Phototherapy: A Conventional Approach to Overcome the Barriers in Oncology Therapeutics

Abstract

Cancer disease has outgrown a life-threatening disease. Having reference to preceding reports provided by the International Agency for Research on Cancer, an estimated 9.6 million deaths transpired from cancer worldwide in 2018. Similarly, about 18.1 million new cases of cancer are being reported. The rise in conventional treatments akin to surgeries, chemotherapies, and radiotherapies was enormously observed to eradicate cancer tumors. These studies have shown unfavorable side effects in clinical treatments. Drug resistivity and drug cytotoxicities are also major issues to overcome. Considering these, researchers are developing alternative methods that are robust, economical, and safe. The use of light for therapeutic purposes shows a great history in vitiligo treatment. The combination of an effective activating agent and phototherapy could result as the best alternative with a great outcome to minimize adverse effects on healthy tissues. The utilization of light in the deletion of tumors using photothermal agents, and photosensitizers, hence the phototherapies in oncology were discovered and rapidly involved in the advancement of clinical approach. Here, in this article, we tried to highlight the recent trends in phototherapy and reviewed different types of phototherapy methods in cancer treatments and their latest clinical, preclinical, and in vivo studies.

Introduction

Drug resistance and toxic side effects are the enormous outgrowing factors in recent studies on cancer therapeutics. ¹ Researchers have been keen to assess and study these challenges.^2,3 The influence of light for therapeutic purposes has been observed for erstwhile 4000 years for vitiligo treatments. ⁴ The breakthrough approach and the advancements in technology over the last few decades made phototherapy reach another milestone. Recently, phototherapy has been used often in both diagnosis and treatment. ⁵ More specifically the modern clinical use of phototherapy began at the Roswell Park Cancer Institute with anticancer photodynamic therapy (PDT) in the 1970s. ⁶ Next, the manual operation of light irradiation outcomes in a controlled manner with minimal invasiveness. Consequently, phototherapy has been undertaken with a growing focus in recent decades to identify successful anticancer therapies. When light waves of a specific wavelength are combined with photothermal agents or activating chemicals, it results in the elimination of cancer cells. ⁷ Phototherapy has been known as a safe and secure way of utilizing the mechanism of light-to-heat conversion. Phototherapy has demonstrated prominent results in oncological treatments. The latest studies on the use of PDT/photothermal therapy (PTT) have shown some challenges. To surmount these challenges several approaches were made with the effective utilization of PTT and photoimmunotherapy.^8–10 These studies have shown significantly effective therapeutic in solid tumors therapies. ¹¹ Earlier usage of photosensitizer was the only approach to treat cancer regardless of cell specificity. ¹² Later, to tackle these challenges researchers introduced photothermally triggered nanoparticles/nanomaterial-induced treatments. These involve the subjects summarizing the details of the photothermal ablation of cancer cells by engineering versatile nanomaterials. The nanomaterials modification led to the formation of the cell specificity and targeting of the selective site of action. Simultaneously several reviews are suggesting the recent clinical studies on photothermal therapeutics. ¹³ This alteration toward the nanomaterials in developing cell-susceptible photothermal elements in exerting phototherapy on cancer cells. Subsequently, the researchers were keen to utilize photothermally triggered cancer drug release by encapsulation of different anticancer therapeutics drugs. Utilizing the light energy to create heat by applying the light-to-heat conversion therapy and denaturing the engineered nanomaterial/nanoparticles core to release the anticancer drugs. Based on preceding studies, there are several reviews available that showcase the term “phototherapy” thoroughly. ² Here, we reviewed the latest studies on the different types of phototherapies in oncology therapeutics.

PDT in Cancer Therapeutics

PDT includes the combination of nontoxic components, the combination is activated by the presence of oxygen. ⁷ The combination includes a photosensitizer (Figure 1) and light of a specific wavelength and oxygen. Considering the basic progress in research PDT received its first approval from Food and Drug Administration (FDA) four decades ago. ⁸ The PDT mechanism involves singlet oxygen-caused toxicity. ¹⁴ Photosensitizers are activated by light and pass their energy to cellular oxygen. The photosensitized mediated reaction mechanism exerts in two stages, type I reaction involves the passing of photon energy from the photosensitizers to oxygen where radicals are involved. Whereas in type II reaction, light energy passes directly to oxygen from photosensitizers. This oxygen is highly toxic and causes cell apoptosis/cell necrosis. ⁸ Globally, numerous clinical trials have been performed but only a few studies have crossed the margin and are being reported. In the following section, we tried to discuss the latest clinical studies.

Figure 1.

Schematic description of the mechanism in photodynamic therapy and overview of clinically approved photosensitizers corresponding to their excitation wavelengths.

In clinical studies, photosensitizers are employed first in the near 1980s for bladder cancer.^15,16 Subsequently, the enormous discoveries and contributions have increased lately in the past two decades. Therefore, we reviewed the photosensitizers employed in clinical trials in the past two decades (Figure 2). In 2001, the European Medical Agencies approved 16% methyl aminolevulinate topical cream (MAL) with the combination of light (570–670 nm wavelength) for actinic keratosis in the face and scalp treatment. ¹⁷ Similarly, in 2001, European Medical Agency (EMA) approved Temoprofin for basal cell carcinoma and oesophageal cancer. In late 2003, Talaporfin was approved in Japan for the treatment of early-stage endobronchial cancer.^18,19 In 2004, MAL was also approved by the FDA for actinic keratosis, whereas Sweden along with US FDA and EMA sanctioned Hexaminolevulinate for the treatment of bladder cancer diagnosis.^20,21Likewise, the EMA approved the aminolevulinate (10%) gel for the treatment of actinic keratosis for the face and scalp in 2011. Next, EMA sanctioned the use of aminolevulinate (10%) gel in daylight PDT for basal cell carcinoma. The latest clinical approval in PDT by EMA is Padeliporfin for early stages of prostate cancer in 2018.^22,23 The role of PDT in bone cancer therapy has been undulating until the preliminary studies were carried out in the 1980s. Fingar et al ²⁴ used a Photofrin II photosensitizer in rats to explore PDT applications. Similarly, PDT's role in bone cancer treatments became highly inquisitive. In the following years, researchers studied PDT therapy and different photosensitizer's active role in bone cancer treatments.^25–27 Recently to address bone cancer therapeutics in reference to phototherapy, Sun et al ²⁸ have well-reviewed studies on bone cancer therapeutics and their mechanism briefly.

