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DOI: 10.1039/D4BM00662C (Review Article) Biomater. Sci., 2024, 12, 4590-4606

Recent advances in near-infrared stimulated nanohybrid hydrogels for cancer photothermal therapy

Yongjun Hu† ab, Yi Zhou† d, Kaichun Li *a and Dong Zhou *c
aDepartment of Oncology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China. E-mail: likaichun@tongji.edu.cn
bGuangzhou University of Chinese Medicine, Guangzhou 510405, China
cEngineering Research Centre for Biomedical Materials of Ministry of Education, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China. E-mail: dongzhou@email.ncu.edu.cn
dHuanggang Central Hospital of Yangtze University, Huanggang, 438000, China

Received 14th May 2024 , Accepted 30th July 2024

First published on 1st August 2024

Abstract

Nanomedicine has emerged as a promising avenue for advancing cancer treatment, but the challenge of mitigating its in vivo side effects necessitates the development of innovative structures and materials. Recent investigation has unveiled nanogels as particularly compelling candidates, characterized by a porous, three-dimensional network architecture that exhibits exceptional drug loading capacity. Beyond this, nanogels boast a substantial specific surface area and can be tailored with specific chemical functionalities. Consequently, nanogels are frequently engineered as a multi-modal synergistic platform for combating cancer, wherein photothermal therapy stands out due to its capacity to penetrate deep tissues and achieve localized tumor eradication through the application of elevated temperatures. In this review, we delve into the synthesis of diverse varieties of photothermal nanogels capable of controlled drug release triggered by either chemical or physical stimuli. It also summarizes their potential for synergistic integration with photothermal therapy alongside other therapeutic modalities to realize effective tumor ablation. Moreover, we analyze the primary mechanisms underlying the contribution of photothermal nanogels to cancer treatment while underscoring their adeptness in regulating therapeutic temperatures for repairing bone defects resulting from tumor-associated trauma. Envisioned as an auspicious strategy in the realm of cancer therapy, photothermal nanogels hold promise for furnishing controlled drug delivery and precise thermal ablation capabilities.

1. Introduction

In clinical practice, the use of small molecule drugs is often constrained by considerable side effects, low drug utilization rates, and insufficient targeting of specific disease sites.1 The delivery of small molecule drugs to targeted sites with enhanced drug utilization has emerged as a pressing concern in disease treatment. In recent years, there has been notable advancement in nanotechnology, leading to the development of various nano-systems as carriers for drug delivery to diseased tissues.2 These include liposomes,3 inorganic nanoparticles,4 micelles,5 and dendrimers.6 However, these nano-systems frequently exhibit inadequate stability in the bloodstream and poor biosafety and are unable to selectively accumulate at specific sites while preventing drug leakage through blood vessels.7 Therefore, the design of suitable nanocarriers for the delivery of drugs to diseased tissues is of paramount importance.

Hydrogels, featuring a unique three-dimensional (3D) network structure capable of water absorption and swelling in aqueous environments,8 exhibit remarkable similarities to the natural extracellular matrix (ECM) present in the human body, thus demonstrating exceptional biocompatibility and degradation characteristics.9 The ability to engineer hydrogels into nanoscale forms known as nanogels through physical or chemical crosslinking techniques imparts further advantages.10 Compared to their inorganic nanoparticle counterparts, nanogels offer a pliable structure, enhanced biocompatibility, and improved dispersibility, thereby reducing the risk of macrophage uptake and prolonging their circulation within the body.11 Consequently, nanogels emerge as promising carriers for the targeted delivery of small molecule drugs, biomolecules, and nucleic acids within specific microenvironments.12 Moreover, the design of nanogels as stimuli-responsive systems tailored for the distinct conditions found within tumor tissues represents a significant advancement in the field.13 These stimuli-responsive properties can be triggered by internal factors such as pH, redox potential, and enzyme activity, as well as by external stimuli like light, sound, and magnetic fields.14 Notably, near-infrared stimulation stands out due to its non-invasive nature, low toxicity, and precise temporal-spatial resolution, making it an appealing approach for the treatment of a wide range of diseases.

Photothermal therapy, as an innovative approach to cancer treatment, holds promise for delivering effective results with minimal side effects.15 By harnessing the power of a near-infrared laser (NIR) to convert light into heat, this technology targets and eradicates cancer cells by raising the temperature within the tumor.16 While the mechanism involves disrupting tumor cell membranes and inducing protein degeneration, it is crucial to address the potential risk of thermal damage to the surrounding healthy tissues.17 To optimize the efficacy of cancer cell destruction, the synergistic combination of photothermal agents (PTAs) with nanogels for controlled drug delivery has garnered significant attention.18 By exploring the utilization of nanogels in conjunction with PTAs, researchers aim to enhance the precision of drug release in response to local thermal cues and the unique conditions of the tumor microenvironment. This strategic approach facilitates the modulation of the tumor inhibitory environment and enables targeted tumor cell elimination. This review delves into the current advancements in utilizing nanogels coupled with PTAs for cancer therapy, as depicted in Fig. 1. By leveraging the capabilities of various photothermal reagents in conjunction with nanogels as carriers, a comprehensive discussion is provided on the opportunities and challenges associated with employing these innovative therapeutic agents for combating cancer. Through a concerted effort to capitalize on this cutting-edge strategy, the landscape of cancer treatment is poised for significant advancements.


image file: d4bm00662c-f1.tif
Fig. 1 Schematic diagram of photothermal therapy and chemotherapy for cancer treatment. Photothermal nanogels exhibit good colloidal stability and high drug loading capacity, and can selectively accumulate at the tumor site through active or passive targeting, and then synergise with photothermal therapy to kill the tumor.

