Introduction

Drug delivery systems generally maximize the efficiency of drug delivery to a target site. Because of the enhanced permeability and retention effect, tumor targeting is possible even with simple nanoparticles (NPs) (Iyer et al. 2006; Shim et al. 2020a, b; Le et al. 2021). However, clinical studies have reported many controversial results and limitations associated with this effect. Therefore, ligand-modified NPs have been studied as an alternative for increasing the distribution to the target site (Le et al. 2019; Shim et al. 2020b; Yang et al. 2020). However, ligand-engineered NPs compensate for the shortcomings of conventional drugs only to some extent. Furthermore, these drug delivery systems do not impact the pharmacokinetic and biodistribution profiles of the drug, and many drugs were reportedly delivered to non-target sites or excreted from the body (Shim et al. 2017).

Photoresponsive materials activated by light can help overcome the limitations of conventional drug delivery systems (Shim et al. 2017; Ko et al. 2018; Le et al. 2019; Wu et al. 2021). Photodynamic therapy (PDT) involves the activation of a drug by light of a specific wavelength. Several PDT agents have received FDA approval, and are currently being marketed (Mang 2004). Moreover, various substances that generate thermal energy by near-infrared (NIR) light are being studied as photothermal therapeutic agents (Ko et al. 2018; Le et al. 2019; Shim et al. 2020a, b; Yang et al. 2020; Wu et al. 2021). The most attractive feature of phototherapy is that the drug can be activated only in the target area. Many attempts have been made to apply photosensitizers in anticancer therapy as photosensitive mechanism induces apoptosis without causing drug resistance (Brackett and Gollnick 2011). However, most photosensitive materials have poor solubility and low biocompatibility. Porphyrin-based photosensitizers possess limited self-activation at non-target sites, and as a result, the treatment has to be performed in a dark room (Moriwaki et al. 2001). Additionally, safety concerns also limit the use of materials with photothermal effects (Miao, et al. 2013a, b; Miao, et al. 2013a, b).

Lipid-based NPs can overcome the drawbacks of photosensitive materials owing to the following advantages (Fig. 1). First, lipid-based NPs used for drug delivery are known to be safe (Al-Jamal and Kostarelos 2011). Lipid NPs have been applied in a variety of platforms, from nanopharmaceuticals encapsulated with antibiotics or anticancer drugs to coronavirus disease vaccines (which have recently emerged as a hot topic); lipid NPs have thus been established as a good fit for nanomedicine (Pacheco et al. 2020; Schoenmaker et al. 2021). Second, lipid NPs are compatible with photosensitive materials. Lipid NPs are formed by self-assembly through hydrophobic interactions among lipids; this process can be easily controlled by controlling the ambient conditions. In other words, it is possible to change the structure of the lipid NPs by modulating the environment using a photosensitizer; this mechanism can be useful for controlling the release of drugs. It is also possible to introduce various moieties not only into the outer and inner spaces of the lipid NPs, but also into the space between the two layers of the lipid bilayer. Photosensitive substances and therapeutic agents with different physicochemical properties can be mounted in different spaces within the lipid NPs. Therefore, lipid NPs are highly suitable as drug delivery systems for combined phototherapy. We herein present a review of recent studies on photosensitive lipid NPs, focusing on the types of photosensitizers and the design of NPs. We also discuss the current status and challenges in translational research on these NP.

Fig. 1
figure 1

Lipid-based photoresponsive drug delivery systems. A Platinum prodrug and Ce6-loaded lipid NP for anticancer photochemotherapy. Permission from Yang et al. (2021). B Lipid-coated carbon nanotube for photothermal-gene therapy. Permission from Zhao et al. (2021). C Photosensitizer and iron oxide nanocluster-loaded lipid NP for photo/chemodynamic therapy. Permission from Tang et al. (2018). HGNPs are hollow spheres and have greater photothermal conductivity than GNPs due to their NIR surface plasmon tunability. Thermosensitive lipid NPs were formulated using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; this lipid was selected due to its relatively low phase transition temperature (41 °C). The lipid film was hydrated with the HGNP or GNP solution to produce HGNP-NPs or GNP-NPs, respectively. DOX was then incorporated into the liposomes by the remote loading method. DOX was released from the lipid NPs upon NIR irradiation which caused hyperthermia-mediated destruction of the lipid NPs. HGNP has a much higher light-to-heat conversion efficiency than GNP—in fact, GNP requires five times the amount of light required by HGNP to reach the same temperature. Poly(vinylpyrrolidone), which is used as a stabilizing agent in HGNP synthesis, was reported to contribute to the red-shifted surface plasmon resonance absorption peak at 800-nm. Treatment with DOX/HGNPs (+ NIR) showed a remarkable reduction in tumor volume that was 2.77- or 2.12-fold lower than that due to treatment with free DOX or HGNP-TL (+ NIR), respectively.

