Recent Advances in Photothermal Therapies Against Cancer and the Role of Membrane Transporter Modulators on the Efficacy of This Approach

Abstract

Recently, much research is focused on the use of photothermal therapy (PTT) as an advanced method to treat various types of cancer. The PTT approach primarily utilizes nanoparticles (NPs) made from metals, carbon, or semiconductors that can convert near-infrared laser irradiation, which penetrates tissues, into local heat that induces cancer cell death. An alternative approach is to utilize NPs (such as liposomes) to carry suitable dye molecules to the same end. Numerous studies concerning PTT have shown that local heat released in cancer cells may suppress the expression of membrane transporter proteins such as P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), thus enhancing cytotoxicity and reverse multidrug resistance. In addition, because NPs may be loaded with different substances, researchers have designed multifunctional NPs for PTT by including several agents such as membrane transporter modulators, anticancer drugs, and photothermal agents. This review will focus on the recent advances in PTT utilizing various types of NPs, and their components and characteristics. In addition, the role of membrane transporters in PTT will be highlighted and different methods of transporter modulation will be summarized from several PTT studies in which multifunctional NPs were used to treat cancers in vitro and in vivo.

Keywords

photothermal therapy gold nanoparticles monoclonal antibodies and membrane transporters

Introduction

Cancer is a group of diseases that affects millions of patients annually. According to the World Health Organization (WHO), cancer accounted for nearly 10 million deaths in 2020; and the most common types of cancer affected the breast, lung, colon, prostate, skin, and stomach.¹ For instance, in 2022, 1 918 030 new cancer cases were projected to occur in the United States,² and around 3 million people are currently living with cancer in the UK.³ These horrible numbers could adversely progress due to the Coronavirus disease 2019 (COVID-19) pandemic that led to delays in both diagnosis and treatment.⁴

The main cancer treatment modalities are surgery, radiotherapy (RT), chemotherapy (CT), and biotherapeutic antibodies. However, these therapies could be either associated with severe side effects or not being sufficiently effective.^5,6 The recent technological advances have enhanced our understanding of cancer and the importance of using multidisciplinary approach to tackle this disease. Photothermal therapy (PTT) is an approach that has attracted extensive research attention as a noninvasive and selective treatment strategy for numerous cancers.⁷ The photothermal concept depends on photothermal agents that convert light (typically near-infrared) energy into heat, thus increasing the temperature of surrounding tissue and triggering cancer cell death.⁸ These agents typically possess the ability for specific targeting and high photothermal conversion efficiency without excessive thermal damage to surrounding tissues.⁹

Various review articles have focused on different aspects of the PTT including properties of the implemented nanoparticles, temperature optimization, and their clinical development.^10–12 In addition, several articles showed that the heat generated from PTT may enhance the cytotoxicity of PTT in cancer cells.^13–15 This enhancement was related to the effect of heat on the expression of membrane transporters which is one of the major causes of the multidrug resistance phenomenon. Much research thereafter has shown that the loading of PTT nanoparticles with membrane transporter modulators improved the outcomes of PTT both in vitro and in vivo.^16–18 Consequently, this review will specifically provide an updated summary of the current advances in this field and will highlight the important role of membrane transporters on the efficacy of the PTT approach.

The Nanoparticle Component of PTT

Nanotechnology has rapidly evolved over the past few years to provide significant potential in combating cancer.¹⁹ Nanoparticles exhibit unique characteristics that enhance their application in the field of cancer treatment. These mainly include their selective accumulation into tumor tissues, their versatile structures which facilitate their surface modification for enhanced targeting, along with their ability to load various types of therapeutic agents.²⁰ The large surface-to-volume ratio of nanoparticles represents an additional advantage²¹; the nanoparticle surfaces can be densely coated with different molecules that have targeting properties²² as well as other functionalities.

In order to meet the high nutrient and oxygen demands, tumor tissues are characterized by massive and irregular neovascularization with structural and functional abnormalities in the blood vessels presented as very dense and tortuous with fenestrated structure. This will facilitate the penetration of macromolecular compounds with sizes above 40 kDa.^23,24 Moreover, these tissues do not have efficient lymphatic drainage system which will result in the trapping of the penetrated macromolecules inside the tumor tissues for prolonged period of time.^25,26 Together, the increase in the penetration of macromolecules and their retention in the tumor tissues, form the enhanced permeability and retention (EPR) phenomena. The EPR phenomenon has been observed in various solid tumors in rodents, rabbits, dogs, and humans.^27–29 This effect has been later used in the targeting of anticancer therapeutics into the solid tumor by controlling the size and the characteristics of the drug delivery system.³⁰ Nanoparticles can be effectively used for this purpose since they can accumulate in cancer tissues due to the EPR effects.³¹ Different factors seem to affect the use of nanoparticles in PTT including their size, surface properties, shape, and concentration.³²

A wide range of nanoparticles has been adopted in PTT-based cancer treatments, such as metal nanomaterials (platinum and gold), carbon nanomaterials (graphene and carbon nanotubes), semiconductor nanomaterials (copper), and conducting polymers.^33,34

Iron oxide nanoparticles (IONPs) are metal-based nanoparticles with magnetic properties. They are safe, biocompatible, with a high ability to absorb both visible, and NIR light and generate heat for PTT.³⁵ Similar to other nanoparticles, IONPs can accumulate in the tumor tissues based on the EPR effect and the generated heat from the IONPs can result in intense cancer cell death. Moreover, since these nanoparticles have magnetic properties, their accumulation in the cancer tissues can be increased by applying an external magnetic field before exposing them to NIR light. This external magnetic field can also result in the generation of magnetic hyperthermia with subsequent destruction to cancer cells.³⁶ Moreover, the iron present in these nanoparticles can contribute to iron hemostasis in the body after the metabolism of these IONPs into elemental iron.

Carbon nanotubes are a class of carbon-based nanoparticles that are employed in PTT based on their ability to absorb light energy at wavelengths from 750 to 1000 nm followed by heat generation. The implementation of carbon nanotubes in sensing/monitoring of cancer has been comprehensively reviewed.³⁷ Carbon nanotubes are present as either single-walled carbon nanotubes (SWCNTs) or multiple-walled carbon nanotubes (MWCNTs) based on the number of the tube wall layers. The SWCNTs, developed by Liang et al, exhibited an effective destruction of metastatic tumors in an in vivo mice model. This was a result of the accumulation of these SWCNTs in the tumor followed by heat generation in response to light irradiation.³⁸ Yang et al developed PEGylated nanographene sheets (NGS) coated with polyethylene glycol with a size of 10–50 nm in the form of 1–2 layers which showed high tumor accumulation through passive targeting. These NGS showed strong optical absorbance in the NIR region which resulted in a temperature increase by more than 30 °C with a subsequent efficient tumor ablation based on this PTT.³⁹

Semiconducting polymer-based nanoparticles (SPNs) used for PTT exhibit favorable properties such as biological compatibility and excellent optical properties. Li et al synthesized highly biodegradable SPNs with photothermic activity which upon NIR irradiation resulting in a local temperature increase up to 45 °C leading to collagen digestion in the tumor extracellular matrix.⁴⁰

Quantum dots (QD) contain several types of materials and are characterized by their small size which promotes their use in PTT. The optical properties of QD can be adjusted by controlling their size and composition, which can result in improved heat generation, high production of reactive oxygen species (ROS), and fast metabolic rate to avoid long exposure toxicity. Black phosphorus quantum dots (BPQDs) are one type of QD that exhibit novel PTT. BPQDs with a lateral size around 2.6 nm have efficient NIR photothermal performance with high photostability. Under irradiation with 808 nm laser, BPQDs resulted in complete in vitro killing of cancer cells. Moreover, in the absence of irradiation, these types of nanoparticles have negligible toxicity even at high concentrations resulting in high biocompatibility profile.⁴¹

Manganese dioxide (MnO₂) nanosheets have been also applied in the field of PTT. pH-/H₂O₂-responsive MnO₂ nanosheets anchored with up-conversion nanoprobes were developed by Fan et al. These can exert excellent PTT under hypoxic conditions by the conversion of the NIR into short-wavelength light which will result in a local temperature increase. In this system, the pH and the H₂O₂ consumption at tumor sites will result in oxygen production to enhance the PTT and at the same time the emitted light quenching in this system protects the normal tissues from ROS-mediated damage.⁴²

Gold nanoparticles (AuNPs) are another important type of metal-based nanoparticles that exhibit excellent photothermal activities due to their ability to passively accumulate in the tumor tissues by the EPR effect and their strong absorbance of NIR light. The NIR exposure of these nanoparticles will enhance the resonance of the high number of free electrons present within the metal and on its surface and induce surface plasmon resonance (SPR). This will result in high photothermal conversion activity which will promote apoptosis and necrosis in the cancerous tissues. Once accumulated at the tumor tissues, AuNPs can strongly absorb the laser irradiation and immediately generate heat locally with minimal damage to the adjacent normal tissues.