Figure 2.

The flowchart of the approvals of photodynamic therapy (PDT) photosensitizers in oncology therapeutics by different agencies.

PTT in Cancer Therapeutics

PTT is a more advanced therapeutic method for treating cancer locally. ²⁹ The heat generated by photon energy destroys the tumor cells. This makes PTT highly precise, less invasive, and effective. The intense light beam is directly focused on the target tumor.^30,31 In PTT, photothermal agents of a specific wavelength are irradiated by the light then photons transform the absorbed energy from the ground singlet state to an excited singlet state. The electronic excitation energy then goes through vibrational relaxation, which is a nonradiative type of decay. Collisions between excited photothermal agents and their surrounding molecules mediate a return to the ground state. The change in kinetic energy causes an elevation of temperature around the on-site. Hence, the elevated temperature delivers to cause a heat-shock response that induces a rapid change in gene expression.^32,33 This change ultimately leads to generating heat-shock proteins that further minimize the consequences of the initial thermal damage. The rise in temperature causes irreversible damage heating tissues to a temperature resulting in cell necrosis. Furthermore, cell ablation starts with a rise in temperature that is generally (<60 °C) in PTT. Recently, researchers have shown great enthusiasm toward PTT due to the unhindered utilization of nanotechnology with light in cancer therapeutics.^34,35 Nanomaterials having high optical absorbance in near-infrared regions contribute to passing photo energy to heat at an assembled/desired site of action. In August 2019, Rastinehad et al ¹³ reported a study on the clinical trial of gold–silica nanoshells as a photothermal agent in the ablation of the prostate as per their report, gold–silica nanoshells-mediated thermal therapy was effective up to 94% in (15 out of 16) of patients. The fabrication of photothermal agents using nanoparticles and organic molecules has been vastly studied.^35–40 The leading approach in developing numerous photothermal agents involves the fabrication of biocompatible and stimuli-responsive biomaterials.^41–45

There are several other types of studies involving the light-to-heat mechanism such as laser interstitial thermal therapy, microwave hyperthermia, and so forth.^46,47 These alterations and advancements are being performed to deliver functionalized nanomaterials that fulfill the photothermal agent requirements. The rapid and robust action mechanism of action in phototherapy could unravel the functionalized role in future clinical trials irrespective of oncological therapeutics. PTT and PDT therapeutics have emerged as outdo barriers with negligible side effects. Although, the trivial disadvantage could not be disregarded, as the early phase studies suggest that future studies could decipher the limitation that inhibits phototherapy at a cumulative scale (Table 1). ⁴⁸

Table 1.

Advantages and Limitations of PDT and PTT in Cancer Therapies.

PTT		PDT
Advantages	Limitations	Advantages	Limitations
1) Spatiotemporal selectivity 2) Oxygen independent 3) Immunogenic 4) Thermal ablation 5) Strongly localized heating 6) Improvement in efficacy and safety	1) Limited light penetration 2) Heat-shock response 3) Photothermal agent's limited conduciveness 4) Limited for use primarily in superficial malignant tumors	1) Limited potential for resistance 2) Immunogenic 3) Less invasiveness 4) Lower cost than other cancer treatments 4) Usable in the outpatient setting.	1) Limited light penetrations 2) Oxygen dependency 3) Photosensitivity followed by treatment. 4) Tissue oxygenation is crucial to the photodynamic effect. 5) Less effective in metastatic cancers based on current technologies.

Abbreviations: PDT, photodynamic therapy; PTT, photothermal therapy.

Outlook

In this mini review, we tried to deliver recent clinical progress of phototherapy in cancer treatments. The basic advancements in cancer therapeutic studies play a vital role. Subsequently, the conventional approach and standard treatment strategies discovered reasonable success for specific cancers recently. Despite this, issues relevant to resistant cancer cells, recurrence, and metastases are the challenges that stand firmly. For this reason, new technologies are essential for future cancer treatments. The steering of on-site delivery of photothermal agents, and photosensitizers are the crucial elements that need researchers’ keen attention to advance further. Also, nanoparticle influence in photothermal therapies could alter the cytotoxicity effect. The stimuli-responsive nanoparticle's on-site self-assemblies and followed by diagnosis/phototherapy disassembly may help to reduce the after-therapy side effects. The utilization of advanced nanoparticles could also overcome the “low penetration,” which has been known as one of the main limitations in phototherapies. Further enhancement in addressing the afore-discussed issues could help to overcome these limitations and contribute significantly at a large scale to better therapeutics. The utilization of phototherapy in a constructive parameter is mounted to lead to more feasible human/clinical trials. ⁴⁸ The future goals to outdo the reticence of phototherapies must be based on the approach that leads to addressing biodegradable and biosusceptible as the main issues.