nanogels, whether they contain or are attached to bioactive substances or therapeutic medications, experience physical or structural modifications upon exposure to light. These changes enable the targeted discharge of the drug at a specific location. In drug delivery systems activated by light, three main categories of changes in physical, chemical, or structural properties play a crucial role: (i) photochemical alterations, which involve the oxidation, cleavage of bonds, and photopolymerization; (ii) photoisomerization; and (iii) photothermal variations. These modifications in the nanocarriers enable precise and controlled release of the drug when exposed to light stimuli.
Degradable nanogels with the ability to respond to ultraviolet (UV) light and near-infrared (NIR) light have been developed by Hang et al.101 These nanogels utilize hyaluronic acid-g-7-N,N-diethylamino-4-hydroxymethylcoumarin (HA-CM) and are specifically designed for targeted intracellular delivery of doxorubicin (DOX) through CD44 receptors, offering remote control over the drug discharge (Fig. 14). The nanogels, which are of nanometer size, efficiently encapsulate DOX. The nanogels' response to NIR or UV light leads to a significant increase in the release of DOX. This effect is caused by the light-induced breakdown of the urethane bonds that connect CM to HA. When DOX-loaded HA-CM nanogels are combined with NIR irradiation in MTT assays, they exhibit impressive antitumor activity against MCF-7 cells (CD44+), surpassing the activity against U-87MG cells (CD44−) and free HA-pretreated MCF-7 cells. The uptake of DOX-loaded HA-CM nanogels by CD44+ cells was confirmed through observations made using confocal laser scanning microscopy (CLSM). The uptake process occurs via receptor-mediated endocytosis, and the release of DOX inside the cells is induced by NIR light. These HA-CM nanogels possess favorable characteristics for cancer chemotherapy, such as easy preparation, targeting ability for CD44, and light-controlled release of the drug within cells.
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Fig. 14 Light-sensitive HA-CM nanogels for CD44 targeted and remotely regulated DOX discharge. (i) Receptor-mediated endocytosis and (ii) nanogel swelling and drug discharge upon exposure to light irradiation. Reproduced from ref. 101 with permission from Elsevier, copyright 2017. |
Gao et al.107 have developed a novel type of degradable nanogel known as polymer/Fe3O4 nanocomposite nanogels (NCGs), which possess magnetic, temperature-responsive, and redox-responsive attributes. To produce these NCGs, scientists modified the surface of Fe3O4 magnetic nanoparticles (MNPs) by introducing vinyl groups using 2-isocyanatoethyl methacrylate. Through a process called inverse miniemulsion polymerization, the NCGs were created using poly(N-vinylcaprolactam) (PNVCL) and Fe3O4, employing a cross-linker that contained disulfide. By chemically attaching the Fe3O4 MNPs to the polymer matrix, the structural integrity of the NCGs in water-based environments was ensured. The PNVCL/Fe3O4 NCGs possessed the desirable superparamagnetic properties of Fe3O4 MNPs and demonstrated reversible sensitivity to temperature changes as well as significant responsiveness to redox conditions. The release of a model anticancer drug, 5-fluorouracil, from the PNVCL/Fe3O4 NCGs could be suitably controlled by adjusting the external temperature, the redox state of the surrounding medium, or a combination of both. Moreover, the prepared PNVCL/Fe3O4 NCGs exhibited minimal cytotoxicity, suggesting their potential use as magnetic-guided nanocarriers for precise drug discharge (Fig. 15).