AuNPs have been extensively investigated in the field of PTT. The ability of AuNPs to absorb light in the visible as well as the near-infrared (NIR) region depends on the AuNP shape and dimension, which influence the SPR required for the photothermal effect. Depending on the dimensions, AuNPs can be classified into three categories. One-dimensional AuNPs include gold nanobelts, nanowires, nanotubes, and gold nanorods. Two-dimensional AuNPs include dimpled AuNPs, truncated triangles, square or rectangular nanoparticles, and hexagonal nanoparticles. All these two-dimensional AuNPs are referred to as gold nanoplates. Three-dimensional AuNPs include nanodumbbells, nanotadpoles, nanostars, nanodendrites, and nanopods. The last three types are further classified as branched gold nanoparticles.⁴³ These different types of AuNPs have various characteristics and applications. They differ from each other in terms of their physicochemical characteristics, SPR, optical, and electronic properties.^44,45 These differences resulted from the variability of the size, shape, and aspect ratio. The availability of different types of AuNPs which can be easily synthesized has resulted in various applications in many fields such as diagnosis and imaging, targeted drug delivery into specific diseased tissue or organ, biosensing, and most importantly photothermal and photodynamic therapy.⁴⁶

By changing the size and shape of AuNPs, the SPR can be tuned to the NIR region, which imparts high-depth photothermal penetration in tissues.⁴⁷ Laser wavelength is also crucial in determining the outcomes of the AuNPs action, in the majority of the AuNPs studied, 808 nm PTT laser wavelength was used. A few studies have employed other wavelengths, including 650, 980, and 1064 nm. However, the use of 808 nm has proven to cause the most effective temperature enhancement.⁴⁸

For more efficient cancer treatment, several types of the nanoparticles used to exert PTT can also be loaded with some chemotherapeutic anticancer agents to achieve an enhanced synergistic effects between the chemotherapy and the PTT. In this regard, the nanoparticle will act as a carrier to deliver the loaded drug into the target cancer cells based on the EPR effect, and the same nanocarrier will absorb the NIR light to induce PTT. This will improve the therapeutic outcomes of chemotherapy when combined with PTT using the same nanocarrier. This can be seen in the work of Wu et al who developed an engineered versatile nanoplatform based on graphene oxide (GO) coated with mesoporous silica for synergetic effect between the PTT and doxorubicin. The GO is used for improved photothermal effects, and the mesoporous silica will enhance the doxorubicin loading. The in vivo study demonstrated that these nanoplatform could accumulate in the cancer cells by the EPR effect and the NIR can trigger doxorubicin release and result in a local temperature increase to above 50 °C exhibiting excellent antitumor synergy between chemotherapy and PTT.⁴⁹ Other platforms have employed Cisplatin as a loading agent. Similar to Doxorubicin, Cisplatin have showed enhanced localized antitumor effects by improving hypoxia at the site of action.⁵⁰

Liposomes, which are the most studied type of nanoparticles, are also investigated in PTT. Liposomes are composed of phospholipids, cholesterol, and other components which will self-assemble into a bilayer structure upon hydration.⁵¹ Liposome components by themselves have poor light absorption properties, however, their use in PTT is based on loading NIR absorbing dyes, such as indocyanine green (ICG), IR780, IR820, and IR792. Following the accumulation of these loaded liposomes into the target cancers, the dyes will be released and used for PTT.⁵² The used irradiation wavelength will depend on the selected dye loaded into the liposomes. Moreover, liposomes have another advantage in the context of PTT in that additional molecules can be co-loaded into liposomes such as chemotherapeutic agents for a synergetic effect between PTT and chemotherapy. Xu et al developed ICG-loaded liposomes wrapped with C6 glioma cell membranes for potential application in PTT. The liposomes enhanced the accumulation of the ICG dye in glioma tumors in BALB/c nude mice which showed a peak absorption at 808 nm resulting in complete tumor eradication within 18 days.⁵³

Other types of nanoparticles that can also be used in PTT include sulfide nanoparticles,⁵⁴ silver nanoparticles,⁵⁵ silica,⁵⁶ palladium,⁵⁷ and polymeric nanoparticles.⁵⁸ Each one of them has different features and specific applications in the field of PTT with highly promising future outcomes.

The Targeting Component of PTT

The excellent properties of nanoparticles can be improved through the conjugation of targeting molecules, such as monoclonal antibodies (mAbs), onto the surfaces of nanoparticles to enhance the targeting effect on certain cancer cells.⁵⁹ Antibodies are widely used in cancer due to their versatile targeting capability.⁶⁰ In addition, antibodies can directly target cancer cells while concurrently promoting the induction of long-lasting anti-cancer immune responses.⁶¹ For example, antibodies could target tumor antigens, tumor microenvironment to reduce tumor growth, or to target cells of the immune system to enhance the antitumor immune responses.⁶⁰ In addition, antibodies could manipulate the host immune response to tumors through either antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or the induction of adaptive immune responses.^9,62

The microenvironment of cancer comprises several factors that can inhibit the immune responses against cancer, promote cancer cell growth, and induce pro-tumorigenic angiogenesis.⁶³ Targeting these critical factors and proteins within the cancer microenvironment was proven clinically through the successful approval of several antibodies against different forms of cancer. Consequently, mAbs represent major tools to fulfill this requirement.

Several articles highlighted the utilization of AuNPs-mAbs conjugates within various photothermal approaches (Table 1). Different shapes of AuNPs were used, including nanorods (AuNR), nanoshells (AuNSH), nanostars (AuNST), and nanocages (AuNC). The high representation of AuNR could be attributed to their excellent physical properties represented by strong NIR absorption due to the longitudinal localized SPR band.⁶⁴ The mAbs that have shown promising efficacy (Table 1) included anti-HSP mAb that was used to target HSP70 expression in 4T1 cell lines.⁶⁵ In addition, an anti-HER2 mAbs were tested on SKBR3, MDA-MB-231, MCF-7 and CIK cells, and C57BL/6 and MCF-7 tumor-bearing mice.⁶⁶ Another mAb that provided significant results is the anti-CD33 antibody that was conjugated with AuNST.⁶⁷

Table 1.

Summary of Targeted Therapy Utilization in Gold Nanoparticles.

Shape	Coating and Load	Targeting Agent	Target	Size (nm)	Laser Wavelength (nm)	Laser Power Density (W/cm²)	Duration of Radiation (min)	Cancer Cell Line	Temperature (°C)	Cancer Type (Indication)	Reference
AuNC	-	Anti-HSP monoclonal antibody	HSP70	61.2 ± 4.85	808	1	5	4T1 and Female BALB mice	-	Breast	⁶⁵
AuNR	-	Anti-EGFR antibody	EGFR	-	808	2.5	40 and 75	U373-MG and 1321N1	-	Glioblastoma	⁷²
	-	Anti-EGFR antibody	EGFR	10 × 40	808	1.5	3	MDA-MB-231	T_max = 43	Breast	⁷³
	-	Anti-HER2 antibody and HA	HER2 and CD44	55.1 × 14.1	808	2	10	MCF-7 and MCF-7 tumor bearing mice	≈ 55	Breast	⁶⁶
	-	Anti-EGFR antibody	EGFR	40	850	1.5	5	A549	-	Lung	⁷⁴
	Coated with BSA	R837	DCs, CD8+ T cells	122.1	1064	1	10	B16-F10	-	Melanoma	⁷⁵
AuNSH	Coated with PLGA	Anti-HER2 antibody	EGF/HER-2/CD133 antibody	248.3	808	1	10	SKBR3 and MDA-MB-231	-	Breast	⁷⁶
AuNSH	Chitosan-layered, Paclitaxel loaded	Anti-EGFR antibody	EGFR	9	808	1.2	5	HeLa and MDA-MB-231 cells/ MDA-MB-231 tumor-bearing mice	T_max = 52.5	Breast	⁷⁷
AuNST	ICG	Anti-HER2 antibody (Trastuzumab)	EGF/HER-2/CD133 antibody	135.3	808	0.5	3	CIK cells, SKBR3/C57BL/6 and BALB/c nude mice	-	Breast	⁷⁸
AuNST	-	Anti-CD33 antibody	EGF/HER-2/CD133 antibody	120	808	0.8	5	PC3 cell-line/male BALB/c athymic nude mice	-	Prostate	⁶⁷