2. Preparation of photothermal nanogels

2.1. Physical interaction

Electrostatic interaction and hydrophobic interaction are fundamental physical mechanisms for the creation of photothermal nanogels. In the case of electrostatic interaction, two materials with opposite charges are intricately combined in a solution, allowing for the adjustment of nanogel size and surface characteristics based on nonstoichiometric charge and polymer molecular weight.21 An illustrative instance is the generation of chitosan nanogels prepared from the polyvalent anionic polymer tripolyphosphate (TPP) and the cationic chitosan (CTS) (Fig. 2a). The colloidal stability of these nanogels is shaped by the TPP/CTS ratio and the solution's pH.19 Conversely, hydrophobic interaction facilitates the assembly of amphiphilic substances in aqueous solutions to yield nanogels.22 This reversible self-assembly process depends on polymer functional groups with distinct properties. For example, the negatively charged mono-carboxyl corrole (MCC) can interact with positively charged chitosan through π–π stacking and electrostatic interaction (Fig. 2b), resulting in the formation of photothermal nanogels.20 These physical interactions preserve the photothermal properties of the materials while incorporating chitosan's beneficial attributes into the nanogel, including enhanced solubility. Consequently, these nanogels are well-suited for various biomedical applications.
image file: d4bm00662c-f2.tif
Fig. 2 (a) Construction of a nanogel formed with chitosan through ion complexation and the schematic diagram of the anticancer mechanism. Adapted with permission from ref. 19. Copyright 2020 Royal Society of Chemistry. (b) Schematic diagram of a nanogel formed with chitosan through hydrophobic interaction. Adapted with permission from ref. 20. Copyright 2023 John Wiley and Sons Ltd.

2.2. Chemical crosslinking

Physical interactions are a key factor in the formation of nanogels, and their structural integrity is easily affected by variables like ion concentration, pH, and temperature.24 Hence, the inclusion of chemical crosslinking agents is imperative for establishing a robust three-dimensional (3D) architecture for nanogels.25 For instance, oxidized sodium alginate can serve as a chemical crosslinking agent that reacts with gelatin through Schiff base formation (Fig. 3), resulting in the formation of a multifunctional nanogel.23 The creation of a hybrid photothermal nanogel, incorporating gold nanoparticles in situ, showcases exceptional colloidal stability in body fluids. This nanogel can achieve drug release triggered by stimuli from the tumor microenvironment and synergize with photothermal therapy to eradicate tumor cells effectively.26 Furthermore, crosslinking agents can be employed to produce size- and structure-controllable nanogels using methods such as emulsion polymerization27 and microemulsion techniques.28 The combination of multiple approaches aids in the preparation of multifunctional nanogels, further enhancing their versatility and application potential.
image file: d4bm00662c-f3.tif
Fig. 3 Schematic diagram of the mechanism of preparing multi-responsive nanogels using the chemical crosslinking method. Adapted with permission from ref. 23. Copyright 2013 American Chemical Society.

3. Inorganic-based nanogels with photothermal effects

3.1. Metal-based nanogels

Metal nanoparticles are known for their distinctive characteristics in photothermal response, showcasing robust local surface plasmon resonance (LSPR) effects.29 The manipulation of their size and shape facilitates the extension of the plasmon resonance peak to the near-infrared spectrum, thus facilitating the transformation of light energy into thermal energy.30 Notably, materials such as gold (Au), silver (Ag), and iron oxide nanoparticles (Fe3O4) demonstrate significant photothermal conversion efficiency, albeit accompanied by potential cytotoxicity.31 The coating of these nanoparticles with nanogels serves to diminish toxicity levels while enhancing overall performance. Within the realm of metal-based nanogels, there exists a classification into two categories: those that are augmented by inorganic nanoparticles and hybrid nanogels.32
3.1.1. Nanogels based on Au. Gold nanomaterials have emerged as promising candidates for various biomedical applications due to their unique properties, including good biocompatibility, low cytotoxicity, and remarkable plasmon resonance capabilities for light-to-heat conversion.33 One prevalent approach for the fabrication of gold nanogels involves the in situ reduction of gold nanoparticles within nanogel matrices.34 A notable example entails the construction of a polyethylene glycol (PEG)-based gel network chain by covalently linking ZnO quantum dots to a thermally responsive polymer nanogel, forming a three-dimensional scaffold.35 Subsequently, gold can be selectively grown within these nanogels, yielding hybrid structures that function as high-resolution biosensors for temperature sensing, fluorescent agents for tumor cell imaging, and intelligent drug carriers for synergistic chemo-thermotherapy. In comparison with PEGylated nanogels incorporating Au nanoparticles, pH-responsive PEGylated nanogels containing SiO2/Au hybrid nanoparticles demonstrate enhanced imaging and anti-tumor capabilities.36 These nanogels exhibit surface plasmon bands at longer wavelengths, thereby augmenting their imaging capabilities. Furthermore, gold nanogels possess intrinsic tumor-targeting abilities. In the synthesis of composite nanogels comprising gold organic polymers, near-infrared (NIR) luminescent gold clusters have been successfully developed through the in situ reduction of gold salts within hollow and shell porous polyacrylic acid (PAA) nanogels. These Au-PAA nanogels showcase excellent NIR photoluminescence properties and hold promise for targeted optical imaging in biological systems. Additionally, they boast strong photoluminescence, favorable biocompatibility, high drug loading capacity, and outstanding water dispersibility, rendering them invaluable for bioimaging and therapeutic applications.37

