Abstract

Recent years have seen extensive clinical studies for photothermal treatment (PTT), a very promising anticancer technique that uses near-infrared light-absorbing substances to destroy tumours. The development of mild-temperature PTT, which avoids the drawbacks of traditional PTT (such as thermos resistance and side effects), has considerable promise for upcoming therapeutic applications. However, because to its significantly reduced therapeutic efficiency and lower heat intensity, mild-temperature PTT without adjuvant treatment is unable to entirely destroy malignancies. There is a development of nanomaterials in photothermal therapy of cancer. It is urgently necessary to develop methods that can increase the mild-temperature PTT's anticancer effectiveness. These methods mostly depend on the on-demand manufacturing of functionalized nanoagents. The tactics of mild-temperature PTT promoted by nanoagents are emphasised in this review. Additionally, possibilities and problems in this sector are logically given, and it is hoped that people would be inspired by this potential anticancer therapy. A novel cancer treatment called photothermal therapy has shown positive outcomes in its initial clinical study. This is the first experiment evaluating photothermal therapy's potential as a treatment for cancer patients, despite the fact that it has been widely studied in preclinical models. A cancer treatment known as photothermal therapy (PTT) causes the killing of cancer cells by heating tumour tissue exposed to near-infrared (NIR) light. NIR absorbents are employed to promote effective heat generation. We discuss regarding the challenges, views and certain complications of photothermal therapy and also its future prospects and challenges of its clinical application and uses.

Keywords

Introduction

Table1. Typical nanoparticles utilized in combination therapy as PTT agents.

Complications and its solutions for PTT

Thermal damage caused by photothermal therapy to the normal cells and tissues and its solution:

The effective photothermal therapy is based on photosensitizers' excellent tumour site specificity. The highest agglomerative thermal impact is only produced by high concentrations at the tumour location and the lack of localization of photosensitizer in healthy tissues, which allows for a rise in temperature at a set point and subsequent "heating" of the tumour without causing harm to healthy tissues. Two methods that ensure both the tumour-abusing impact and the security of healthy tissues have been put forth by researchers. The first involves enhancing photosensitizers' targeting capabilities, while the second involves using low-temperature PTT [67]. The tumor site should have a high concentration of photosensitizing substances. To improve the targeting ability. Only the tumour location, which contains the photosensitizers, would produce a significant quantity of heat energy unlike normal tissues, under NIR light stimulation. Nevertheless, low temperature photothermal therapy aims to enhance the effects of photothermal therapy on tumours and lower the temperature needed for the procedure, it also aims to decrease the by inhibiting the production of heat shock protein (HSPs), tumor cells become more resistant to heat. This idea was created by Liu and colleagues and several subsequent scientific investigations reinforced and optimized it in order to get a stronger tumour suppression impact and significantly minimize heat injury to normal tissues.

Increasing Photothermal Materials' Targeting Capability:

Most photothermal materials' ability to target tumours without the addition of tumour-specific targeting agents would rely on the phenomenon known as the increased permeability and retension (EPR) effect, which indicates that macromolecules and particles of particular size(such as liposomes and vesicles) have a higher chance of permeating tumor tissues through the EPR effect and staying there for a predetermined period of time. According to research, tumour cells release vascular endothelial growth factor because they require more nutrients and oxygen to continue their rapid pace of development. The tumour would be extremely reliant on the nourishment and oxygen supplies that tumour blood channels give, particularly when the tumour reaches 150-200 m in size. The shape and architecture of the freshly formed tumour blood vessels now differ significantly from those of normal blood vessels. The blood artery wall's smooth muscle layer is lacking, there is a significant endothelial cell gap, and the angiotensin receptor is not functioning. Additionally, the absence of lymphatic capillaries in tumour tissues inhibits lymph fluid from returning. These elements make it possible for macromolecular chemicals to easily get through blood vessel walls and accumulate in tumor cells. These compounds remain in the tumor tissues for a considerable amount of time because the lymph fluid that returns cannot eliminate them.

 If the photothermal materials' composition, porosity, size, qualities, surface traits, and targeting ligands are all optimal.

Photothermal Therapy at Low Temperature:

The low-temperature PTT is suggested as a solution to the issue of thermal harm to normal tissues caused by thermal distribution throughout the therapeutic process, as was stated above. However, the most pressing problem in this particular field of study is how to guarantee the tumour-abusing impact even at comparatively moderate temperatures (43–45 °C).

Low Photothermal Effect Solutions:

The major issue with PTT is the shallow depth to which light can penetrate, which causes tumours outside of the radiation field to only partially be cured. The majority of the time, monotherapy is insufficient to totally eradicate the tumour, and PTT is no exception. Even while PTT has a strong therapeutic impact, its inherent limits may still cause only partial cancer cell eradication, which in turn causes the tumour to return and spread. The total effectiveness of the treatment would increase if PTT was combined with other therapeutic modalities. In many instances, combining various therapy modalities results in a more effective treatment than simply a basic complement.

