Advances in Hollow Inorganic Nanomedicines for Photothermal-Based Therapies

In the modern world, cancer is a predominant cause of death and is a very serious and challenging health problem currently faced by humanity. A recent study projected that over 1.8 million new cancer cases and over 0.6 million cancer deaths would occur in the US alone in 2020. 1 However, with the advancement of medical technology, many cancer therapies have been developed in the last 20 years, including surgery, radiotherapy and chemotherapy, 2 , 3 resulting in a continuous decline in the mortality rate of cancer. 1 However, there are still some drawbacks to the clinical application of these therapies, including recurrence, non-selective targeting, low therapeutic indices, multiple drug resistance and serious side effects. 4 , 5 In addition, bacterial infections are a serious health problem that account for almost one-third of global mortality 6 and considerable financial losses. 7 Antibiotics are the most effective and frequently used treatments for bacterial infections, but the overuse of antibiotics in the clinical setting has contributed to pathogenic resistance. 8 , 9 Multidrug resistance (MDR) is commonly seen in the context of both cancer and antibacterial therapies. Therefore, novel therapeutic strategies are urgently needed for combating both cancer and bacterial infections. Recently, photothermal therapy (PTT) has been developed as a novel hyperthermia-based disease treatment strategy, in which photo-sensitive photothermal agents (PTAs) delivered at target sites in the body are used to convert near-infrared (NIR) light to heat in order to induce local hyperthermia 10 , 11 The photothermal effect can ablate aberrant cells and pathogenic bacteria, denaturing their proteins and causing cell death. 6 , 12–15 This laser-induced hyperthermia therapy is a robust and efficient therapeutic strategy for disease treatment, with the merits of high selectivity, 16 relatively low rates of side effects 11 and negligible invasiveness. 17 Due to these beneficial features, PTT is believed to be a promising strategy for treating various diseases. Meanwhile, PTT is also deemed as a good helper for other therapies, more and more synergistic therapies combining PTT and other therapies such as chemotherapy, 18 photodynamic therapy, 19 immunotherapy 20 and starvation therapy 21 are developed for cancer treatment. For example, the effect of chemotherapy can be enhanced and the multidrug resistance can be reduced by using a chemo/photothermal synergistic therapy; moreover, the photothermal effect can also contribute to the targeted drug release from nano-carrier at tumor site. In other words, the synergistic therapies are more than simply putting two therapies together, the introduction of PTT can significantly enhance the effect of other therapies. To date, various types of therapeutic PTAs have been discovered, including inorganic types such as gold nanomaterials, 22 carbon-based nanomaterials, 23 silica nanomaterials 24 and metal chalcogenides, 25 and organic types such as conjugated polymers 26 and porphysomes. 27 Although organic nanomaterials are superior to their inorganic counterparts in terms of biocompatibility and biodegradability, they suffer from several limitations, such as unstable photothermal effects and low photothermal conversion efficiency (PCE). Owing to their excellent imaging capacity and PCE, inorganic PTAs are currently prioritised by researchers and have seen wide application in the diagnosis and treatment of diseases. Notably, the morphology of inorganic nanoscale PTAs exerts a great influence on their properties. Specifically, aggregates of nanoparticles (NPs) are usually limited by large size and instability, whereas solid NPs are limited by weak NIR absorption and narrow wavelength adjustability. 28 Thus, the emergence of nanomaterials with hollow structures could provide a solution to these obstacles. By changing the diameter and thickness of the shell, the optical properties of hollow NPs can be easily manipulated, with the absorption wavelength ranging from near-ultraviolet (UV) to infrared. 29 , 30 In addition, hollow nanostructures possess lower mass than other nanostructures of the same size, thereby contributing to a relatively higher PCE per unit mass. 31 Moreover, the hollow interior endows hollow nanomaterials the capacity to be loaded with drugs, including imaging contrast agents (perfluorohexane for ultrasound [US] imaging) and therapeutic drugs (doxorubicin for cancer treatment), thus promoting both imaging and therapeutic efficacies. Owing to their features including high loading capacity, tuneable wavelength, relatively small size and low density, 32 , 33 hollow inorganic nanostructures can be ideal agents in photothermal-based therapies for various diseases. Reviews concerning the application of hollow or inorganic nanomedicines in PTT for cancer have been published. 29 , 34–36 However, reviews of the application of both hollow and inorganic nanomedicines in cancer PTT have not been published in recent three years. Moreover, their applications to other noncancerous diseases have never been summarized in a review. In this review, we focus on the recent advances in the development of hollow inorganic nanomaterials for PTT-based treatments for cancer, bacterial infections and other diseases, including Alzheimer’s disease (AD), obesity and endometriosis ( Figure 1 ). We conclude with our perspectives on the current challenges and future prospects of using hollow inorganic materials in clinical PTT for various diseases. Figure 1 Schematic illustration for the PTT-based treatment in cancer, bacterial infections and other diseases including obesity, Alzheimer’s disease and endometriosis. The outside hollow inorganic materials are examples for different diseases treatment. Schematic illustration for the PTT-based treatment in cancer, bacterial infections and other diseases including obesity, Alzheimer’s disease and endometriosis. The outside hollow inorganic materials are examples for different diseases treatment.