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Fig. 15 (A) Synthesis process for the surface modification of Fe3O4 magnetic nanoparticles (MNPs) using IEM. (B) Schematic representation of the preparation, multi-responsiveness, as well as the loading and discharge actions of PNVCL/Fe3O4 nanocomposite nanogels (NCGs). Reproduced from ref. 107 with permission from Elsevier, copyright 2020. |
DNA nanogels have gained traction as miniature drug carriers in the field of biomedicine and pharmaceuticals due to their exceptional attributes such as biodegradability, biocompatibility, customizable sequence design, and tuning in size.86 The negatively charged nature of DNA facilitates a strong interaction with positively charged drugs like doxorubicin, a potent anticancer medication. This interaction enhances the drug-loading capacity and effectiveness of DNA nanogels.108–111 Recently, Yao et al.,112 devised magnetic nanogels featuring a DNA nanogel shell-core structure incorporating iron oxide (Fe2O4), enabling targeted and triggered release of doxorubicin (DOX) in response to a magnetic field. The magnetic DNA nanogels (M-DNA) with a shell-core structure were created by first generating the DNA shell through a process called rolling circle amplification (RCA), which is an enzymatic DNA polymerization (depicted in Fig. 16A). Subsequently, this DNA shell was coated onto the surface of Fe2O4 nanoparticles modified with amino groups (shown in Fig. 16B). The M-DNA nanogels would accumulate at the tumor site under the influence of an external magnetic field and release the drug in response to pH, temperature, and nuclease as triggers (illustrated in Fig. 16C). Scanning electron microscopy (SEM) imaging revealed the rough surface of the DNA polymer coating on Fe2O4 (shown in Fig. 16D). These meticulously prepared M-DNA nanogels exhibit responsiveness to multiple stimuli, releasing DOX in higher amounts with increasing temperature at pH 7.4 (Fig. 16E) and at lower pH levels (indicating acid sensitivity) (Fig. 16F). Moreover, the application of a magnetic field facilitates the penetration and accumulation of M-DNA nanogels (labeled in green with FTIC) into the tumor, demonstrating enhanced nanoparticle uptake and subsequent release of DOX (in red) into the cytoplasm and nucleus (in blue). This phenomenon becomes more prominent with increased incubation time of nanogels with U87MG cells (as evidenced in Fig. 16G).
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Fig. 16 illustrates the production process of M-DNA nanogels. (A) In the first step, a circular DNA template (circ-DNA) is created and subjected to rolling circle amplification (RCA). (B) Concurrently, amino-modified Fe2O4 nanoparticles are prepared. (C) These nanogels are designed to release DOX drug upon exposure to a magnetic field within tumor cells. (D) The SEM image portrays the structure of M-DNA nanogels. The release of DOX from M-DNA nanogels is showcased under various stimuli, including (E) different temperatures at pH 7.4 and (F) different pH levels at 37 °C. (G) Cellular uptake of FITC-stained M-DNA nanogels carrying DOX (depicted in blue) is observed in fluorescence images after incubation with U87MG cells for varying durations of 1, 3, 6, 12, and 14 hours. Reproduced from ref. 112 with permission from ACS, copyright 2022. |
Maghsoudinia et al.121 investigated the capabilities of theranostic nanoparticles made up of Gd-DOTA/doxorubicin-loaded perfluorohexane (PFH) nanodroplets for both drug delivery and imaging in B16F10 melanoma cancer cells. The internalization of sonicated Gd-DOTA/DOX@PFH nanodroplets by cancer cells was evaluated using inductively coupled plasma optical emission spectrometry (ICP-OES). The analysis indicated a 1.5-fold increase in uptake compared to non-sonicated nanodroplets after a 12 hour period. The biocompatibility of the synthesized nanodroplets was confirmed through in vitro and in vivo toxicity assays, which indicated the absence of organ toxicity. The application of ultrasound notably increased the release of doxorubicin from the nanodroplets, which exhibited strong ultrasound signal intensity and high r1 relaxivity (6.34 mM−1 S−1) for ultrasound echogenicity and T1-MRI relaxometry. The concentration of doxorubicin in the vital organs of mice was significantly lower for Gd-DOTA/DOX nanodroplets compared to free doxorubicin. In the Gd-NDs + US group, which was loaded with doxorubicin, the concentration of doxorubicin in the tumor region reached 14.8 μg g−1 after 150 minutes of sonication, representing a 2.3-fold increase compared to the non-sonicated group. These results emphasize the remarkable diagnostic capabilities (ultrasound/MRI) and therapeutic potential of the synthesized nanodroplets, positioning them as promising theranostic agents for targeted drug discharge in chemotherapy and cancer imaging.