Concurrent Therapy:

Combining PTT with chemotherapy is a typical tactic. For instance, Zhang and colleagues were successful in molybdenum telluride nanosheets functionalization (MoTe2-PEG-cRGD) and loading them with the chemotherapy medication doxorubicin (DOX) for the detection and treatment of tumours. The developed MoTe2-PEG-cRGD/DOX demonstrates good cell abusing capabilities under NIR it is highly efficient in converting light into heat under irradiation. The cyclic arginine-glycine-aspartate (cRGD) motif's particular tumour targeting enables MoTe2-PEG-cRGD/DOX to effectively accumulate in tumours and provide potent cauterising effects. It's significant to note that MoTe2-PEG-cRGD can deteriorate when stimulated by NIR light.It can be used as a food that encourages bacteria at the tumour location to continue reproducing. They incorporated PD-1 immune checkpoint inhibitor added  to the phase-change gel of phospholipids to better apply this therapeutic approach to big tumours that are challenging to conquer (P-AUNP). Through a single subcutaneous injection, a drug depot may be created, and the slowly released PD-1 antagonist can persist for up to 42 days. This prolongs the anticancer impact of the nanosystem by continually altering the immunosuppressive milieu of the tumour. This three-pronged therapeutic approach—bacteria, heat, and immunity—offers a novel approach to tumour immunotherapy.

Bioactive Nanoagents:

The effectiveness of PTT can be impacted by a variety of variables in the very complex tumour microenvironment, including acidity, alkalinity, glutathione level, and oxygen content. As a result, different photothermal materials that take into account the tumour microenvironment and other bioenvironments are continually being created.

Applications of PTT:

1. In order to achieve thermal ablation, clinical PTT therapies now require laser technology. This is because endogenous tissue chromophores can be excited to produce thermal ablation. This tactic lessens the difficulty of regulation and the expense of PTT agent development.
2. For example, endobronchial tumors can be treated using endoscopic ND. A YAG laser is used for photocoagulation treatment.
3. The tumour tissue is thermally destroyed by laser photocoagulation, which targets the blood arteries that surround and deliver oxygen and nutrition to the tumours.
4. For example, Nd: YAG laser therapy for instance, demonstrated therapeutic effects in 603 patients with colorectal carcinoma that had spread to their liver (5 cm in diameter) and 500 patients with hepatocellular carcinoma (3 cm in diameter). This led to an 81 ?lation efficacy for primary liver cancer and a 2% recurrence rate for tumour metastasis.
5. In 899 individuals with malignant liver tumours treated with laser, there were very few problems (1% of patients).
6. The Visualise Thermal Therapy® (150 w, 980-nm laser) and Neuroblasts® laser ablation systems were authorized by the US Food and Drug Administration (FDA) in the 2000s to perform stereotactic laser ablation of high-grade gliomas (12W, 1064-nm laser) using MRI guidance.
7. Indocyanine green (ICG), an FDA-approved medical contrast agent, has generated a lot of interest as a phototherapeutic agent due to its photothermal impact and lethal ROS generation during NIR laser irradiation. ICG in particular has been used to treat cancer as a potent NIR- absorbing PTT agent with high light-to-heat conversion efficiency.
8. Although laser-based PTT has low regulatory barriers and development costs, PTT-agent enhanced thermal ablation offers significant improvements, such as greater selectivity to the target tissue and simple device design by using lower-power lasers.

Current guidelines of PTT:

Photothermal therapy (PTT) has shown promise in treating cancer metastases because of its unique features, which include low invasiveness and useful specificity. PTT can be used in addition to existing medications, in conjunction with multimodal imaging, or alone for the most effective therapy of cancer metastases. A range of photothermal nanotherapeutics (PTN) have been developed with encouraging therapeutic efficacy on metastatic cancer in multiple preclinical animal trials.  Near- infrared (NIR) laser photo absorbers are used in photothermal therapy (PTT), a recently identified and potential therapeutic method, to generate heat for the thermal ablation of cancer cells after NIR laser irradiation [88,89,90]. PTT has several advantages over existing therapeutic approaches for the treatment of cancer, including as precise spatial-temporal selectivity, low invasiveness, and high specificity. [91,92] PTT has the ability to directly destroy cancer cells in the primary tumor or locally spread the cancer to nearby lymph nodes in order to treat the initial stage of cancer metastasis. Additionally, it can be utilized in conjunction with the other therapeutic approaches to treat cancer cells that have spread to other areas. [93,94] The therapeutic efficacy of photothermal therapy (PTT) is largely dependent on the ability of photothermal agents—especially nanoscale agents—to efficiently convert light into sufficient heat. Several photothermal nanotherapeutics (PTN) have been comprehensively studied up to this point, such as organic nanoagents, transition metal sulfide/oxide nanomaterials, noble metal nanostructures, and nanocarbons. [95,96] PTT may eliminate all cancer cells from the primary tumor or local lymphatic metastases in the superficial tissues, stopping the cancer cells from spreading to other distant organs. However, due to the uneven heat distribution throughout these tissues, PTT is not enough to eliminate all cancer cells and stop the tumor from spreading or regenerating. PTN should be developed with deep penetration and specific targeting in tumor tissues to increase its therapeutic effectiveness. Moreover, PTN's significant selectivity for cancer stem-like cells, metastatic cells, and normal tumor cells must be considered in imaging-guided PTT. The imaging guidance provided by the current PTN is rarely employed to image distant metastatic lesions in deep tissues and is often limited to seeing primary tumor or lymph node metastases. PTN should be designed with valuable imaging and high targeting to metastatic disease in order to provide significant imaging advice for PTT alone or additional combination treatment. Combining PTT with immunotherapy, systemic chemotherapy, or stereotactic radiation may be an efficient alternative treatment for metastatic cancer. Concerns about the co-administration of PTN increase since a synergistic interaction between the photothermal agents and combination therapeutic agents is required for the combined therapeutic benefits to be achieved.