Abbreviations: AuNC, gold nanocage; AuNR, gold nanorod; AuNSH, gold nanoshell; AuNST, gold nanostar; BSA, bovine serum albumin; PLGA, polylactic-co-glycolic acid; ICG, indocyanine green; HSP, heat shock proteins; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; R837, imiquimod; CD33, transmembrane receptor; HSP70, family of conserved ubiquitously expressed heat shock proteins; CD44, cell-surface glycoprotein antigen; DCs, antigen-presenting cells for activating native T cells; CD8, transmembrane glycoprotein; CD133, prominin-1; PTT, photothermal therapy; 4T1, cell line posing 6-thioguanine resistance; U373-MG, human glioblastoma cell line; 1321N1, human astrocytoma cell line; MDA-MB-231, triple-negative breast cancer cell line; MCF-7, human breast cancer cell line; A549, lung carcinoma epithelial cell line; B16-F10, cell line of murine melanoma; HOC313, human oral squamous-cell-carcinoma cell line; HSC3, human oral squamous carcinoma cell line; SKBR3, human breast cancer cell line; HeLa, HeLa cell line; CIK, cytokine-induced killer cells; C57BL/6, Inbred strain of laboratory mouse; PC3, prostate cancer cell line.

Different researchers have also investigated the coating of these AuNPs with other molecules like bovine serum albumin, polylactic-co-glycolic acid (PLGA), chitosan, and indocyanine green (ICG) to increase the stability of the AuNPs.^68–70 The implemented antibodies have mainly targeted epidermal growth factor receptors (EGFR) in multiple cancer cell lines, since EGFR is the most commonly overexpressed membranous oncogenic protein in cancer.⁷¹ Numerous cell lines were used to test these particles as, for example, in glioblastoma (U373-MG and 1321N1 cell lines),⁷² breast cancer (MDA-MB-231 and HeLa cells),⁷³ lung cancer (A549 cells),⁷⁴ and oral cancers (HOC313 clone 8 and HSC 3).⁸

Diverse types of gold nanoparticles were utilized in various articles that we examined (Supplemental Table 1). One of the most utilized shapes of gold nanoparticles was AuNR followed by AuNST, AuNP, and AuNC (Figure 1). However, it was noted that a large number of the AuNPs that do not utilize mAbs were coated or had alternative surface modifications.

Figure 1.

Number of examined publications utilizing AuNPs classified by shape. AuNR (gold nanorod), AuNST (gold nanostar), AuNP (gold nanoparticles), AuNC (gold nanocages), AuNSH (gold nanoshell), AuNCL (gold nanoclusters), AuNM (gold nanomaterials), AuNSP (gold nanospheres), and AuNPY (gold nano pyramids). Others include one article for each of the AuNU (gold nanourchins), AuNPR (gold nanoprisms), AuNF (gold nanoflower), and AuND (gold nanodumbbells). The articles were covering the period 2015–2022, as summarized in Supplemental Table 1 and Table 1.

One of the common surface modifications is polyethylene glycol (PEG). In 13 AuNPs, PEG utilization is linked to its ability in improving the distribution of the AuNP throughout blood circulation.⁷⁹ Other platforms tended to assist the AuNPs by using mesoporous silica as a coating agent, because it possesses favorable biocompatibility, thermal stability, and desirable chemical properties. As drug carriers, they facilitate the effective loading and subsequent controlled release of the drugs to the target sites.⁸⁰ The use of hyaluronic acid (HA) as a coating agent has also proved its efficacy in multiple studies.⁶⁶ The combination of AuNPs and HA increases the mobility of the AuNPs, resulting in a better distribution over the cancer site. Other articles have implemented the use of polyethyleneimine (PEI), as it is the most widely used cationic polyelectrolyte for preparing positively charged AuNPs. They feature dual roles as stabilizing/reducing agents for gold ions and their chemical stability.⁸¹

Most of the AuNPs analyzed were studying the efficacy and safety in breast cancer, followed by lung, cervical, and colon cancers (Figure 2). This focus is interestingly reflecting the incidents of these types of cancer. In addition, breast cancer is associated with challenges like treatment-related adverse events, poor outcomes in triple-negative breast cancer and balancing the treatment with quality of life.⁸² The use of AuNPs might be a crucial treatment option due to breast cancer’s high prevalence and the increased focus on localized treatment methods of noninvasive nature. Huang et al prepared gold nanorods that are conjugated to antibodies to specifically bind to the cancer cells before exposing these nanoparticles to continuous red laser at 800 nm to photothermally induce cancer cell killing.⁸ However, gold nanoparticles suffer from some limitations in terms of their long exposure toxicity and their relatively weak optical signal.¹²

Figure 2.

Number of publications classified by cancer type. The articles covered a wide range of cancers. Others include one article focusing on squamous cell, squamous vulvar, osteosarcoma, sarcoma, hepatoma, gastric, lymphoma, and pancreas cancers. The articles were covering the period 2015–2022, as summarized in Supplemental Table 1 and Table 1.

Other promising approaches for enhanced phototherapy might focus on improving the efficiency of photosensitizers. Mitochondria-targeted nanomedicines are being developed to focus on damaging the mitochondria DNA, disturbing respiratory chain and redox balance, and increasing reactive oxygen species (ROS). Such attempts to enhance the photothermal efficacy have been comprehensively reviewed by Gao et al.⁸³ For instance, targeting the mitochondria, by diketopyrrolopyrrole-based photosensitizer,⁸⁴ has demonstrated an efficient approach to produce thermal energy and singlet oxygen under 635 nm laser irradiation with ideal cytocompatibility and highly effective antitumor effects. Furthermore, Lv et al⁸⁵ have utilized polydopamine-coated hollow copper sulfide nanoparticles as the photothermal nanoagents and thermosensitive drug carriers for loading hypoxia-activated prodrug. Chlorin e6 (Ce6) and triphenylphosphonium (TPP) were conjugated onto the surface of the nanoplatform. The former can generate ROS and simultaneously exacerbate the cellular hypoxia, while the latter aided accumulation of the nanoplatform in mitochondria to restore the drug activity and avoid drug resistance. Consequently, this approach highlights the potential of using additional molecules and substances to synergize the photothermal effect in cancer treatment. In a similar vein, we will focus on the use of membrane transporters in the following section.

The Role of Membrane Transporters in PTT

Membrane transporter proteins, which transport drug substances, are usually referred to as drug transporters in biomedical sciences. Two major families of membrane transport proteins are the ATP binding cassette (ABC) family and solute carrier (SLC) family. Solute carriers mediate the transport of ions or other solutes including vitamins, minerals, peptides, toxins, as well as numerous drug substances across cell membranes.^86,87 ABC transporters efflux molecules from the cell membrane in a process requiring energy in the form of ATP^86,88; while SLC is both cellular influx and efflux carriers not directly dependent on ATP use, but often utilize the ion gradient across the cell membrane found for eg Na⁺ or H⁺.⁸⁹ In humans, membrane proteins are expressed in different tissues and organs such as the intestine, liver, kidney, blood-brain barrier, and testes.⁹⁰ Importantly, ABC transporters were found to be highly expressed in cancer cells which may lead to efflux of diverse structurally and mechanistically unrelated anticancer drug substances, and this is a major cause of multidrug resistance.^91,92 ABC transporters of importance in multidrug resistance are mainly permeability glycoprotein 170 (P-glycoprotein, P-gp which is encoded by the ABCB1 gene), multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), and breast cancer resistance protein (BCRP, encoded by ABCG2).^91–94