Degirmenci et al.125 have developed a method for creating a modular nanogel system that responds to changes in oxidation and reduction and was created by self-assembling dextran-based polymers through host–guest interactions. Nanogel construction involved the intentional utilization of the self-assembly process in a water-based environment, utilizing adamantane (Ada) and β-cyclodextrin (β-CD). By capitalizing on the particular host–guest interactions between β-cyclodextrin (β-CD) and adamantane (Ada), the nanogels were formed through the natural assembly of these molecular constituents. This self-assembly process allowed the fabrication of stable and well-defined nanogels with the desired properties and functionalities. Importantly, they deployed a crosslinker containing disulfide and bis-adamantane, which allowed the nanogels to degrade in response to glutathione (GSH), a naturally occurring reducing agent. In their experiments, the researchers also investigated the potential of loading doxorubicin (DOX) into these nanogels and combining them with a cyclic peptide-based targeting component that contains adamantane, allowing for a non-covalent interaction. Various in vitro studies were performed, focusing on drug release, cytotoxicity, and cellular internalization. The results demonstrated that the nanogels exhibited an enhanced release of the drug in an acidic and glutathione (GSH)-rich environment. Although the empty nanogels demonstrated no toxicity towards cells, the nanogels containing the drug displayed cytotoxic effects against MDA-MB-231 breast cancer cells. The highest level of cytotoxicity was observed in cells with elevated GSH levels when targeted with the drug-loaded nanogels incorporating the targeting component (Fig. 17).
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Fig. 17 (A) A diagram demonstrating the production process of targeted nanogels containing drugs. (B) The procedure for synthesizing βCD-Dex copolymer using a synthetic route. (C) The range of sizes observed in empty and DOX-loaded βCD-nanogels. (D) The release of DOX in a laboratory setting under different conditions: at pH 5.4 with and without GSH (5 mM), and at pH 7.4 with and without GSH (5 mM). Reproduced from ref. 125 with permission from Elsevier, copyright 2022. |
Eskandani et al.126 developed a magnetic hydrogel termed FSRMH, which is a stimuli-responsive system conjugated with folate (FA). This hydrogel has the capability to respond to changes in pH and redox conditions. The researchers utilized tragacanth gum (TG) as the main material for constructing the hydrogel, with the objective of employing it in chemo/hyperthermia therapy of MCF7 cells; the anti-cancer drug doxorubicin hydrochloride (Dox) was loaded into the FSRMH. The hydrogel's porous structure, along with strong hydrogen bonding and ionic interactions between its functional groups and the drug, facilitated efficient drug loading (LE; 8.1 ± 0.25%) and encapsulation (EE; 81 ± 2.50%). In vitro studies on drug release demonstrated that the FSRMH/Dox system exhibited minimal drug release under physiological conditions but displayed pH- and redox-triggered drug release behavior in cancerous conditions characterized by lower pH and higher glutathione (GSH) concentrations (Fig. 18). The biocompatibility of FSRMH was confirmed through an MTT assay, which indicated its cytocompatibility. Hemocompatibility assessment revealed that FSRMH had a hemolysis rate of 2.4 ± 0.17% at 100 μg mL−1, thus affirming the safety of the drug delivery system (DDS). Moreover, the DDS demonstrated a protein adsorption capacity of 59.6 ± 1.70 mg g−1. The cytotoxicity of FSRMH/Dox was evaluated against MCF7 cells through an MTT assay, revealing a synergistic effect between chemotherapy and hyperthermia therapy, with a combination index (CI) of 0.609.
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Fig. 18 (A) The synthetic pathway for producing FSRMH. (B) SEM images of native TG FSRMH and TEM images of FSRMH and Fe3O4–NH2 nanoparticles. (C) The in vitro drug release profiles of the formulated FSRMH/Dox are evaluated under various conditions; temperature is set at 37 °C, except for FSRMH (pH 7.4; temperature = 45 °C). Reproduced from ref. 126 with permission from Elsevier, copyright 2023. |
The drug delivery system based on nanohydrogels has immense promise, primarily attributed to its key characteristics such as stability in encapsulation, intelligent discharge mechanisms, solubility in water, biodegradability, and biocompatibility.127 These properties have paved the way for the advancement of functionalized nanoparticles, serving as carriers for drugs and therapeutics; they allow for targeted and controlled release at precise locations within the body. In recent years, nanotechnology has emerged as a promising avenue for addressing diverse medical conditions, including diabetes, cancer, etc. This section discusses the numerous biomedical applications of nanogels.