In this review, we discussed the recent biomedical applications of hollow inorganic nanomaterials in PTT for various diseases. PTT, along with the advancements in nanotechnology, has been widely investigated by scientists owing to the high therapeutic efficiency of PTT and the properties of hollow nanoplatforms, which can provide an ideal method for combining different therapies and enhance the treatment efficiency. Specifically, the hollow structures can significantly boost the loading capacity of nanostructures, allowing them to serve as perfect carriers for imaging contrast agents and therapeutic drugs. With the help of PTT, controlled drug release can be realised at laser-irradiated sites. Given these properties, many theranostic nanomedicines (based on gold, metal chalcogenides, carbon, silica, etc.) have been developed to treat intractable health problems. First, we introduced the application of hollow inorganic nanomedicines to PTT-based cancer treatment. By loading various drugs and agents on nanostructures, a combination therapy consisting of PTT and other therapies, such as chemotherapy (DOX-loaded) and photodynamic therapy (Ce6- or ICG-loaded) can be achieved to improve therapeutic efficacy and prevent cancer recurrence. Moreover, loading of contrast agents can allow precise monitoring using a combination of MR, PA, fluorescence and US imaging. Second, we discussed a promising strategy for combating infections caused by drug-resistant bacteria. The synergistic effects of antibiotics and hyperthermia can effectively inhibit bacterial growth, preventing “superbug” drug resistance. Third, we mentioned the application of hollow inorganic nanomedicines for the treatment of other diseases, including AD, obesity and endometriosis. As in the cases of cancer and bacterial infections, the mechanism underlying the treatment of obesity and endometriosis with hollow inorganic nanomedicine was the ablation of adipocytes and endometrial cells. However, apart from the ablative effect and controlled drug release, NIR light-induced hyperthermia had a novel usage in AD treatment, which was to increase the BBB permeability of nanodrugs. These studies suggest a novel approach for the development of drugs for brain diseases. Drugs for other diseases may also benefit from this enhanced permeability of biological barriers. All of these achievements suggest the promise of applying hollow inorganic nanomedicines for treatment in clinical patients. However, to date, according to the data from ClinicalTrials.gov, only 19 photothermal therapies have been registered for clinical trials, of which only two nanomedicines have completed clinical trials. Different from traditional energy-based ablation therapies including high energy laser and focused ultrasound, nanoparticle-based tissue ablation can achieve high specificity towards solid tumor, thereby contributing to relative negligible side-effects to normal tissue. One of the two nanophotothermal therapies named NANOM-FIM (Identifier: NCT01270139 ) was successfully carried out. In this study, silica-gold nanoparticles were delivered by a bioengineered stem cell patch, with the help of minimally invasive cardiac surgery (MICS CABG), significant regression of coronary atherosclerosis was achieved through plasmonic photothermal therapy. 152 Moreover, the long-term outcome showed that NANOM-FIM was superior to stent XIENCE V in safety and mortality. 153 The clinical trial of the other nanomedicine was gold nanoshells, named Auroshell ® (Identifier: NCT00848042 ) they were developed to treat head and neck and prostate cancers. Although their preclinical experiments demonstrated that Auroshell ® showed low toxicity to Beagle dogs, 154 some patients still had serious side-effects during the clinical trial, where 11 people were involved and only 5 people completed the trial. We believe that the main clinical limitation of hollow inorganic PTAs is their safety and toxicity. However, these drawbacks can be overcome to some extent. In this review, we described three methods for alleviating chronic toxicity and improving safety, including using biodegradable materials, reducing the dose of NPs and encapsulating NPs in biocompatible materials such as silica. More experiments using cell or animal models should be performed to ensure the safety of nanomedicines, following these suggested approaches. Moreover, insufficient PCE and photothermal stability are further obstacles in the clinical application of hollow inorganic nanomedicines. Thus, scientists should focus on improving the photothermal stability and PCE