Liposomal iridium nanocrystals (IrNCs) have been applied to overcome hypoxic conditions in solid tumors, resulting in improved efficacy of radiotherapy (Feng et al. 2018). Liposomal IrNCs exert catalytic activity to degrade H2O2 to O2 under NIR treatment, leading to increased tumor oxygenation; this increased oxygenation was reported to sensitize the tumor tissue to radiotherapy. Liposomal IrNCs were formulated for prolonged blood circulation and tumor retention. An intravenous injection of IrNC in 4T1 tumor-bearing mice showed saturated tumor accumulation of the IrNCs at 8 h after injection. Moreover, liposomal IrNCs caused a significant decrease in hypoxia levels in tumors after NIR irradiation. Mice treated with liposomal IrNCs and exposed to NIR irradiation and X-ray radiation (6 Gy) showed significantly suppressed tumor growth compared to the mice in the groups that received either phototherapy or radiotherapy alone.

Poly-branched Au–Pd bimetallic-nanoflower-coated betulinic acid lipid NPs (BA-Lips@Pd@Au NFs) showed great potential when applied in photothermal therapy (PTT) combined with chemotherapy (Liu et al. 2018). The BA-Lips@Pd@Au NFs were composed of soya lecithin, cholesterol, and betulinic acid, and coated with Pd seeds and Au growth solution in a layer-by-layer manner. The BA-Lips@Pd@Au NFs can generate heat upon 808-nm laser irradiation; this leads to phase transition and triggers drug release. BA-Lips@Pd@Au NFs were intratumorally injected into mice bearing U14 cells under 808-nm irradiation. These NPs caused tumor cell ablation due to local hyperthermia, and thus exhibited antitumor activity.

Photoswitchable chemicals

Studies on photoswitchable chemical-encapsulated lipid NPs are summarized in Table 4. A photoswitchable system was formulated by introducing an azobenzene moiety into lipid NPs (Liu and An, 2019). Phosphatidyl choline-based lipid NPs were used for encapsulating curcumin and 4-butylazobenzene-4-hexyloxy-trimethyl-ammoniumtrifluoro-acetate (BHA), which can be isomerized upon ultraviolet (UV) irradiation. BHA inserted into the BHA-curcumin-NP isomerizes in response to light, and curcumin is released when the lipid bilayer structure of the liposome is breached. Approximately 90% of the curcumin in the BHA- curcumin-NP was observed to be released in 6 h under UV irradiation. Additionally, UV and visible light irradiation were able to alternatively control drug release.

Table 4 Examples of photoswitchable chemical-encapsulated lipid nanoparticles
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UV-induced rotation of molecular motor liposomes can facilitate the release of cargo molecules (Ribovski et al. 2020). The tetrapodal molecular motor (5,5′-(9-(2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ylidene)-9H-fluorene-3,6-diyl)diisophthalic acid) can be loaded into the hydrophobic regions of the lipid NPs and unidirectionally rotated using UV light. Photoisomerization of molecular motors in liposomes can lead to disassembly of the nanostructures, resulting in the release of the cargo drug.

DNA oligonucleotide-attached lipid NPs can be assembled or disassembled by various stimuli including UV light (Hernández-Ainsa et al. 2016). Trans-azobenzene-oligonucleotide (AZO-ON) and cis-AZO-ON-modified lipid NPs showed differences in the degree of lipid NP assembly. While it was easy to assemble lipid NPs with trans-AZO-ON, it was more difficult to assemble lipid NPs with cis-AZO-ON. When irradiated with light at a wavelength of 365-nm, trans-AZO-ON gets converted to cis-AZO-ON; irradiation with light at a wavelength of 420-nm causes the conversion of cis-AZO-ON to trans-AZO-ON. Thus, the assembly and disassembly of lipid NPs can be controlled by irradiating with the light of different wavelengths. This concept can be applied to regulate drug release and control the behavior of lipid NPs.

Carbon-based materials

Studies on carbon-modified lipid NPs are summarized in Table 5. Lipid-coated carbon nanotubes were utilized in conjunction with small interfering RNA for photothermal gene therapy (Zhao et al. 2021). Carbon nanotubes were coated with peptide lipids and sucrose laurate, and this complex exhibited a phase transition temperature of 42 °C. Due to the positive charge of the peptide lipid, small interfering RNA can be loaded onto the carbon nanotube surface. Irradiation with NIR light leads to an increase in temperature, which releases the lipid layer from carbon nanotube; this consequently results in the release of the small interfering RNA into the cytoplasm.