NG systems | Active therapeutic agent | NG size (nm) | Stimuli-responsive | Ref. |
---|---|---|---|---|
Sugarcane bagasse cellulose | Doxorubicin (DOX) | 90 to 180 | Redox/pH/thermal-responsiveness | 11 |
Chitosan hydrochloride-carboxymethyl starch | Curcumin (Cu) | 378 | pH responsiveness | 130 |
Hyaluronic acid (HA) | Doxorubicin (DOX) | 22 to 433 | Redox responsiveness | 131 |
Carboxymethyl cellulose | Curcumin (Cu) | 120 to 333 | Enzyme responsiveness | 132 |
Hyaluronic acid-g-7-N,N-diethylamino-4-hydroxymethylcoumarin (HA-CM) | Doxorubicin (DOX) | 147 to 165 | Light responsiveness (irradiated by a UVITRON INTELLI-RAY-400 system operated at 315–400 nm) | 101 |
Protein/sodium alginate | Curcumin (Cu) | — | pH responsiveness | 13 |
Poly-N-isopropylacrylamide (PNIPAM) | Indocyanine green (ICG)/5-fluorouracil (5-Fu) | 808 | Thermo responsiveness | 133 |
Chitin | 5-Fluorouracil (5-Fu) | 120 to 140 | pH responsiveness | 134 |
2-(2 methoxyethoxy)ethyl methacrylate (MEO2MA) | Curcumin (Cu) | 30 and 5 | Thermo responsiveness | 135 |
P(DEAEMA-co-HEMA-g-PEGMA) | SiRNA | 71 to 111 | pH and redox responsiveness | 136 |
Chitosane-poly(N-isopropylacrylamide-co-acrylamide) | Paclitaxel | — | Thermo responsiveness | 137 |
O-Carboxymethyl-chitosan/thiolated chitosan | Doxorubicin (DOX) | 123 to 150 | pH and redox responsiveness | 138 |
Dex-SS | Doxorubicin (DOX) | 592 nm | pH and redox responsiveness | 34 |
Poly(N-isopropylacrylamide-maltodextrin) | Folic acid (FA)/resveratrol (RSV) | 101 to 159 | Thermo-/pH responsiveness | 91 |
Chitosan/agarose/graphene oxide | 5-Fluorouracil (5-Fu) | 197 | pH responsiveness | 139 |
Alginate co-gold nanoparticles | Cisplatin | 20 to 80 | Thermo responsiveness | 140 |
FCNGL | 5-Fluorouracil (5-Fu) | 100 to 250 | pH responsiveness | 141 |
4-Mercaptophenyle boronic acid/oxidized alginate | Doxorubicin (DOX) | 155 | pH and redox responsiveness | 142 |
PVP | 5-Fluorouracil (5-Fu) | 41 | pH responsiveness | 143 |
Bovine serum albumin-gum arabic aldehyde (BSA-GAA) | 5-Fluorouracil (5-Fu) | 231 | Thermo-/pH responsiveness | 144 |
An optimal smart insulin delivery system aims to promptly and accurately respond to fluctuations in blood sugar levels by delivering the appropriate dose of insulin. To fulfill these requirements, these systems must incorporate continuous glucose monitoring sensors and an insulin infusion pump. Consequently, these advanced systems are commonly referred to as glucose-responsive insulin delivery systems (Table 3).