Gold nanomaterials, including gold nanocages and gold nanorods, have proven to be exceptional photothermal reagents beyond gold nanoparticles.38 For example, a thermosensitive and pH-responsive poly(N-isopropylacrylamide-co-acrylic) nanogel can be synthesized and used as a drug carrier for chemotherapeutic agents. By electrostatically adsorbing positively charged chemotherapeutic drugs like doxorubicin onto the negatively charged nanogel in its swollen state, enhanced drug delivery is achieved. To enhance tumor targeting capability, fluorescent bovine serum albumin-encapsulated gold nanoclusters are attached to the surface of the nanogel, along with the tumor-targeting peptide iRGD. This precise system facilitates targeted delivery of chemotherapeutic drugs to tumors and endothelial cells, thereby enhancing anti-tumor efficacy while ensuring controlled drug release.39 Another noteworthy application involves the combination of PEGylated nanogels with gold nanoparticles, significantly amplifying cell radiosensitivity by inducing apoptosis and impeding DNA double-strand break repair through ER stress mediation.40 Furthermore, the utilization of hybrid nanorods featuring a core–shell structure—comprising a single gold nanorod encapsulated in a poly(N-isopropylacrylamide) nanogel—showcases a remote, reversible pulse phase transition upon near-infrared laser irradiation. These advancements exhibit promising in vivo effects and implications for future biomedical applications.41

The functionalization of a gold nanomaterial with phthalocyanine green, up-converting nanoparticle-loaded photosensitizers, and a chlorine-loaded chitosan-based nanogel in a core–shell structure has opened up new avenues for synergistic cancer therapy. This innovative approach combines the strengths of photothermal therapy and chemotherapy to effectively eradicate tumor cells.42 Furthermore, by introducing targeted molecular modifications, such as incorporating hyaluronic acid onto the surface of gold nanorods, subsequently loading cisplatin drugs, and coating cancer cell membranes, the tumor-targeting capacity of gold nanogels can be significantly enhanced. This sophisticated strategy ensures the colloidal stability of drugs in the circulatory system and facilitates precise delivery to cancer cells, thereby unleashing a potent synergistic impact of photothermal therapy and chemotherapy in combating tumor growth (Fig. 4).43


image file: d4bm00662c-f4.tif
Fig. 4 (a) Real-time thermal imaging of mice. (b) The corresponding temperature change of the tumor. (c) Drug distribution in tumor-bearing mice at different time points. (d) The tissue distribution of mice at 32 and 48 h. Adapted with permission from ref. 43. Copyright 2020 Wiley-VCH Verlag.
3.1.2. Nanogels based on Ag. Silver ions have long been recognized for their potent antibacterial properties, yet their use within the human body poses concerns regarding cytotoxicity. However, recent advancements in silver-based surface modifications and hybrid materials have paved the way for enhancing efficacy while mitigating adverse effects, thus expanding their scope in biomedical applications. For example, a composite nanogel based on a silver-based organic polymer incorporates polymer poly(N-isopropylacrylamide) and doxorubicin (DOX) on its surface, and these nanogels exhibit pH-responsive properties, thereby offering a multifunctional approach to combating infections (Fig. 5).44 This innovation not only harnesses the antimicrobial prowess of silver ions but also capitalizes on the therapeutic capabilities of drug delivery systems, promising targeted and controlled release within the body. Furthermore, the emergence of silver-releasing biomaterials, such as ultra-short peptides that self-assemble into hydrogels, represents a groundbreaking strategy in wound healing applications. These peptides facilitate the in situ synthesis of silver nanoparticles (Ag NPs) through UV irradiation, eliminating the need for additional chemical reduction steps. As a result, these biomaterials exhibit immense potential in treating a myriad of wounds, including surgical incisions, diabetic ulcers, and severe burns. By simultaneously reducing inflammation, preventing infections, and offering ease of application, they address critical challenges in wound care management.45
image file: d4bm00662c-f5.tif
Fig. 5 Preparation and antitumor mechanism of silver nanogels. Adapted with permission from ref. 44. Copyright 2020 Springer US.

Similarly, advancements in nanotechnology have led to the development of innovative composite nanogels that leverage the unique properties of gold and silver organic polymers. One notable example is Ag/Au nanorods coated with DNA crosslinked polymer shells, which function as a near-infrared photo-responsive drug delivery platform. These nanogels offer the flexibility of easy functionalization with targeting moieties, enhancing their specificity in recognizing and interacting with tumor cells.46 In the realm of intracellular drug delivery, water-dispersible hybrid nanogels have emerged as a promising solution for transporting hydrophobic compounds such as curcumin. These nanogels boast a core–shell architecture, with Ag/Au bimetallic nanoparticles (NPs) enveloped by a hydrophilic poly(ethylene glycol) (PEG) gel layer and a hydrophobic polystyrene (PS) gel layer serving as the inner shell.47 Furthermore, a novel hybrid nanogel combines a thermally coated Ag/Au bimetallic NP core with a non-linear PEG-based hydrogel shell, complemented by a semi-interpenetrating ligand that targets the hyaluronic acid chain. This unique nanogel design not only enhances therapeutic efficacy but also enables the integration of local specific chemotherapy with external near-infrared (NIR) photothermal treatment. The diverse structures and compositions of these nanogels underscore the immense potential of silver-based hybrids and surface modifications in advancing biomedical applications.48