Recently, photothermal therapy used in cancer treatment was found to influence the expression of membrane transporters through the effect of hyperthermia which may either denaturate membrane transporters such as P-gp and MRP1 or increased the expression of heat shock factor-1 (HSF-1) which in turn decreased the expression of membrane transporters in cancer cells.^13,14,16 In addition, the substantial progress in designing nanoparticles that may accommodate different types of molecules such as anticancer drug substances, surfactants, and biological materials such as RNA and monoclonal antibody, enabled nanoparticles containing a photothermal agent and a membrane transporter modulator. These nanoparticles have been investigated in vitro and in vivo.^17,95–97

Nanoparticles for Photothermal Effect and Modulation of Membrane Transporters In Vitro

In order to obtain a synergistic effect of ablating the cancer cells and reversing the multidrug resistance related to overexpression of ABC transporters, different methods were utilized to modulate membrane transporter abundance. Molecules or biological materials that have been combined with photothermal nanoparticles include (1) Photothermal agent which produces heat when exposed to NIR light and the released heat may decrease the expression of membrane transporters such as P-gp¹³ and MRP1,¹⁴ or induce P-gp denaturation,¹⁵ (2) P-gp monoclonal antibody,⁹⁶ (3) Nonionic surfactants such as Pluronic P123 and TPGS,^17,95 (4) siRNA to downregulate the expression of a membrane transporter protein,^18,97 (5) Nitric oxide donor molecule to liberate nitric oxide which decreases the expression of membrane transport proteins,^98,99 (6) Natural product with specific P-gp inhibitory properties such as curcumin,¹⁰⁰ and (7) Combination of different methods (Table 2).

Table 2.

Nanoparticles for Photothermal Therapy and Modulation of Membrane Transporters In Vitro and In Vivo.

Nanoparticle Components	Targeted Transporter	Transporter Substrate	Transporter Modulator	Effect of Transporter Modulator In Vitro	Effect of Nanoparticle + NIR Light In Vivo	Reference
Gold, silicon dioxide, doxorubicin	P-gp	Doxorubicin	Hyperthermic effect	Hyperthermia increased the expression of heat shock factor-1 (HSF-1). HSF-1 depressed the expression of P-gp on cell membrane of MCF-7/ADR cells		¹³
Cyanine dye, cisplatin prodrug	MRP1	Cisplatin prodrug	Hyperthermic effect	Hyperthermia inhibited the expression of MRP1 and enhanced the cytotoxicity in A549 cells and resistant A549R cells	Successful ablation of A549R tumor and A549 tumor in mice without regrowth, and no effect on other organs	¹⁴
Oxidized carbon nanohorns, PEG, etoposide, P-gp monoclonal antibody	P-gp	Etoposide	P-gp monoclonal antibody	P-gp inhibited by direct interaction between the antibody and P-gp. Decrease the cellular efflux of etoposide in A549 and A549R cells	Significant reduction of relative tumor volume (RTV) in A549R tumor-bearing mice	⁹⁶
Polydopamine, doxorubicin, PEG, folic acid, P-gp siRNA	P-gp	Doxorubicin	P-gp siRNA	P-gp expression was downregulated by 57% in MCF-7/ADR cells	Significant reduction in tumor volume and weight in mice bearing MCF-7/ADR tumor	⁹⁷
Polydopamine, black phosphorus, doxorubicin, P-gp siRNA, PEG, aptamers	P-gp	Doxorubicin	P-gp siRNA	P-gp expression decreased by 68% and the cellular efflux of doxorubicin decreased, thus the cytotoxicity improved in MCF-7 and MCF-7/ADR cells	Significant tumor ablation in MCF-7/ADR tumor-bearing nude mice, and no effect on other organs	¹⁸
IR820 dyes, doxorubicin, porous silicon attached with amine group	P-gp	Doxorubicin	Hyperthermic effect	Hyperthermia induced P-gp denaturation in MCF-7 cells and MCF-7/ADR cells		¹⁵
P-Cypate, doxorubicin, pluronic P123	P-gp	Doxorubicin	Pluronic P123, Hyperthermic effect	Pluronic P123 inhibited P-gp activation by depleting ATP production in MCF-7/AD. Hyperthermia increased the expression of HSF-1, which in turn depressed the expression of P-gp	Tumor growth was completely inhibited in MCF-7/ADR tumor-bearing mice	⁹⁵
Polydopamine, doxorubicin, TPGS	P-gp	Doxorubicin	TPGS	The cytotoxicity of doxorubicin increased by TPGS due to P-gp inhibition effect in MCF-7/ADR cells. It was suggested that TPGS reduced the transmembrane potential of mitochondria and consequently inhibited the ATP-production activity		¹⁰¹
Indocyanine green, Doxorubicin, TPGS	P-gp	Doxorubicin	TPGS	TPGS inhibited P-gp expression and enhanced the cytotoxicity of doxorubicin inSCG7901/VCR cells		^102,103
Polydopamine, 12-aminododecanoic, BNN6, doxorubicin, TPGS-Galactose	P-gpMRP3	DoxorubicinRhodamine 123	TPGSNitric oxide	Nitric oxide decreased the expression of P-gp and MRP3 in HepG2/ADR cells. TPGS decreased the intracellular ATP content and P-gp expression on cell membrane, and this inhibited P-gp and enhanced doxorubicin accumulation in the cells	Inhibited the tumor growth in HepG2/ADR-tumor-bearing mice. Significant reduction in tumor weight without affecting the body weight of the mice	¹⁷
Indocyanine green, curcumin, molybdenum disulfide	P-gp		Curcumin	Nanoparticles containing curcumin inhibited the expression of P-gp in HepG-2 cells	Tumor volume and weight reduced significantly in hepatocellular carcinoma H22 tumor-bearing mice	¹⁰⁴
Copper selenide, N-diazeniumdiolate, doxorubicin	P-gp	Doxorubicin	Nitric oxide	The released nitric oxide gas inhibited P-gp expression by (≈ 40%) in MCF-7/ADR cells	Tumor growth was completely inhibited (TIR = 100%), with no side effects on other organs	⁹⁸
N-doped graphene oxide (N-GO), BNN6, mitoxantrone	P-gp	Mitoxantrone	Nitric oxide	The released nitric oxide gas inhibited P-gp expression on the membrane of MCF-7/ADR cells	Significant decrease in tumor volume in MCF-7/ARD tumor-bearing nude mice without side effects on other organs	⁹⁹

Abbreviations: BNN6, nitric oxide donor agent, NN′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine; PEG-b-PDPA, cypate-conjugated poly(ethylene glycol)-block-poly(diisopropanolamino ethyl methacrylate; TPGS, diblock copolymer, D-α-tocopheryl polyethylene glycol 1000 succinate; A549, nonsmall cell lung cancer cell line; A549R, multidrug resistant variant of A549 cells; MCF-7, breast cancer cells; MCF-7/ADR, adriamycin resistant cell line of MCF-7; SGC7901/VCR, vincristine-resistant human gastric cancer cell line; HCC, hepatocellular carcinoma; TIR, tumor inhibitory rate; HepG-2 cells, human hepatoma cells.

Wang and coworkers used gold nanoparticles which were loaded with the anticancer drug substance doxorubicin (P-gp substrate).¹³ They found that hyperthermia increased the expression of HSF-1 which depressed the expression of P-gp, thus decreased the efflux of doxorubicin and enhanced the cytotoxic effect in MCF-7/ADR cells.¹³ When cyanine dye-loaded nanoparticles were exposed to NIR laser irradiation, the ensuing hyperthermia was found to decrease the expression of MRP1, thus increasing cisplatin-prodrug cytotoxicity in A549 and A549R cells, and enhancing the ablation effect of the nanoparticles.¹⁴

Previous research has also reported that hyperthermia decreased MRP1 expression in HeLaMRP1 cells.¹⁶ In addition, P-gp monoclonal antibodies were included in oxidized carbon nanoparticles to reverse P-gp activity and to decrease etoposide (P-gp substrate) efflux in A549 and A549R cells.⁹⁶ Besides the photothermal effect mediated by oxidized carbon nanohorns, utilization of the P-gp monoclonal antibody suppressed the efflux activity of P-gp and increased the intracellular concentration of etoposide, and enhanced the cytotoxic effect of the nanoparticles.⁹⁶

Zeng et al¹⁸ were able to augment the photothermal effect of polydopamine-modified black phosphorus by inclusion of doxorubicin (P-gp substrate) and P-gp siRNA in nanosheets. P-gp siRNA downregulated P-gp and enhanced the anticancer cytotoxicity in MCF-7 and MCF-7/ADR cells. Moreover, Cheng et al⁹⁷ included a P-gp siRNA in polydopamine nanoparticles decorated with folic acid and these nanoparticles showed outstanding photothermal effect, P-gp downregulation, and a selective cell targeting ability mediated by the presence of folic acid in the formulation.