of nanomedicines to ensure sufficient photothermal effects at lower doses. Notably, although robust photothermal ablation could efficiently eliminate the target cells, the surrounding normal tissues are also likely to undergo apoptosis. Thus, the PTT strategy for each disease should be designed to be disease-specific. Specifically, higher temperatures can be used to kill cancer cells, whereas only mild hyperthermia should be used at some bacterial infection sites, such as eyes. In addition, the clinical application of many photothermal therapies are facing challenges such as limited light penetration depth. For most NIR-I PTAs, light penetration depth is confined to several millimeters due to the tissue scattering; however, as mentioned, by using NIR-II PTAs the penetration depth would be deeper, along with higher maximum permissible exposure (MPE), the clinical application of noninvasive deep tissue PTT would be possible. At present, for some diseases including macular diseases, acne vulgaris, oral cancer, and gastric cancer, NIR laser can be easily delivered to the superficial lesion via direct irradiation or gastroscope. While, for some diseases whose lesions are deeply buried in abdomen, such as pancreatic cancer (PC), NIR light cannot be delivered to the lesion directly. Recently, a novel method named interventional PTT (IPTT) was employed by Tian’s group to ablate PC deep in the abdomen. 155 In IPTT, an NIR optical fiber runs through an 18-gauge (G) percutaneous transhepatic cholangiography (PTC) needle to form the IPTT device. By using this device, NIR light can be easily delivered to the deep-buried tumor site; moreover, precise PTT can also be achieved, thereby reducing the ablative effect on normal tissues. At present, many researchers are focusing on combating cancer, for which a considerable number of hollow inorganic nanoscale PTAs have been developed compared to those for other diseases. Here, we described the potential of these materials in treating other health problems, including bacterial infections, AD, obesity and endometriosis. We hope that this review can arouse the interest of researchers in applying hollow inorganic nanoscale PTAs to treat these conditions, and that in the future, more diseases would be successfully treated using hollow inorganic nanomaterial-based PTT.

As a common neurodegenerative disease, AD is usually seen in patients with dementia 124 and is considered a worldwide health problem. 125 The extracellular accumulation of amyloid plaques is one of the hallmarks of AD. These plaques are mainly composed of amyloid‐β peptides (Aβ). 126 Given this fact, a promising strategy for treating AD involves preventing Aβ aggregation and destroying the already-formed Aβ fibrils. To date, various therapies for inhibiting Aβ aggregation have been investigated. 127–129 However, these methods often provide insufficient inhibition of aggregation and suffer from a poor disaggregating capacity. Therefore, localised PTT may be a robust tool and an ideal hyperthermia therapy for AD treatment, with minimal side effects to surrounding tissues. In 2017, Ruff et al developed hollow Au NPs (HAuNS) conjugated with CLPFFD peptides for selectively binding Aβ structures. 130 They fabricated CLPFFD-PEG-HAuNS via two approaches, first by binding the CLPFFD peptides directly to the HAuNS and second by binding the peptides indirectly to a PEG ligand shell. The authors used in vitro blood-brain barrier (BBB) model to prove that the impedance of BBB passage caused by the negative charge on the peptide was countered by coupling peptides to the PEG ligand. The Aβ aggregation-inhibiting effect of CLPFFD peptide-modified HAuNS was demonstrated experimentally in a later work 131 and in in vivo work performed previously. 132 , 133 These studies showed that HAuNS has potential for application in AD treatment. The hyperphosphorylation of tau protein is also a main culprit in AD, contributing to the aggregation of the protein followed by the production of ROS. 134 Abnormal production of ROS in the brain results in inflammatory reactions, which can impair neuron function and cause neuronal apoptosis, consequently influencing the basic functions of the brain such as learning and memory. In case of AD, repairing the impaired neurons and preventing tau protein hyperphosphorylation represent a promising treatment for AD. This year, Zhou et al fabricated nerve growth factor (NGF)-loaded hollow ruthenium (NGF-PCM@Ru) nanoflowers for AD treatment. 