3.1.3. Fe3O4-based nanogels. Magnetic nanogels represent a groundbreaking advancement in the treatment of tumors, offering a range of unique functionalities that have the potential to revolutionize this field. With capabilities for magnetothermal and magnetic targeting, these innovative nanogels have opened up new frontiers in precision medicine. By harnessing the power of an external magnetic field, magnetic nanogels loaded with drugs can accurately pinpoint and target the lesion, exhibiting exceptional precision and efficacy. Furthermore, when subjected to an alternating magnetic field, they are able to generate heat, further enhancing their therapeutic potential. Additionally, the nanogels can also respond to near-infrared light, triggering the generation of heat, enabling an integrated approach to the diagnosis and treatment of tumors. This multifaceted functionality positions magnetic nanogels as a promising avenue for the advancement of personalized cancer treatment.

Magnetic nanomaterials play a crucial role in the field of materials science, encompassing two main categories: magnetic polymer materials and inorganic magnetic materials. These categories are distinguished by their material compositions,49 with inorganic magnetic materials primarily including substances such as Fe3O4,50 Fe2O3,51 and NiFe2O4.52 Different components are introduced into magnetic nanogels to bestow various functional properties, making them essential in a wide range of applications. Superparamagnetic iron oxides (SPIONs) have garnered widespread attention due to their exceptional superparamagnetism, high magnetic field saturation strength, and robust magnetic responsiveness. Moreover, SPIONs serve as contrast agents in the diagnosis of diverse diseased organs within the human body, such as breast tumors and liver cancer.53,54 Additionally, aggregated Fe3O4 nanoparticles have been shown to significantly increase near-infrared (NIR) absorption, thereby enhancing their capacity to eliminate cancer cells.55 Another significant development is the co-loading of magnetic ferric oxide and anti-cancer drugs in nanogels, which acts as a contrast agent for tumor growth. This co-loading mechanism subsequently impacts tumor development by influencing macrophage reactive oxygen species (ROS) production. Under near-infrared light stimulation, the presence of magnetic nanoparticles enriched around the tumor can synergistically enhance the anti-tumor activity of anti-cancer drugs (Fig. 6).56 Overall, the diverse functional properties and applications of magnetic nanomaterials, particularly in the context of healthcare and disease diagnosis, illustrate their significant potential and importance in modern materials science and nanotechnology.


image file: d4bm00662c-f6.tif
Fig. 6 Magnetic nanogels combined with photothermal therapy and chemotherapy for tumor treatment. Adapted with permission from ref. 56. Copyright 2019 Elsevier BV.

3.2. Metal sulphide-based nanogels

Metal sulfides, which are remarkable materials boasting high extinction coefficients, excellent thermal stability, and easy functionalization, hold immense potential in various biomedical applications. Their exceptional photothermal properties, particularly in the near-infrared region (1000–1700 nm), allow them to penetrate deep tissues, offering exceptional imaging capabilities and therapeutic potential for diagnosing and treating various diseases. Combining metal sulfides with nanogels enhances their circulation time and activity in vivo. For instance, the surface modification of copper sulfide with hydrophilic PEG and targeting folic acid facilitates the construction of a degradable nanogel with targeting capability. This nanogel, responsive to near-infrared light stimulation, demonstrates a synergistic anti-tumor effect by releasing drugs selectively.57 In the realm of tumor immunity, metal sulfides, owing to their controllable size and morphology, are proving invaluable. Copper sulfide nanoparticles, for instance, when loaded into the shell of a nanogel, exhibit high photothermal conversion efficiency and multiple stimulus response abilities. This innovative approach has shown effectiveness in inhibiting tumor recurrence (Fig. 7).58 The versatility and efficacy of metal sulfide-based nanostructures highlight their potential as promising tools in biomedical research and clinical applications, offering new avenues for disease diagnosis, treatment, and prevention.
image file: d4bm00662c-f7.tif
Fig. 7 Preparation and precision treatment of a modularly assembled copper sulfide nanoplatform based on cationic NGs. Adapted with permission from ref. 58. Copyright 2021 Wiley-VCH Verlag.

3.3. Graphene-based nanogels

Graphene, characterized by its two-dimensional structure and polycyclic aromatic hydrocarbons on the surface, exhibits outstanding photothermal properties. Its exceptional ability to absorb and transform light energy into heat renders it highly valuable across a range of applications. Both nanoscale graphene and graphene oxide display photoluminescence properties, making them effective agents in photothermal applications.59 Recent studies have demonstrated that graphene surpasses carbon nanotubes (CNTs) in terms of photothermal sensitivity, particularly in the context of cancer treatment through photothermal therapy. Notably, the efficient photothermal conversion of graphene leads to the rapid gelation of graphene oxide/pluronic hydrogel under near-infrared laser exposure.60 Furthermore, the expansive aromatic surface area of graphene oxide enables high drug loading capacity and exceptional photothermal performance upon near-infrared light activation. These advancements in graphene and graphene oxide technology herald a new era of diverse and promising applications in the realms of phototherapy and drug delivery.61