Nonionic surfactants which were shown to inhibit P-gp in vitro and in vivo^105–109 were included in the design of photothermal nanoparticles.^95,102 TPGS is a nonionic surfactant with P-gp inhibitory properties¹¹⁰ and was included in nanoparticles containing a photothermal agent indocyanine green, and doxorubicin.¹⁰² In the latter study, it was shown that TPGS decreased the expression of P-gp and enhanced the cytotoxicity of doxorubicin in SGC7901/VCR cells.¹⁰² To potentiate the photothermal effect of nanoparticles, inclusion of several molecules to inhibit membrane transporter activities was also investigated. Du et al included TPGS and nitric oxide donor molecules (N,N′-di-sec-butyl-N,N′-dinitroso-1,4-phenylenediamine [BNN6]) in polydopamine/doxorubicin nanoparticles.¹⁷ TPGS and the released nitric oxide decrease P-gp and MRP3 expression, and reduced intracellular ATP content, thus enhanced intracellular doxorubicin, and increased the cytotoxicity in HCC cells. Other studies reported using nitric oxide donor molecules as P-gp modulators in order to enhance the photothermal effect of nanoparticles.^98,99 In these studies, nitric oxide decrease the expression of P-gp on MCF-7 and MCF-7/ADR cells, thus reversed multidrug resistance and potentiated the effect of anticancer drug substances included in the nanoparticles, consequently, the photothermal effect was augmented.^98,99

Nanoparticles for Photothermal Effect and Modulation of Membrane Transporters In Vivo

In vivo studies were conducted in mice to compare the effect of multifunctional nanoparticles in the presence or absence of NIR light (Table 2). In these studies, researchers designed and characterized nanoparticles containing a photothermal agent, membrane transporter modulator, and/or a chemotherapeutic agent. Membrane transporter modulators used in in vivo studies were nonionic surfactants, siRNA, monoclonal antibody, and/or nitric oxide donor compounds to reverse multidrug resistance in tumors.^{14,17,18,95,96,98,99,104} Xenograft tumors were implanted into mice to investigate the effect of the multifunctional nanoparticles, with or without NIR light, on tumor volume, and the overall tumor growth in animals. Several studies showed a significant reduction in tumor volume and weight in mice treated with nanoparticles and exposed to NIR laser compared to control (without laser exposure; Table 2).^{14,17,18,95,96,98,99,104} Histopathological studies were also performed to assess the effect of nanoparticles components on other tissues and no side effects were reported on other organs such as heart, liver, and kidneys.^{14,17,18,95,96,98,99,104}

Pharmacokinetic studies conducted in Sprague–Dawley rats showed prolonged systemic circulation time of photothermal nanoparticles in blood compared to circulation of anticancer drug substances not loaded in nanoparticles.^18,97 The prolonged circulation time may increase the exposure of photothermal agents and anticancer drug substances to the tumor sites, enhance the uptake of the nanoparticles by the tumors, and achieve a maximum inhibition of cancer growth. Interestingly, one study reported a 152- and 12-fold increase in the maximal plasma concentration (C_max) and in the area under the plasma concentration time profile (AUC), respectively, in rats received intravenous P-cypate micellar formulation containing doxorubicin compared to control (rats receiving doxorubicin only).⁹⁵ After intravenous administration, a single dose of polydopamine nanoparticles containing doxorubicin, researchers reported a prolonged blood circulation of doxorubicin administered in the nanoparticles formulation noted as a seven-fold increase in half-life (t½) compared to rats received equivalent dose of free doxorubicin.¹⁷ The results from these preclinical studies in animals indicated a promising future for photothermal therapy when included in multifunctional nanoparticles to simultaneously reverse multidrug resistance by membrane transporter modulation and ablate human tumors.

Conclusions

Photothermal therapy seems a promising approach to treat patients with cancer diseases in the future. Gold nanoparticles are the most utilized type of nanoparticles in PTT. Targeting cancer by conjugating the PTT nanoparticles with monoclonal antibodies or by alternative coatings enhances the therapeutic efficacy of the PTT approach. In addition, the inclusion of membrane transporter modulators in PTT nanoparticles enhanced the efficacy of the formulation in vitro and in vivo. It seems that the current advancement in designing multifunctional nanoparticles will assist researchers to create more effective and safe nanoparticles for PTT by the inclusion of different substances in the formulation, with each having a specific role in the treatment of cancer diseases.

Despite the remarkable progress in the development of the photothermal concept, different challenges are still to be fine-tuned, and these can mainly affect the safety and efficacy of the developed therapies. The improvements could be directed toward the three components of the photothermal therapies: targeting molecules, linkers, and nanoparticles. The development of gold nanorods that are free from cetyltrimethylammonium bromide (CTAB), which, for example, is currently implemented by companies like Sona Nanotech Inc.,¹¹¹ could significantly reduce any potential toxicity of CTAB. Further research could also enhance the NIR penetration depth by optimizing the aspect ratio, shape, and composition of the selected nanoparticles. The targeting molecules could be optimized through the implementation of smaller antibody fragments or multispecific antibodies. The selection of efficient linkers that can specifically bind to the antibodies, without affecting the binding regions, while remaining stable within the physiological system is also essential and is currently the focus of different companies like SiMologics Ltd¹¹² and BroadPharm.¹¹³ Other enhancements could be achieved through the utilization of membrane transporter modulators, heat resistance blockers, and optimization of the cancer cell-death mechanisms (apoptosis vs necroses), and successful regulation of the tumor microenvironment. Moreover, many studies currently investigating the effect of PTT in cell cultures and animal models require follow-on clinical trials to confirm the overall efficacy in humans.

Supplemental Material

sj-docx-1-tct-10.1177_15330338231168016 - Supplemental material for Recent Advances in Photothermal Therapies Against Cancer and the Role of Membrane Transporter Modulators on the Efficacy of This Approach

Supplemental material, sj-docx-1-tct-10.1177_15330338231168016 for Recent Advances in Photothermal Therapies Against Cancer and the Role of Membrane Transporter Modulators on the Efficacy of This Approach by Ahmed A. Abdulhussein Al-Ali, Nameer Al Ward, Mohammad A. Obeid, Carsten Uhd Nielsen, Paul A. Mulheran and Mohammed M. Al Qaraghuli in Technology in Cancer Research & Treatment

Footnotes

Abbreviations

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Mohammed Al Qaraghuli is employed by the company SiMologics Ltd.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Nameer Al Ward

Mohammed M. Al Qaraghuli

Supplemental Material

Supplemental material for this article is available online.

References

WHO. Cancer. 2022. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed December 27, 2022.

Siegel

Miller

Fuchs

Jemal

. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708

Macmillan Cancer Support. Statistics Fact Sheet. 2022. https://www.macmillan.org.uk/dfsmedia/1a6f23537f7f4519bb0cf14c45b2a629/9468-10061/2022-cancer-statistics-factsheet.

Yabroff

Negoita

, et al. Association of the COVID-19 pandemic with patterns of statewide cancer services. J Natl Cancer Inst. 2022;114(6):907-909. doi:10.1093/jnci/djab122

Nurgali

Jagoe

Abalo

. Editorial: adverse effects of cancer chemotherapy: anything new to improve tolerance and reduce sequelae? Front Pharmacol. 2018;9:245. doi:10.3389/fphar.2018.00245

Majeed

Gupta

. Adverse effects of radiation therapy. In: StatPearls. StatPearls Publishing; 2022. http://www.ncbi.nlm.nih.gov/books/NBK563259/. Accessed December 27, 2022.

Han

Choi

. Advances in nanomaterial-mediated photothermal cancer therapies: toward clinical applications. Biomedicines. 2021;9(3):305. doi:10.3390/biomedicines9030305

Huang

El-Sayed

Qian

El-Sayed

. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J Am Chem Soc. 2006;128(6):2115-2120. doi:10.1021/ja057254a

Al Qaraghuli

. Biotherapeutic antibodies for the treatment of head and neck cancer: current approaches and future considerations of photothermal therapies. Front Oncol. 2020;10:2710. doi:10.3389/fonc.2020.559596

10.