NG systems | Therapeutics (drugs) | NG size (nm) | Stimuli-responsive | Ref. |
---|---|---|---|---|
Kappa-carrageenan/chitosan | Insulin | 18 to 22 | pH responsiveness | 43 |
Concanavalin A/starch | Insulin | 100 to 300 | Glucose responsiveness | 145 |
Oxidized starch | Exenatide | 100 to 200 | Glucose responsiveness | 146 |
Dextran-4-carboxyphenylboronic acid-NIPAM | Insulin | 160 | Glucose responsiveness | 96 |
300 | ||||
Dextran | Insulin | 293 to 340 | Glucose responsiveness | 147 |
P(NIPAM-co-Dex-co-DDOPBA) | Insulin | 160 to 300 | Glucose responsiveness | 96 |
Methoxyl poly(ethylene glycol) acrylate and N-acryloyl-3-aminophenylboronic acid | Insulin | 80 | Glucose responsiveness | 148 |
107 | ||||
Carboxymethyl-hexanoly-chitosan-lysozyme | Insulin | 40 | Enzyme responsiveness | 149 |
Hydroxypropyl methylcellulose methacrylic acid | Insulin | 210 | Thermo responsiveness | 150 |
170 | ||||
Chitosan-based luminescent/magnetic (CLM) | Insulin | 160 | Magnetic responsiveness | 151 |
NG systems | Therapeutics (drugs) | NG size (nm) | Stimuli-responsive | Ref. |
---|---|---|---|---|
Starch | Oncocalyxone A | 143 | Magnetic responsiveness | 67 |
HA-CysNG@AuNR | Doxorubicin (DOX) | 80 to 250 | Redox responsiveness | 131 |
Chitosan-g-PNVCL | Doxorubicin (DOX) | 180 to 250 | Thermo-/pH responsiveness | 152 |
Poly(N-vinylcaprolactam) (PNVCL)/Fe3O4 | 5-Fluorouracil (5-Fu) | 210 | Thermo-/redox responsiveness | 107 |
423 | ||||
(Au/Fe3O4@PEG-b-P(DMAEMA-co-HEMA)-g-PNIPAAm) | Methotrexate (MTX) | 50 | Thermo-/pH responsiveness | 153 |
92 | ||||
MNP@DAS | Doxorubicin (DOX) | 6–10 | pH responsiveness | 154 |
42–52 | ||||
Chitosan-g-N-isopropylacrylamide | Doxorubicin (DOX) | 30 to 50 | Thermo-/pH responsiveness | 155 |
Poly(N-isopropylacrylamide-co-acrylic acid) | Doxorubicin (DOX) | 60 | Thermo-/pH responsiveness | 156 |
380 | ||||
PLP | Doxorubicin (DOX) | 121 | Thermo responsiveness | 157 |
163 | ||||
Silk fibroin | Curcumin (CUR) | 130 to 210 | Magnetic/pH responsiveness | 158 |
O-carboxymethylchitosan (O-CMCS) | Maleimides | 4.2 | Magnetic responsiveness | 159 |
Alginate | Doxorubicin (DOX) | 120 to 320 | Magnet-, pH-, and reduction responsiveness | 160 |
NG systems | Therapeutics (drugs) | NG size (nm) | Stimuli-responsive | Ref. |
---|---|---|---|---|
CS/PNIPAM | Gold | 90–150 | Magnetic and light (green light irradiation at 530 nm) responsiveness | 25 |
PNIPAM/chitosan | Curcumin (CUR) | 167 | Thermo-/pH responsiveness | 162 |
CS-g-poly(N-vinylcaprolactam) | Doxorubicin (DOX) | 180 to 250 | pH/thermo responsiveness | 152 |
Hyaluronic acid/polypyrrole | Doxorubicin (DOX) | 77 | Light responsiveness (808 nm laser irradiation) | 163 |
CS-GCNCs | 5-Fluorouracil (5-Fu) | 960 | Light responsiveness (microwave irradiation) | 164 |
Au nanoclusters-Cu2+@sodium alginate/hyaluronic acid | HAuCl4·4H2O | 193 | Light responsiveness (light yellow) | 165 |
275 | ||||
NanoGold-core dendrimeric | Methotrexate (MTTX) | 108 | Light responsiveness (NIR laser-mediated at λ = 808 nm) | 166 |
118 | ||||
Chitosan | Gold | 140 | Light (irradiated alternately with a 655 nm laser light (20 J cm−2) for PDT)/thermo responsiveness | 167 |
DNA/TB | Cisplatin | 175 | Light responsiveness (irradiated by an LED light source (660 nm, 25 mW cm−2)) | 168 |
236 | ||||
Graphene/hyaluronic acid | Doxorubicin (DOX) | 120 | Light responsiveness (red color light emitted by graphene at 670 nm) | 169 |
HTCCm-CECm-(HP-β-CD-A) | Paclitaxel (PTX) | 305 | pH responsiveness | 170 |
308 | ||||
336 | ||||
ICG/PNIPAM | 5-Fluorouracil (5-Fu) | — | Thermo responsiveness | 133 |
CS-CD hydrid | Doxorubicin (DOX) | 65 nm | pH responsiveness | 171 |
(P(NIPAM-co-AAM)) | Doxorubicin (DOX) | — | Light (near-infrared (NIR) light at 700 to 900 nm)/thermo responsiveness | 172 |
NG systems | Therapeutics (drugs) | NG size (nm) | Stimuli-responsive | Ref. |
---|---|---|---|---|
Dendritic polyglycerol/polyethylenimine | siRNA | 79 ± 3 | pH responsiveness | 173 |
GS-AS1411/siRNA | siRNA | 162.3, 216.5, and 234.9 | Redox responsiveness | 174 |
P(DEAEMA-co-HEMA-g-PEGMA) | siRNA | 71.0 ± 0.7 to 524.6 ± 10.7 | pH and redox responsiveness | 136 |
75.1 ± 3.4 to 699.5 ± 20.0 | ||||
Cationic glycol | siRNA | 750 (∼400 to 500) | Thermo responsiveness | 175 |
PEI/PNIPAM | microRNA | 50–70 and 20–40 | Redox/pH responsiveness | 176 |
1. Exceptional biocompatibility renders nanogels a highly promising avenue for drug delivery systems.179