135 As a member of the neurotrophin family, NGF could serve as an inhibitor of tau hyperphosphorylation. However, the very low rate of BBB passage and short blood circulation time limited its biological application. As shown in Figure 5 , Ru NPs were utilised as carriers for NGF. Under NIR laser irradiation, BBB permeability was enhanced, helping the nanocarriers to enrich in brain tissue. Simultaneously, as the temperature rose, NGF was released via a phase-change process of PCM. Using the water maze test and nesting experiments, the authors proved the validity of NGF-PCM@Ru in rescuing memory loss in mice with AD. Figure 5 NGF-PCM@Ru NPs were used to cross BBB under NIR irradiation, and then PCM triggered the release of NGF in response to thermal effects, thereby achieving reduction of ROS production and mitigation of neuronal damage by inhibiting tau hyperphosphorylation. Data from Zhou et al. 135 NGF-PCM@Ru NPs were used to cross BBB under NIR irradiation, and then PCM triggered the release of NGF in response to thermal effects, thereby achieving reduction of ROS production and mitigation of neuronal damage by inhibiting tau hyperphosphorylation. Data from Zhou et al. 135 In modern society, obesity is a fast-growing disease that can cause serious health impairments. 136 In children in particular, the obesity ratio dramatically increased to 47% in the 30+ years from 1980 to 2013. 137 In addition, obesity is implicated in many chronic diseases, including ischemic stroke, 138 type-2 diabetes 139 and fatty liver disease. 140 At present, liposuction and anti-obesity drugs are the two major treatment methods to combat obesity. However, discomfort and pain caused by liposuction and side effects stemming from drug abuse are the major drawbacks restricting their clinical application. Recently, a novel obesity treatment that utilised NPs was developed. 141 The therapeutic strategy in most of these treatments was photothermal lipolysis. Han and Kim developed polypyrrole (PPy)-covered hollow gold nanoshells (HAuNS@PPy) for adipocyte ablation 142 and performed ex vivo experiments to evaluate their therapeutic efficiency. They found that subcutaneous adipose tissue was degraded, along with apoptosis of adipocytes. However, this method non-selectively ablated both adipose tissues and normal tissues, limiting its clinical application. To address this limitation, Lee et al developed HA-HAuNS-ATP for targeted transdermal delivery of the nanoshells. 143 In this study, hyaluronate was conjugated to HAuNS, endowing the nanoshells with transdermal ability, and the targeting capacity of the nanoshells was derived from the ATP sequence. The nanodrugs penetrated the epidermis and targeted adipocytes. Under laser irradiation, adipocytes were ablated by the photothermal effect, which could be visualised using PA imaging. The results showed that 20% of the initial lipid was eliminated, thus demonstrating a potential novel non-invasive therapy for obesity. Endometriosis is a common oestrogen-dependent gynaecological disease, which is defined as the growth of endometrial cells outside the uterine cavity. 144 Endometriosis is implicated in many health problems, including dysmenorrhea, dyspareunia, pelvic pain and infertility. 145 , 146 The disease affects 10% of women of reproductive age. In patients with endometriosis, the endometrial cells exhibit a decreased rate of apoptosis and an increased rate of proliferation. The environment in the ectopic endometrial tissue can prompt the implantation of endometrial cells and help them escape immune clearance. 147 , 148 At present, there is no cure for this disorder, and the most frequently used treatment strategy is surgical, which is associated with a high recurrence rate (>50%) due to from the presence of endometriotic residues after surgical excision. 149 Given that endometriosis is similar to solid cancer in many aspects and the diseases are usually concomitant, 150 NP-based PTT could be an ideal therapeutic strategy for endometriosis. In 2017, Guo et al developed targeted HAuNS for photothermal-based endometriosis therapy. 151 Neovascularisation, a common feature of both cancer and endometriosis, is closely associated with the overexpression of Eph receptors. To achieve the targeting effect, HAuNS was conjugated with TNYL peptides, which possess remarkable binding efficiency to EphB4 receptors. In in vivo experiments, under NIR light irradiation, TNYL-HAuNS remarkably inhibited lesion growth by photothermal ablation, with negligible damage to normal tissues. However, patients whose uterus is in a congestive state (menses) cannot be treated with this method since EphB4 is also highly expressed in the uterus.