Lovell

Yoon

Chen

. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat Rev Clin Oncol. 2020;17(11):657-674. doi:10.1038/s41571-020-0410-2

11.

Yang

Zhao

Wang

Lan

Song

. Low temperature photothermal therapy: advances and perspectives. Coord Chem Rev. 2022;454:214330. doi:10.1016/j.ccr.2021.214330

12.

Gupta

Malviya

. Understanding and advancement in gold nanoparticle targeted photothermal therapy of cancer. Biochim Biophys Acta BBA - Rev Cancer. 2021;1875(2):188532. doi:10.1016/j.bbcan.2021.188532

13.

Wang

Lin

Wang

, et al. Novel insights into combating cancer chemotherapy resistance using a plasmonic nanocarrier: enhancing drug sensitiveness and accumulation simultaneously with localized mild photothermal stimulus of femtosecond pulsed laser. Adv Funct Mater. 2014;24(27):4229-4239. doi:10.1002/adfm.201400015

14.

Deng

Tian

, et al. Multipronged design of light-triggered nanoparticles to overcome cisplatin resistance for efficient ablation of resistant tumor. ACS Nano. 2015;9(10):9626-9637. doi:10.1021/acsnano.5b05097

15.

Xia

Zhang

Shi

Chen

Wang

. Co-loading of photothermal agents and anticancer drugs into porous silicon nanoparticles with enhanced chemo-photothermal therapeutic efficacy to kill multidrug-resistant cancer cells. Colloids Surf B Biointerfaces. 2018;164:291-298. doi:10.1016/j.colsurfb.2018.01.059

16.

Souslova

A-B

. Multidrug-resistant Hela cells overexpressing MRP1 exhibit sensitivity to cell killing by hyperthermia: interactions with etoposide. Int J Radiat Oncol Biol Phys. 2004;60(5):1538-1551. doi:10.1016/j.ijrobp.2004.07.686

17.

Mao

Zhang

, et al. TPGS–galactose-modified polydopamine co-delivery nanoparticles of nitric oxide donor and doxorubicin for targeted chemo–photothermal therapy against drug-resistant hepatocellular carcinoma. ACS Appl Mater Interfaces. 2021;13(30):35518-35532. doi:10.1021/acsami.1c09610

18.

Zeng

Luo

Liu

, et al. Polydopamine-modified black phosphorous nanocapsule with enhanced stability and photothermal performance for tumor multimodal treatments. Adv Sci. 2018;5(10):1800510. doi:10.1002/advs.201800510

19.

Thakor

Gambhir

. Nanooncology: the future of cancer diagnosis and therapy. CA Cancer J Clin. 2013;63(6):395-418. doi:10.3322/caac.21199

20.

Obeid

Tate

Mullen

Ferro

. Lipid-based nanoparticles for cancer treatment. In: Grumezescu

, ed. Lipid nanocarriers for drug targeting. Elsevier; 2018:313-359. doi:10.1016/B978-0-12-813687-4.00008-6.

21.

Song

Qin

Huang

Fan

Chen

. Functional nanoprobes for ultrasensitive detection of biomolecules. Chem Soc Rev. 2010;39(11):4234-4243. doi:10.1039/c000682n

22.

Zhang

Gao

Chen

Liu

. Nanotechnology in cancer diagnosis: progress, challenges and opportunities. J Hematol OncolJ Hematol Oncol. 2019;12(1):137. doi:10.1186/s13045-019-0833-3

23.

. The enhanced permeability and retention (EPR) effect: the significance of the concept and methods to enhance its application. J Pers Med. 2021;11(8):771. doi:10.3390/jpm11080771

24.

Sangboonruang

Semakul

Obeid

, et al. Potentiality of melittin-loaded niosomal vesicles against vancomycin-intermediate Staphylococcus aureus and staphylococcal skin infection. Int J Nanomedicine. 2021;16:7639-7661. doi:10.2147/IJN.S325901

25.

Aljabali

AAA

Obeid

. Inorganic-organic nanomaterials for therapeutics and molecular imaging applications. Nanosci Nanotechnol-Asia. 2020; 10(6):748-765.

26.

Alyamani

Obeid

Tate

Ferro

. Exosomes: fighting cancer with cancer. Ther Deliv. 2019;10(1):37-61. doi:10.4155/tde-2018-0051

27.

Hansen

Petersen

Henriksen

, et al. Positron emission tomography based elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano. 2015;9(7):6985-6995. doi:10.1021/acsnano.5b01324

28.

Wong

Ulmschneider

Searson

. Quantitative analysis of the enhanced permeation and retention (EPR) effect. PLoS One. 2015;10(5):e0123461. doi:10.1371/journal.pone.0123461

29.

Obeid

Gany

SAS

Gray

Young

Igoli

Ferro

. Niosome-encapsulated balanocarpol: compound isolation, characterisation, and cytotoxicity evaluation against human breast and ovarian cancer cell lines. Nanotechnology. 2020;31(19):195101. doi:10.1088/1361-6528/ab6d9c

30.

Obeid

Alyamani

Amawi

, et al. siRNA delivery to melanoma cells with cationic niosomes. Methods Mol Biol Clifton NJ. 2021;2265:621-634. doi:10.1007/978-1-0716-1205-7_42

31.

Matsumoto

Nichols

Toh

, et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat Nanotechnol. 2016;11(6):533-538. doi:10.1038/nnano.2015.342

32.

Xie

Fan

, et al. Emerging combination strategies with phototherapy in cancer nanomedicine. Chem Soc Rev. 2020;49(22):8065-8087. doi:10.1039/D0CS00215A

33.

Chen

Ning

Zhou

, et al. Nanomaterials as photothermal therapeutic agents. Prog Mater Sci. 2019;99:1-26. doi:10.1016/j.pmatsci.2018.07.005

34.

Zhu

Feng

Chang

, et al. Temperature-feedback upconversion nanocomposite for accurate photothermal therapy at facile temperature. Nat Commun. 2016;7:10437. doi:10.1038/ncomms10437

35.

Man

Jia

. Photothermal effect of superparamagnetic Fe₃O₄ nanoparticles irradiated by near-infrared Laser. J Nanomater. 2020;2020:e2832347. doi:10.1155/2020/2832347

36.

Chu

Shao

Peng

, et al. Near-infrared laser light mediated cancer therapy by photothermal effect of Fe3O4 magnetic nanoparticles. Biomaterials. 2013;34(16):4078-4088. doi:10.1016/j.biomaterials.2013.01.086

37.

Ahmadian

Janas

Eftekhari

Zare

. Application of carbon nanotubes in sensing/monitoring of pancreas and liver cancer. Chemosphere. 2022;302:134826. doi:10.1016/j.chemosphere.2022.134826

38.

Liang

Diao

Wang

, et al. Tumor metastasis inhibition by imaging-guided photothermal therapy with single-walled carbon nanotubes. Adv Mater. 2014;26(32):5646-5652. doi:10.1002/adma.201401825

39.

Yang

Zhang

Sun

Lee

Liu

. Graphene in mice: ultrahigh in vivo tumor uptake and efficient photothermal therapy. Nano Lett. 2010;10(9):3318-3323. doi:10.1021/nl100996u

40.

Xie

Huang

Jiang

Miao

. Semiconducting polymer nanoenzymes with photothermic activity for enhanced cancer therapy. Angew Chem Int Ed. 2018;57(15):3995-3998. doi:10.1002/anie.201800511

41.

Sun

Xie

Tang

, et al. Ultrasmall black phosphorus quantum dots: synthesis and use as photothermal agents. Angew Chem Int Ed. 2015;54(39):11526-11530. doi:10.1002/anie.201506154

42.

Fan

Shen

, et al. Intelligent MnO2 nanosheets anchored with upconversion nanoprobes for concurrent pH-/H2O2-responsive UCL imaging and oxygen-elevated synergetic therapy. Adv Mater. 2015;27(28):4155-4161. doi:10.1002/adma.201405141

43.

Elahi

Kamali

Baghersad

. Recent biomedical applications of gold nanoparticles: a review. Talanta. 2018;184:537-556. doi:10.1016/j.talanta.2018.02.088

44.