Table 5 Examples of carbon or polymer-modified lipid nanoparticles
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Liposomal DOX was coated with graphene oxide for chemo-PTT (Hashemi et al. 2018). Graphene-coated liposomes were prepared using the layer-by-layer method. First, DOX was incorporated into the cationic lipid NPs through remote loading. Then, the surface of the cationic liposome was coated with graphene oxide by electrostatic attraction. Finally, the liposome was coated with the graphene oxide modified with poly-l-lysine (a cationic polymer) to obtain graphene-coated liposomes. The outer layer of the graphene-coated liposomes contributes to the intracellular delivery of the drug because of its positive charge. Because the layer-by-layer method uses electrostatic attraction and can easily cause precipitation, it is important to optimize the concentration of each component to formulate stable NPs. Further studies on in vivo applications of these liposomes are required.

Polymers

Studies on polymer-modified lipid NPs are summarized in Table 5. A malachite green moiety was adopted as a photoresponsive material to trigger the release of drugs from lipid NPs (Uda et al. 2016). Lecithin-based lipid NPs were loaded with a fluorescent dye. The lipid NPs were formulated with egg yolk lecithin and chloroform, and the fluorescent dye was encapsulated at the aqueous core phase. Under UV light, the malachite moiety photoisomerizes, and the positively charged moiety binds to the lipid NPs through electrostatic interactions. When the malachite moiety binds to the lipid NPs, it releases the encapsulated fluorescent dye due to membrane destabilization.

Lipid/polydopamine hybrid NPs have been formulated for tumor-targeted PTT (Yang et al. 2020). Anionic lipid NPs, including maleimide-conjugated lipids, were co-extruded with polydopamine to produce maleimide-modified lipid/polydopamine hybrid NPs. Anti-claudin 3 antibody was added to the NPs through a maleimide-thiol reaction. Antibody-modified NPs bind strongly to tumor cells in a claudin 3-specific manner. The increased accumulation of NPs in the tumor results in a potent photothermal ablation of the tumor.

Translational research and perspectives

PDT is the mainstay of phototherapy, and several drugs have been approved by the Food and Drug Administration (Allison et al. 2004) in this regard (Table 6). Most of these drugs have been approved for use in dermal applications. When free drugs are administered, it is impossible to target a specific organ or lesion, and there is a high possibility that they will eventually be activated in a non-target organ. In addition, because the depth of light irradiation is shallow, the range of indications is limited if the light is applied to the body externally (Arslan et al. 2018). One solution is the development of medical devices that facilitate the endoscopic application of light. In the case of Photofrin®, an optiguide fiber optic diffuser was developed for irradiating the lungs using endoscopically applied light (Harewood et al. 2005).

Table 6 FDA-approved photodynamic therapy agents
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A nanoformulation of photosensitizers is a promising solution to control the systemic distribution and activity of photosensitizers. Despite the various research results described above, a photosensitizer drug formulated with NPs has not yet been developed. Currently, a phase 1/2 clinical trial (NCT02367547) is underway to study the application of PDT against cancer using a nanoscale lipid vesicle gel formulation (Salmivuori et al. 2020). In addition, PTT therapy using silica-GNPs has been evaluated in a human study (NCT01270139). PTT using implanted NPs has been applied for the treatment of atherosclerosis. Significant lesion reduction was observed after treatment, and the side effects were less severe than those with stenting (Kharlamov et al. 2015, 2017).

Among the liposomal drugs currently being tested in clinical trials, ThermoDox® is noteworthy (Swenson et al. 2015; Lyon et al. 2017). ThermoDox® is a system that releases DOX sealed in lysolipid thermally sensitive liposomes at temperatures greater than 40 °C. Thus, it is possible to achieve a local DOX concentration in the lesion that is 25-fold higher than that achieved by conventional systemic administration (Bulbake et al. 2017). A phase 3 clinical trial in primary liver cancer patients is underway to evaluate the effectiveness of ThermoDox®/OPTIMA. This system is used in combination with thermal treatments such as ThermoDox® and radiofrequency thermal ablation, microwave hyperthermia, or high-intensity focused ultrasound (Tagami and Ozeki 2017). ThermoDox® alone is being evaluated preclinically for efficacy against bladder cancer. If an external stimulus that generates heat is replaced with a light source, then the expandability of this nanoplatform will be high.

Conclusion

Although there have been many interesting studies, photoresponsive material-based NPs that can be applied clinically are yet to be developed. However, several lipid NPs have already been clinically approved. The fact that there are many approved lipid nanoparticles implies that the lipid NPs are relatively safe, and that experience has been accumulated with regard to the manufacturing process. For the development of photoresponsive material-based NPs, an appropriate lipid formulation should be developed to increase the biocompatibility of the photosensitive materials. In addition, medical devices capable of applying light locally to the lesion should be developed. Although several challenges remain, photosensitive lipid nanoparticles show potential for application as a non-invasive treatment technology.