Graphene oxide (GO), a derivative of graphene created through oxidation, showcases a unique single-layered lamellar structure distinct in polarity from graphene. Embedded with various functional groups like carboxyl and hydroxyl, it readily reacts chemically or physically to form derivatives or encapsulate drugs.63 Despite its inorganic nature, GO's colloidal stability remains limited by its notable electronegativity and structural traits, hindering drug release.64–66 A compelling solution involves photopolymerization of GO and PEG in the presence of a photoinitiator, resulting in a superior hydrogel with enhanced properties.67 Notably, PEG plays a crucial role in augmenting GO's hydrophilicity, facilitating efficient drug loading such as SN38 and DOX.68,69 Moreover, a dual-emulsion strategy melded graphene oxide nanoparticles with alginate, creating a versatile nano-hydrogel that elevates GO's functionality manifold.70 By grafting PEG onto nanographene oxide (NGO), Octreotide (OCT) can be efficiently coupled with targeted biological molecules, showcasing exceptional loading efficacy and precise delivery of the anticancer drug doxorubicin (DOX). This innovative approach brings about effective tumor cell ablation upon near-infrared stimulation (Fig. 8).62


image file: d4bm00662c-f8.tif
Fig. 8 (a) UV-vis spectra of different samples. (b) FT-IR spectra of different samples. (c) 1H NMR spectra of different samples. (d) Circular dichroism spectra of different samples. (e) The cell viability of MCF-7 cells after incubation for 24 h, and (f) with or without NIR laser irradiation for 24 h. Adapted with permission from ref. 62. Copyright 2021 Wiley-VCH Verlag.

4. Organic-based nanogels with photothermal effects

Organic photothermal nanogels have emerged as a promising solution for a diverse array of biological applications.71 These materials, comprising organic photothermal reagents and nanogels, are highly regarded for their exceptional biocompatibility and degradation properties.72 The molecular structure of small organic molecules within the nanogels features extensive Π-conjugated backbones, leading to heightened absorption coefficients and superior photothermal conversion efficiency, thereby enabling remarkable light-to-heat conversion capabilities.18 Notable examples of these small organic molecules encompass polydopamine (PDA), polypyrrole (PPy), polyaniline (PANI), and poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS).73 A pivotal strength of organic photothermal reagents is their profusion of functional groups, facilitating facile creation of functional nanogels. This versatility in incorporating various drug molecules into nanogels opens up exciting prospects for synergistic therapies and targeted drug delivery, particularly in combating tumors.74 Ultimately, the amalgamation of organic photothermal reagents and nanogels in organic photothermal nanogels epitomizes a significant breakthrough in biological applications and presents a promising trajectory for the future.

4.1. PDA-based photothermal nanogels

Dopamine, as a typical catechol derivative, has the unique ability to self-polymerize into polydopamine under alkaline conditions, forming a structure with a quinone composition.75 This characteristic structure of polydopamine contains a large conjugated system, allowing for efficient electron flow and excellent photothermal conversion efficiency. Leveraging this property, various nanogels with interpenetrating and semi-interpenetrating network structures have been designed, utilizing polydopamine as a key component.76 The network structure of these nanogels not only contributes to better colloidal stability but also enhances their drug loading capacity. For instance, the formulation of hybrid nanogels based on a multifunctional metal–organic skeleton (MOF) by incorporating dopamine monomers within the MnCo skeleton has shown promising results. Comparing these hybrid nanoparticles to pure polydopamine or MnCo nanoparticles synthesized using similar methods, it is evident that hybrid nanoparticles exhibit enhanced photothermal conversion efficiency, thus demonstrating significant potential for in vivo photothermal therapy (PTT). This breakthrough paves the way for novel advancements in the field of nanogels and their applications in medical treatment.77

Due to the unique catechol and polyhydroxyl structure of polydopamine (PDA), it possesses outstanding adhesive properties to various surfaces. This distinctive characteristic makes PDA a valuable mediator between nanogels and targeting agents, thereby enhancing the targeted uptake and penetration of nanogels. An illustrative example of this concept can be seen in the work of Zhang et al., who engineered a nucleic acid nanogel enveloped by PDA. In this innovative model, PDA functions as a low-temperature photothermal agent for delivering siRNA that targets heat shock proteins, thereby facilitating tumor ablation. Furthermore, PDA serves a crucial role as an outer protective layer, safeguarding RNA against enzymatic degradation during transport. Additionally, the synergistic effect of combining PDA with chemotherapy drugs significantly boosts the tumor-killing potency of the nanogel.78 For instance, utilizing polydopamine as a photothermal agent, when coupled with anti-tumor drugs loaded into a poly(n-isopropylacrylamide-co-sulfobetaine methacrylate) (PNS) nanogel, sustained release of the therapeutic agent can be maintained upon exposure to near-infrared light, while possessing a robust photothermal killing ability towards tumor cells (Fig. 9).79


image file: d4bm00662c-f9.tif
Fig. 9 (a) The cell viability and (b) fluorescence images of HepG2 cells after different treatments. (c) The cell viability of the L929 cells after different treatments. Adapted with permission from ref. 79. Copyright 2020 Royal Society of Chemistry.