Zhang

Wang

, et al. Ph and near-infrared light dual-stimuli responsive drug delivery using DNA-conjugated gold nanorods for effective treatment of multidrug resistant cancer cells. J Control Release Off J Control Release Soc. 2016;232:9-19. doi:10.1016/j.jconrel.2016.04.001

45.

Aljabali

AAA

Zoubi

MSA

Al-Batanyeh

, et al. Gold-coated plant virus as computed tomography imaging contrast agent. Beilstein J Nanotechnol. 2019;10:1983-1993. doi:10.3762/bjnano.10.195

46.

Dykman

Khlebtsov

. Gold nanoparticles in biomedical applications: recent advances and perspectives. Chem Soc Rev. 2012;41(6):2256-2282. doi:10.1039/C1CS15166E

47.

Huang

El-Sayed

. Gold nanoparticles: optical properties and implementations in cancer diagnosis and photothermal therapy. J Adv Res. 2010;1(1):13-28. doi:10.1016/j.jare.2010.02.002

48.

Bianchi

Mooney

Cornejo

, et al. Thermal analysis of laser irradiation-gold nanorod combinations at 808 nm, 940 nm, 975 nm and 1064 nm wavelengths in breast cancer model. Int J Hyperthermia. 2021;38(1):1099-1110. doi:10.1080/02656736.2021.1956601

49.

Shao

Zhang

Zhao

Deng

. Mesoporous silica coated polydopamine functionalized reduced graphene oxide for synergistic targeted chemo-photothermal therapy. ACS Appl Mater Interfaces. 2017;9(2):1226-1236. doi:10.1021/acsami.6b11209

50.

Cui

Wen

Xie

Yao

. Oxygen self-enriched nanoplatform combined with US imaging and chemo/photothermal therapy for breast cancer. Nanomed. 2020;29:102238. doi:10.1016/j.nano.2020.102238

51.

Obeid

Teeravatcharoenchai

Connell

, et al. Examination of the effect of niosome preparation methods in encapsulating model antigens on the vesicle characteristics and their ability to induce immune responses. J Liposome Res. 2021;31(2):195-202. doi:10.1080/08982104.2020.1768110

52.

Aboeleneen

Scully

Harris

Sterin

Day

. Membrane-wrapped nanoparticles for photothermal cancer therapy. Nano Converg. 2022;9(1):37. doi:10.1186/s40580-022-00328-4

53.

Shen

Lin

, et al. Homing of ICG-loaded liposome inlaid with tumor cellular membrane to the homologous xenografts glioma eradicates the primary focus and prevents lung metastases through phototherapy. Biomater Sci. 2018;6(9):2410-2425. doi:10.1039/C8BM00604K

54.

Wang

Cai

, et al. Surface-Functionalized modified copper sulfide nanoparticles enhance checkpoint blockade tumor immunotherapy by photothermal therapy and antigen capturing. ACS Appl Mater Interfaces. 2019;11(15):13964-13972. doi:10.1021/acsami.9b01107

55.

Shipunova

Belova

Kotelnikova

, et al. Photothermal therapy with HER2-targeted silver nanoparticles leading to cancer remission. Pharmaceutics. 2022;14(5):1013. doi:10.3390/pharmaceutics14051013

56.

Ha Lien

Phan

Van Khanh

, et al. Applications of mesoporous silica-encapsulated gold nanorods loaded doxorubicin in chemo-photothermal therapy. ACS Omega. 2020;5(32):20231-20237. doi:10.1021/acsomega.0c01939

57.

Xiao

Fan

Wang

Sun

Zheng

Yan

. Porous Pd nanoparticles with high photothermal conversion efficiency for efficient ablation of cancer cells. Nanoscale. 2014;6(8):4345-4351. doi:10.1039/C3NR06843A

58.

Vines

Lim

Park

. Contemporary polymer-based nanoparticle systems for photothermal therapy. Polymers (Basel). 2018;10(12):1357. doi:10.3390/polym10121357

59.

Obeid

Qaraghuli

Alsaadi

, et al. Delivering natural products and biotherapeutics to improve drug efficacy. Ther Deliv. 2017;8(11):947-956. doi:10.4155/tde-2017-0060

60.

Weiner

Surana

Wang

. Antibodies and cancer therapy: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10(5):317-327. doi:10.1038/nri2744

61.

Zahavi

Weiner

. Monoclonal antibodies in cancer therapy. Antibodies. 2020;9(3): 34. doi:10.3390/antib9030034

62.

Hendriks

Choi

de Bruyn

Wiersma

Bremer

. Chapter 7: Antibody-based cancer therapy: successful agents and novel approaches. In: Galluzzi

, ed. International Review of Cell and Molecular Biology. Vol 331. Academic Press; 2017:289-383. doi:10.1016/bs.ircmb.2016.10.002.

63.

Jiang

Wang

Deng

, et al. The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res CR. 2020;39:204. doi:10.1186/s13046-020-01709-5

64.

Zheng

Wang

Rao

. Chapter 27: The chemistry in surface functionalization of nanoparticles for molecular imaging. In: Ross

Gambhir

, eds. Molecular imaging (second edition). Academic Press; 2021:493-516. doi:10.1016/B978-0-12-816386-3.00021-1.

65.

Cheng

Bao

Chen

, et al. Microwave-triggered/HSP-targeted gold nano-system for triple-negative breast cancer photothermal therapy. Int J Pharm. 2021;593:120162. doi:10.1016/j.ijpharm.2020.120162

66.

Qian

Hou

, et al. A dual-targeted hyaluronic acid-gold nanorod platform with triple-stimuli responsiveness for photodynamic/photothermal therapy of breast cancer. Acta Biomater. 2019;83:400-413. doi:10.1016/j.actbio.2018.11.026

67.

Tan

Hou

Liu

, et al. CD133 Antibody targeted delivery of gold nanostars loading IR820 and docetaxel for multimodal imaging and near-infrared photodynamic/photothermal/chemotherapy against castration resistant prostate cancer. Nanomedicine Nanotechnol Biol Med. 2020;27:102192. doi:10.1016/j.nano.2020.102192

68.

Bolaños

Kogan

Araya

. Capping gold nanoparticles with albumin to improve their biomedical properties. Int J Nanomedicine. 2019;14:6387-6406. doi:10.2147/ijn.S210992

69.

Silva

Ladchumananandasivam

Nascimento

JHO

, et al. Multifunctional chitosan/gold nanoparticles coatings for biomedical textiles. Nanomaterials. 2019;9(8):1064.

70.

Essa

Kondiah

PPD

Choonara

Pillay

. The Design of Poly(lactide-co-glycolide) nanocarriers for medical applications. Front Bioeng Biotechnol. 2020;8:1–20. doi:10.3389/fbioe.2020.00048

71.

Thomas

Weihua

. Rethink of EGFR in cancer with its kinase independent function on board. Front Oncol. 2019;9:1–16. doi:10.3389/fonc.2019.00800

72.

Fernández-Cabada

Sánchez

Pisarchyk

Serrano Olmedo

Ramos

. Optical hyperthermia using anti-epidermal growth factor receptor-conjugated gold nanorods to induce cell death in glioblastoma cell lines. J Nanosci Nanotechnol. 2016; 16:7689-7695. doi:10.1166/jnn.2016.12570

73.

Zhang

Kim

Jin

Woo

Piao

Moon

. Near-infrared photothermal therapy using anti-EGFR-gold nanorod conjugates for triple negative breast cancer. Oncotarget. 2017;8(49):86566-86575. doi:10.18632/oncotarget.21243

74.

Knights

Freear

McLaughlan

. Improving plasmonic photothermal therapy of lung cancer cells with anti-EGFR targeted gold nanorods. Nanomaterials. 2020;10(7):1307. doi:10.3390/nano10071307

75.

Zhou

Song

Wang

, et al. BSA-bioinspired gold nanorods loaded with immunoadjuvant for the treatment of melanoma by combined photothermal therapy and immunotherapy. Nanoscale. 2018;10(46):21640-21647. doi:10.1039/C8NR05323E

76.

Dong

Yang

Wan

, et al. Her2-Functionalized gold-nanoshelled magnetic hybrid nanoparticles: a theranostic agent for dual-modal imaging and photothermal therapy of breast cancer. Nanoscale Res Lett. 2019;14(1):235. doi:10.1186/s11671-019-3053-4

77.