FUTURE PROSPECTIVE

Preclinical studies have tested a number of PTT-based strategies, and the results have been encouraging for some cancer treatments. In this field, many nanomaterials have been developed to cause localized hyperthermia in response to NIR light irradiation. In addition, combining PTT with different conventional therapies may be able to cure cancers that are not amenable to laser irradiation and produce better therapeutic results than PTT alone. This could lower the dose of PTT agents needed to destroy tumours and minimise any potential adverse effects. Tumors have been effectively removed from the body using photothermal ablation, which is based on an external laser device. However, due to the heat-sink effect, which causes heat loss and, consequently, lower photothermal effectiveness, it is challenging to efficiently treat lesions close to significant vascular systems utilising laser treatment without PTT drugs [104]. Additionally, the only tissues that laser light-induced thermal ablation is used to treat are superficial tumors due to human tissue's high absorption coefficient in the visible light spectrum and the possibility of harming non-cancerous cells. For successful clinical translation, improvements in light delivery are just as important as improvements in PTT agents themselves. The minimal depth of laser light penetration in biological tissues (less than 1 cm), for example, is a difficulty to the clinical translation of PTTs and leads to inadequate treatment for deep-tissue cancers. Because NIR lasers have a lower tissue absorption and dispersion than visible light, they can penetrate deeper than visible light, making them a highly recommended option for PTT. Therefore, the following new generation technologies are part of the present approaches:

1. Reaching tumors using fiber-optic NIR lasers
2. Using PTT in conjunction with laser-irradiated surgery on a surgical table
3. Creating PTT compounds in the NIR II (1000-1700 nm) range, which has a greater maximum allowable exposure and a longer penetration depth than NIR I (700-1000 nm), in order to achieve deep tissue tumor imaging and treatment.

In conclusion, next-generation technologies such as appropriate PTT agents with optimal optical characteristics, safety, and tumor-specific targeting, as well as enhanced laser fiber devices (multiple interstitial fibers) can be developed to provide superior cancer therapy. In order to optimize the therapeutic results, PTT should be properly matched with subsequent treatments. Innovative design and advancements in PTT platforms have a significant possibility of transferring from the lab to the clinic and expanding in clinical use.

CONCLUSION:

Photothermal therapy is now able to treat both local tumours and advanced metastatic malignancies, having evolved from a technique for ablating small tumours. From a functional viewpoint, we have evaluated the main nanoparticles employed in PTT of cancer in this paper. PTT is capable of completely eliminating cancer cells from the initial tumour or local lymphatic metastases in the superficial tissues, preventing them from spreading to other distant organs. However, PTT by itself is not enough to completely eradicate cancer cells in order to stop tumor recurrence and spread due to the uneven heat distribution inside these tissues. To increase the treatment efficacy, PTN should be created with precise targeting and deep penetration capabilities in tumour tissues. Additionally, PTT cannot be used to treat metastatic cancer cells at deep remote areas because to NIR light's low depth of penetration, which is a key contributing factor to the high mortality of cancer metastasis. An effective alternate treatment for metastatic cancer may involve combining PTT in conjunction with systemic chemotherapy, immunotherapy, or stereotactic radiation. The development of co-administered PTN poses extra questions since, in order to achieve the desired combined therapeutic effects, it is necessary to administer photothermal agents and combination therapeutic agents in a synergistic manner. In conclusion, PTT has shown considerable potential for treating cancer metastasis both on its own and in conjunction with existing medicines or imaging guidance. These advantages, nevertheless, have only just begun to be seen in animal experiments, and few have been verified in human clinical trials. To better their further clinical translation, significant efforts are required in the development of a therapeutically effective PTT that is biocompatible The PTT or their combination therapy, in our opinion, can offer a very promising therapeutic approach and renew hope for the future battle against cancer metastasis.

ACKNOWLEDGEMENTS

We thank Dr. Ashish Jain (principal of Shri D DVispute College of Pharmacy and Research Center, Panvel) for providing the invaluable support. We would also like to thank Mrs. Gangotri Yadav for her assistance.

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