2. The significant biodegradability of nanogels is vital in preventing the buildup of nanogel material within bodily organs, consequently mitigating toxicity and adverse effects.180
3. In the bloodstream and internal aqueous environment, nanogels remain inert, causing no immunological reactions within the body.181
4. Nanogels can be delivered through diverse methods, such as oral, pulmonary, nasal, parenteral, intra-ocular, and topical routes of administration.182
5. Nanogels are appropriate for delivering both water-loving (hydrophilic) and water-repelling (hydrophobic) medications, as well as charged substances and various diagnostic agents. This characteristic is greatly affected by the kinds of functional groups found in the interconnected polymer chains, the degree of crosslinking, and the specific crosslinking agent integrated into the polymeric structure.183
6. Nanogels exhibit a strong attraction to aqueous solutions, enabling them to expand or contract by absorbing water when placed in certain environments. This quality stands as the most advantageous aspect of nanogels, positioning them as excellent options for absorbing and transporting proteins, peptides, large biomolecules, and voluminous medications.184
7. The drug encapsulation within nanogels surpasses that of other nanocarriers and drug delivery systems, demonstrating notably superiority. This heightened loading capacity can be attributed to the impact of functional groups within the polymer structure. These functionalities create hydrogen bonds or similar weak connections within the polymer network, thus enhancing the capacity to load drugs or proteins by engaging with molecules at the interface.182
8. Integrating drugs into nanogels is a straightforward and natural process, often not dependent on specific chemical reactions. This characteristic streamlines the preparation of nanogels, as the drug doesn't have to be present in the initial stages of manufacturing. Instead, it can be introduced into the nanogel network in subsequent stages, particularly when the nanogels expand with water or aqueous biological fluids.185
9. Nanogels are engineered to release drugs in a controlled and consistent manner at the intended site, ultimately amplifying the drug's therapeutic effectiveness while mitigating any undesirable reactions.186
Overall, nanogels exhibit significant potential as vehicles for transporting drugs, offering promising prospects for intelligent drug delivery. The formulation of nanogels as optimal drug carriers should encompass several key attributes, including a high capacity for drug loading, an extended duration of circulation within the body, the presence of specific ligands that can be recognized by target cells, and the ability to degrade in response to specific stimuli. Undoubtedly, drug carriers play a vital role in tumor treatments by minimizing drug toxicity, enhancing therapeutic effectiveness, and improving patient tolerance. While numerous research endeavors have evaluated the effectiveness and safety of nanogel formulations, there is a scarcity of data regarding their long-term buildup and breakdown patterns. Thus, safety remains a principal apprehension for the prospective clinical use of nanogels. It's important to emphasize that a nanogel suitable for clinical use ought to be created using biocompatible and biodegradable materials, ensuring a chemistry that is safe and devoid of toxicity. Innovative design strategies, coupled with thorough in vivo investigations of nanogels, are pivotal in advancing them towards the clinical implementation.
In conclusion, we believe that polysaccharides-based nanocarriers represent a category of transporters that are straightforward to manufacture, feature a broad range of functions, and are economically viable. These carriers have significant promise for advancing precision medicine by enhancing targeted drug delivery to augment the drug absorption and mitigate drug-related toxicity. Additionally, these deliberations may serve as a catalyst for future investigations into the potential secondary effects, including potential side effects of drug-loaded polysaccharide-based nanogels. This exploration is crucial for optimizing this drug delivery system for eventual clinical application, especially with a focus on achieving anti-inflammatory effects.
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