4.2. PPY-based nanogels

In 1979, Diaz et al. of IBM Corporation in the United States achieved a significant milestone by successfully synthesizing a conductive polypyrrole (PPy) film of remarkable conductivity. This accomplishment was realized through the process of electrochemical oxidation and polymerization on a platinum electrode in an acetonitrile electrolyte.80 Subsequent research revealed that PPy not only possesses exceptional conductivity qualities but also exhibits efficient light-to-heat conversion abilities upon exposure to near-infrared light, attributed to its extensive π bond structure. The advent of uniform PPy@BSA nanoparticles, created through a straightforward in situ chemical oxidative polymerization method, has introduced new avenues for exploration. The amalgamation of photodynamic therapy (PDT) and photothermal therapy (PTT) treatments has unveiled a synergistic effect, leading to heightened tumor uptake rates post-intravenous injection.81 Furthermore, the realm of surprise thermal/photoacoustic (PA) imaging and radiotherapy (RT)-enhanced tumor photothermal therapy (PTT) has seen groundbreaking developments through the fabrication of gamma-polyglutamic acid (γ PGA) magnetic nanogels (NGs) loaded with polypyrrole (CCPA@PPy NGs), showcasing superior photothermal stability. Of particular note is the successful utilization of polypyrrole as a potent photothermal agent, combined with a PNA–CS carrier for DOX, showcasing promising outcomes in cancer treatment.82 Similarly, the innovative UCNP@PPY@DNADOX nano-platform has proven effective in releasing DOX via DNA-assisted mechanisms, while also achieving reduced drug residues and enhanced drug detoxification capabilities.83 These advancements in harnessing the potential of polypyrrole underscore its versatile applications, spanning from cutting-edge cancer treatments to pioneering drug delivery systems.84

4.3. PANI-based nanogels

The discovery made by American scientists has challenged the conventional belief regarding the function of polymers as mere insulators. Through doping, polyacetylene has exhibited a remarkable metal-like conductivity, sparking a significant shift in focus towards research on conjugated polymers. This shift has led to the identification of numerous polymers with electrical conductivity capabilities, with polyaniline standing out as a notable example. Polyaniline (PANI), with its alternating benzene ring and anthracene ring structure, showcases exceptional photothermal properties attributed to its extensive conjugated π bond structures. A groundbreaking advancement emerged with the introduction of a novel polymer that excels in absorbing near-infrared light. This extraordinary material comprises a biocompatible, thermally responsive nanogel semi-interpenetrated with polyaniline, resulting in exceptional near-infrared light absorption capabilities. Consequently, this polymer nanocomposite has demonstrated the ability to induce localized hyperthermia upon exposure to near-infrared light, presenting a promising avenue for both in vitro and in vivo photothermal cancer treatment.85 Furthermore, research involving the PANI nanomaterial cell has highlighted its potential as a viable photothermal therapy (PTT) drug for tumor ablation. Notably, the minimal toxicity exhibited by PANI towards biological systems underscores their potential as a robust platform for developing the next generation of PTT drugs in vivo.86 The synthesis process involving γ PGA/Cys@PANI NGs has introduced an innovative technique ensuring water-dispersible colloidal stability. This advancement has proven invaluable for photoacoustic (PA) imaging of in vitro tumor cells, serving as a crucial guide for PTT and in vivo xenograft tumor models.87 Furthermore, the PNIPAM-dPG/polyaniline near-infrared-sensitive organic nanoparticles show tremendous potential for further research endeavors. Their simple and cost-efficient synthesis process, coupled with minimal cytotoxicity and exceptional therapeutic effects, makes them prime candidates for advancing exploration in this field (Fig. 10).85 These groundbreaking advancements underscore the immense potential of conjugated polymers, particularly polyaniline-based nanoparticles, in revolutionizing the landscape of cancer treatment through photothermal therapy.
image file: d4bm00662c-f10.tif
Fig. 10 Schematic diagram of thermo-sensitive photothermal nanogels triggered by PTT. Adapted with permission from ref. 85. Copyright 2016 Royal Society of Chemistry.

5. Composite nanogels

Combining different photothermal materials to form multifunctional composite nanogels has shown promising potential in the treatment of cancer. While single inorganic or organic photothermal materials may not achieve the desired therapeutic effect, the use of composite nanogels can enhance the efficacy of photothermal therapy. For instance, the combination of GO and PDA can efficiently absorb ICG fluorescent small molecules, leading to enhanced photothermal therapy effects and improved PA contrast compared to the original gel.88 Therefore, the development of multifunctional composite nanogels by combining organic and inorganic photothermal reagents represents a promising strategy for cancer treatment.

Combination therapy utilizing the thermosensitive effect of polymers and the photothermal effect represents a novel approach to nanogel-based anticancer drug treatment. In recent years, the thermosensitive polymer poly(N-isopropylacrylamide) (PNIPAM) has garnered increasing attention from researchers.89 PNIPAM is frequently employed to modify the surface of various nanoparticles. Upon temperature elevation, PNIPAM undergoes shrinking, facilitating drug release. PNIPAM demonstrates exceptional characteristics when utilized in conjunction with PNIPAM polymerization as the shell, and a core–shell structure composed of nano-silver as the core, exhibiting remarkable pH responsiveness and near-infrared light exothermic capability.90,91