Manivasagan

Nguyen

Jun

, et al. Anti-EGFR antibody conjugated thiol chitosan-layered gold nanoshells for dual-modal imaging-guided cancer combination therapy. J Control Release Off J Control Release Soc. 2019;311-312:26-42. doi:10.1016/j.jconrel.2019.08.007

78.

Liang

Sun

, et al. Cytokine-induced killer cells-assisted tumor-targeting delivery of Her-2 monoclonal antibody-conjugated gold nanostars with NIR photosensitizer for enhanced therapy of cancer. J Mater Chem B. 2020;8(36):8368-8382. doi:10.1039/D0TB01391A

79.

Chen

Liu

, et al. Assessment of polyethylene glycol-coated gold nanoparticle toxicity and inflammation in vivo using NF-κB reporter mice. Int J Mol Sci. 2020;21(21):1–16. doi:10.3390/ijms21218158

80.

Bharti

Nagaich

Pal

Gulati

. Mesoporous silica nanoparticles in target drug delivery system: a review. Int J Pharm Investig. 2015;5(3):124-133. doi:10.4103/2230-973x.160844

81.

Cho

Gorham

Pettibone

Liu

Tan

Hackley

. Parallel multi-parameter study of PEI-functionalized gold nanoparticle synthesis for bio-medical applications: part 1—a critical assessment of methodology, properties, and stability. J Nanoparticle Res. 2019;21(8):188. doi:10.1007/s11051-019-4621-3

82.

Lee

Chatterjee

Lee

Krishnan

. Gold nanoparticles in breast cancer treatment: promise and potential pitfalls. Cancer Lett. 2014;347(1):46-53. doi:10.1016/j.canlet.2014.02.006

83.

Gao

Tong

, et al. Mitochondria-targeted nanomedicine for enhanced efficacy of cancer therapy. Front Bioeng Biotechnol. 2021;9:720508. doi:10.3389/fbioe.2021.720508

84.

Zhang

Liu

Xie

. Mitochondria-targeting organic nanoparticles for enhanced photodynamic/photothermal therapy. ACS Appl Mater Interfaces. 2020;12(27):30077-30084. doi:10.1021/acsami.0c06144

85.

Wang

Qiao

Lin

. Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy. J Nanobiotechnology. 2022;20(1):42. doi:10.1186/s12951-022-01244-9

86.

Higgins

. ABC Transporters: physiology, structure and mechanism–an overview. Res Microbiol. 2001;152(3-4):205-210. doi:10.1016/s0923-2508(01)01193-7

87.

Lee

VHL

. Membrane transporters. Eur J Pharm Sci. 2000;11:S41-S50. doi:10.1016/S0928-0987(00)00163-9

88.

Dean

Moitra

Allikmets

. The human ATP-binding cassette (ABC) transporter superfamily. Hum Mutat. 2022;43(9):1162-1182. doi:10.1002/humu.24418

89.

Hediger

Romero

Peng

Rolfs

Takanaga

Bruford

. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins introduction. Pflugers Arch. 2004;447(5):465-468. doi:10.1007/s00424-003-1192-y

90.

International Transporter Consortium, Giacomini

Huang

, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236. doi:10.1038/nrd3028

91.

Gottesman

Fojo

Bates

. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48-58. doi:10.1038/nrc706

92.

Szakács

Paterson

Ludwig

Booth-Genthe

Gottesman

. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5(3):219-234. doi:10.1038/nrd1984

93.

Bukowski

Kciuk

Kontek

. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21(9):3233. doi:10.3390/ijms21093233

94.

Saraswathy

Gong

. Different strategies to overcome multidrug resistance in cancer. Biotechnol Adv. 2013;31(8):1397-1407. doi:10.1016/j.biotechadv.2013.06.004

95.

Cui

, et al. pH- and NIR light-responsive micelles with hyperthermia-triggered tumor penetration and cytoplasm drug release to reverse doxorubicin resistance in breast cancer. Adv Funct Mater. 2015;25(17):2489-2500. doi:10.1002/adfm.201404484

96.

Wang

Zhang

, et al. Overcoming multidrug resistance by a combination of chemotherapy and photothermal therapy mediated by carbon nanohorns. J Mater Chem B. 2016;4(36):6043-6051. doi:10.1039/C6TB01469K

97.

Cheng

Nie

Gao

, et al. A multifunctional nanoplatform against multidrug resistant cancer: merging the best of targeted chemo/gene/photothermal therapy. Adv Funct Mater. 2017;27(45):1704135. doi:10.1002/adfm.201704135

98.

Wang

Qin

, et al. NIR-II light triggered nitric oxide release nanoplatform combined chemo-photothermal therapy for overcoming multidrug resistant cancer. J Mater Chem B. 2021;9(6):1698-1706. doi:10.1039/D0TB02626C

99.

Huang

Zhong

, et al. Nitric oxide-sensitized mitoxantrone chemotherapy integrated with photothermal therapy against multidrug-resistant tumors. Mater Chem Front. 2021;5(15):5798-5805. doi:10.1039/D1QM00523E

100.

Lopes-Rodrigues

Sousa

Vasconcelos

. Curcumin as a modulator of P-glycoprotein in cancer: challenges and perspectives. Pharm Basel Switz. 2016;9(4):71. doi:10.3390/ph9040071

101.

Xing

Zhang

Chen

Liu

Cai

. Mesoporous polydopamine nanoparticles with co-delivery function for overcoming multidrug resistance via synergistic chemo-photothermal therapy. Nanoscale. 2017;9(25):8781-8790. doi:10.1039/C7NR01857F

102.

Gao

Bai

Chen

Ei Fakhri

Wang

. Self-Assembly nanoparticles for overcoming multidrug resistance and imaging-guided chemo-photothermal synergistic cancer therapy. Int J Nanomedicine. 2020;15(6499):809-819. doi:10.2147/IJN.S232449

103.

Gao

Bao

Mao

, et al. Rapid development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020;369(6499):1–9. doi:10.1126/science.abc1932

104.

Yang

Liu

, et al. Enhanced photothermal-photodynamic therapy by indocyanine green and curcumin-loaded layered MoS2 hollow spheres via inhibition of P-glycoprotein. Int J Nanomedicine. 2021;16:433-442. doi:10.2147/IJN.S275938

105.

. Relationships between the hydrophilic-lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in caco-2 cells and rat intestines. J Control Release Off J Control Release Soc. 2003;90(1):37-48. doi:10.1016/s0168-3659(03)00163-9

106.

Rege

Kao

JPY

Polli

. Effects of nonionic surfactants on membrane transporters in caco-2 cell monolayers. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2002;16(4-5):237-246. doi:10.1016/s0928-0987(02)00055-6

107.

Al-Ali

AAA

Nielsen

Steffansen

Holm

Nielsen

. Nonionic surfactants modulate the transport activity of ATP-binding cassette (ABC) transporters and solute carriers (SLC): relevance to oral drug absorption. Int J Pharm. 2019;566:410-433. doi:10.1016/j.ijpharm.2019.05.033

108.

Al-Ali

AAA

Quach

JRC

Bundgaard

Steffansen

Holm

Nielsen

. Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats. Int J Pharm. 2018;543(1-2):352-360. doi:10.1016/j.ijpharm.2018.04.006

109.

Al-Ali

AAA

Steffansen

Holm

Nielsen

. Nonionic surfactants increase digoxin absorption in Caco-2 and MDCKII MDR1 cells: impact on P-glycoprotein inhibition, barrier function, and repeated cellular exposure. Int J Pharm. 2018;551(1-2):270-280. doi:10.1016/j.ijpharm.2018.09.039

110.

Hanke

May

Rozehnal

Nagel

Siegmund

Weitschies

. Commonly used nonionic surfactants interact differently with the human efflux transporters ABCB1 (p-glycoprotein) and ABCC2 (MRP2). Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Verfahrenstechnik EV. 2010;76(2):260-268. doi:10.1016/j.ejpb.2010.06.008

111.

Sona Nanotech - Next generation gold nanorods. Sona Nanotech. https://www.sonanano.com/. Accessed February 19, 2023.

112.

SiMologics Ltd. https://www.simologics.co.uk/. Accessed February 19, 2023.

113.

BroadPharm. https://broadpharm.com/. Accessed February 19, 2023.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.17 MB