The integration of ligand peptides at the core, pNIPAAm-co-pAAm, enhances its LSCT re-encapsulation with Au and ligand peptides, forming a novel nanogel known for its exceptional temperature responsiveness and efficacy in targeting tumor cells.92 Notably, curcumin has garnered significant attention as an anti-inflammatory and antioxidant agent within nanogel systems. PNIPAM nanogels, renowned for their reversible thermal response properties, prove highly proficient in temperature-sensing capabilities for controlled release applications. The amalgamation of PNIPAM with organic polymers, serving as photothermal materials, is a prevalent approach in nanogel fabrication (Fig. 11).93,94 When DOX-loaded nanoparticles are subjected to near-infrared irradiation, superior performance is observed with back-illuminated CS/PNIPAAm@CNT-loaded DOX. This enhanced performance leads to heightened cytotoxicity, albeit with a relatively increased resistance exhibited by cancer cells.95 Moreover, exposure to near-infrared light prompts another nanogel to release polyethersulfone, thereby mitigating cellular heat resistance upon polyether wind loading. This enables enhanced tissue penetration at lower temperatures, culminating in a highly efficacious therapeutic outcome.96


image file: d4bm00662c-f11.tif
Fig. 11 (a) Schematic diagram of the preparation of stimuli-sensitive photothermal nanogels. (b) Schematic diagram of multifunctional nanogel synergistic phototherapy for cancer. Adapted with permission from ref. 97. Copyright 2022 American Chemical Society.

6. Potential mechanisms for photothermal cancer therapy

Photothermal therapy (PTT) is a cutting-edge approach that leverages the power of light to induce localized heat, which can result in a range of outcomes such as cell sensitization or ablation, as well as enhanced drug penetration and release.85 This innovative technology represents a promising frontier in the realm of tumor treatment, offering the potential to address tumors with minimal associated toxicities. Studies have highlighted the varying temperature sensitivities and tolerances of different cells and tissues, with tumor cells often exhibiting heightened temperature tolerance.98 Specifically within tumor tissues, temperatures exceeding 41 °C have been shown to trigger temporary deactivation of protein-denatured cells, while temperatures surpassing 50 °C have the capacity to directly eradicate tumor cells, albeit possibly leading to collateral damage in adjacent tissues.99

In addressing the challenges outlined, scientists have undertaken investigations into the incorporation of photothermal materials within a three-dimensional network structure utilizing nanogels. Through the focal accumulation of these photothermal nanogels at the tumor site and the utilization of near-infrared laser irradiation, localized elevated temperatures are harnessed to efficiently combat cancerous cells. This innovative therapeutic approach showcases remarkable attributes such as exceptional photostability,100 high photothermal conversion efficiency,101 ease of implementation, non-invasiveness, safety, and precise control,102,103 underscoring its significant advantages.

7. Photothermal facilitation of bone regeneration after tumor removal

The treatment of cancer has long been a challenging task for medical professionals worldwide. However, the advent of nanotechnology has brought a new ray of hope in the fight against this debilitating disease.104 Nanocarriers, specialized vehicles designed to transport drugs directly to affected areas and release them in response to specific stimuli, have transformed the landscape of cancer treatment.105 One of the key advantages of nanocarriers is their ability to target lesions directly, thereby significantly reducing the side effects associated with traditional drug delivery methods. This targeted approach not only minimizes harm to healthy tissues but also helps overcome drug resistance, a common hurdle in cancer treatment. Moreover, nanocarriers offer a solution to the problem of poor drug solubility, which often limits the effectiveness of certain medications.106 By encapsulating drugs, nanocarriers enhance their bioavailability and ensure more efficient delivery to the intended site of action. Additionally, these advanced delivery systems help bypass issues related to drug metabolism when administered orally, further optimizing treatment outcomes. Furthermore, the use of nanocarriers enables a higher accumulation of drugs in specific target areas, thereby increasing the efficacy of cancer treatment. By minimizing damage to normal cells and reducing drug resistance, nanocarriers represent a promising approach in the quest for more effective and personalized cancer therapies.107

The application of photothermal nanogels, a subset of nanocarriers, in cancer treatment represents a promising advancement in the field. These nanogels exhibit the ability to respond to photothermal stimulation, allowing for the selective release of drugs upon near-infrared light exposure, thereby enabling precise targeting of cancer cells.108 This innovative methodology offers a glimpse into a future of more effective and targeted cancer therapies, providing newfound hope for patients grappling with this complex disease.85 The integration of nanotechnology into cancer treatment has showcased remarkable potential in addressing the limitations associated with traditional drug delivery mechanisms. As research endeavors delve deeper into the intricacies of these technologies and seek to further optimize their functionality, the evolution of nanocarrier-based drug delivery systems is projected to occupy a prominent position in the ongoing battle against cancer.

The use of gold and silver nanogels as inorganic nanocarriers has become widely recognized and essential in various applications, ranging from their antibacterial effects to cancer treatment.109 Particularly, the combination of gold and silver nanoparticles has shown remarkable antibacterial effects and potent photothermal effects, enabling effective targeting and elimination of cancer cells.110 Moreover, the development of PEG-modified Ag–Au@PEG-HA hybrid nanogels has led to the creation of intense visible fluorescence, which can respond to local environmental temperature changes and enhance tumor cell imaging. When loaded with anticancer drugs, these modified nanogels demonstrate a robust thermal triggering mechanism.48 In the realm of organic nanoparticles, polymer molecules like PNIPAM have exhibited remarkable responsiveness to photothermal stimulation. For example, utilizing IPN-PNIPAAM as a shell for AuNPs has allowed for the synthesis of reversible thermal-responsive nanogels. When combined with the anticancer drug 5-fluorouracil, these nanogels enable near-infrared light-triggered drug release, offering a highly effective and promising approach to photothermal therapy. This approach maximizes therapeutic effects while minimizing side effects.111 Furthermore, porous nanogels, especially when combined with targeted receptors, have emerged as versatile carriers for anticancer drugs. This has led to the design of intelligent nanogels for diverse therapeutic and diagnostic probes, highlighting their potential in advancing cancer treatment strategies.112 In the fields of science and medicine, nanoparticles have evolved beyond their role as mere transportation carriers. Through meticulous modification and integration, nanoparticles have become integral in bridging the gap between diagnosis and treatment, paving the way for a new era of holistic and personalized medical interventions.

Near-infrared light has emerged as a pivotal element in the treatment of cancer, particularly within the realm of bone tissue-related tumors (Table 1). This innovative methodology not only directly targets malignant cells but also emphasizes the enhancement of bone tissue growth, thereby facilitating restoration and thwarting the recurrence of bone tumors. The significance of this approach stems from the composite nature of bone, primarily composed of organic and inorganic components. Conventional materials utilized for bone repair in cases of cancer-induced bone defects, such as hydroxyapatite (HA),118 tricalcium phosphate (TCP), polylactic acid (PLA),119 polyglycolic acid (PGA), collagen,120 and chitosan,121 have been plagued by issues like subpar interface properties, susceptibility to bacterial infections, and a predisposition to tumor reappearance. Amidst these challenges, the advent of photothermal nanogels signifies a substantial leap forward. These nanogels not only showcase exceptional antibacterial and anti-tumor attributes but also demonstrate the capacity to promote bone tissue regeneration upon exposure to near-infrared light. Research indicates that beyond their cancer cell eradication role, gentle photothermal stimulation can further catalyze bone tissue regrowth. Noteworthy instances include the utilization of siRNA as a crosslinking agent to form a nanogel derived from DNA-grafted PCL, which has exhibited promising outcomes in achieving tumor eradication at low temperatures facilitated by dopamine. Additionally, findings underscore that modest temperatures within the 40–43 °C range can spur bone tissue regeneration.78 Consequently, leveraging a polypeptide-modified platinum-copper alloy nanogel could serve as a targeted intervention for bone tissue, selectively accumulating around bone tumors and effectively inhibiting their growth under near-infrared light exposure. This approach also holds the potential to significantly curtail osteoclast damage, showcasing a multifaceted and promising strategy in the realm of cancer treatment within bone tissue.122

Table 1 Photothermal nanogels for tumor therapy
Material Laser wavelength (nm) Properties Ref.
Asp-DPCN 808 Accumulates more efficiently around bone tumors and reduces osteoclastic bone destruction 122
DNA-g-PCL 808 Effectively ablates the tumor under relatively mild conditions 78
PP-FNANG 808 Effectively induces immunogenic cell death (ICD), and promotes the activation and infiltration of T lymphocytes 113
PDA-SN38@SCM 808 Lowers nonspecific macrophage uptake, offers longer retention in blood, and enables effective accumulation at tumor sites 114
P-TN-Dox@CM 808 Generates enhanced synergistic chemo-photothermal therapy to thoroughly eradicate tumors 115
NP/CMP@PAM 808 Excellent dual functions of suppressing osteosarcoma recurrence and repairing bone defects 116
PNIPAM-CDs 606 Overcomes multiple biological barriers to enhance therapeutic efficacy and decrease side effects 117

8. Conclusion and outlook

Nanohybrid hydrogels, despite their numerous advantages in various applications, also come with a set of disadvantages. These drawbacks need to be carefully considered when evaluating the overall potential of these materials. One major disadvantage of nanohybrid hydrogels is their potential for reduced biocompatibility. Nanohybrid hydrogels, due to the presence of incorporated nanoparticles, can introduce a level of cytotoxicity or allergic responses in certain biological systems. This limitation must be carefully considered when designing nanohybrid hydrogels for biomedical applications, as their interactions with living tissues need to be thoroughly evaluated to ensure patient safety. Polymer materials with good biocompatibility are often chosen as the primary constituents of photothermal nanogels. These nanogels hold significant promise in the field of nanotechnology, owing to their impressive ability to convert light into heat, thereby enabling various applications in the biomedical and healthcare sectors.

Photothermal nanogels, encompassing both organic and inorganic types, have garnered significant attention for their potential applications in disease diagnosis and treatment. This paper provides a comprehensive overview of these materials, delving into their mechanisms, drug release capabilities, and specific materials utilized within each class. The paper explores the mechanisms governing the response and drug release of photothermal materials. It identifies the specific materials utilized within both organic and inorganic classes and highlights their unique capabilities in targeted drug delivery and release. Photothermal nanogels have rapidly evolved from simple carriers to multifunctional tools for disease diagnosis and treatment. Their unique response mechanism and carrier advantages position them as a prominent research focus for numerous development applications. Therefore, photothermal nanogels hold significant potential as drug carriers, with the capacity to play a crucial role in combating conditions such as cancer and other diseases. Their ability to facilitate targeted drug delivery and release, along with their multifunctional nature, underscores their importance in advancing therapeutic approaches.

Author contributions

Yongjun Hu: writing – original draft. Yi Zhou: designing figures and investigation. Kaichun Li: writing – reviewing and editing and funding acquisition. Dong Zhou: writing – reviewing and editing, supervision, and funding acquisition.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was funded by the scientific research project of the Hongkou District Health Committee of Shanghai (No. 2302-09) and by the research project of Shanghai Fourth People's Hospital (sykyqd-00701, 00702, 00703&xkzt-2022-1019, 2020-1020).

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Footnote

† These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2024