Combination Therapy Of Photodynamic Therapy Research Articles

Deep near infrared light-excited stable synergistic photodynamic and photothermal therapies based on P-IR890 nano-photosensitizer constructed via a non-cyanine dye

The cyanine dyes represented by IR780 can achieve synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) under the stimulation of near-infrared (NIR) light (commonly 808 nm). Unfortunately, the stability of NIR-excited cyanine dyes is not satisfactory. These cyanine dyes can be attacked by self-generated reactive oxygen species (ROS) during PDT processes, resulting in structural damage and rapid degradation, which is fatal for phototherapy. To address this issue, a novel non-cyanine dye (IR890) was elaborately designed and synthesized by our team. The maximum absorption wavelength of IR890 was located in the deep NIR region (ca. 890 nm), which was beneficial for further improving tissue penetration depth. Importantly, IR890 exhibited good stability when continuously illuminated by deep NIR light. To improve the hydrophilicity and biocompatibility, the hydrophobic IR890 dye was grafted onto the side chain of hydrophilic polymer (POEGMA-b-PGMA-g-CCH) via click chemistry. Then, the synthesized POEGMA-b-PGMA-g-IR890 amphiphilic polymer was utilized to prepare P-IR890 nano-photosensitizer via self-assembly method. Under irradiation with deep NIR light (850 nm, 0.5 W/cm2, 10 min), the dye degradation rate of P-IR890 was less than 5%. However, IR780 was almost completely degraded with the same light output power density and irradiation duration. In addition, P-IR890 could stably generate a large number of ROS and heat at the same time. It was rarely reported that the stable synergistic combination therapy of PDT and PTT could be efficiently performed by a single photosensitizer via irradiation with deep NIR light. P-IR890 exhibited favorable anti-tumor outcomes through apoptosis pathway. Therefore, the P-IR890 could provide a new insight into the design of photosensitizers and new opportunities for synergistic combination therapy of PDT and PTT.

Combinatorial approach of cannabidiol and active-targeted-mediated photodynamic therapy in malignant melanoma treatment.

Malignant melanoma (MM) continues to claim millions of lives around the world due to its limited therapeutic alternatives. Photodynamic therapy (PDT) has gained popularity in cancer treatment due it increased potency and low off-target toxicity. Studies have pointed out that the heterogeneity of MM tumours reduces the efficacy of current therapeutic approaches, including PDT, leading to high chances of recurrences post-treatment. Accumulating evidence suggests that cannabidiol (CBD), a non-psychoactive derivative of cannabis, can synergise with various anticancer agents to increase their efficacy. However, CBD demonstrates low bioavailability, which is attributed to factors relating to poor water compatibility, poor absorption and rapid metabolism. Nanotechnology offers tools that address these issues and enhance the biological efficiency and targeted specificity of anticancer agents. Herein, we highlighted the standard therapeutic modalities of MM and their pitfalls, as well as pointed out the need for further investigation into PDT combination therapy with CBD.

Treatment of Nevus Sebaceous with Short-term Photodynamic therapy combined with simple Surgery

SignificanceNevus sebaceous is a benign cutaneous hamartoma involving the epidermis, pilosebaceous units, and other adnexal structures. To avoid or minimize the scar, photodynamic therapy (PDT) is recommended as a non-surgical treatment. ApproachIn this report, we present a successful case of recurrent nevus sebaceous treated with a combination therapy of PDT and surgical excision. The patient was followed-up for a period of 6 months to evaluate the effectiveness of the treatment. ResultsThe patient underwent three sessions of PDT at three-week intervals, followed by surgical resection. Following the procedure, there was no recurrence of the lesion after 6 months, and the achieved a favorable cosmetic outcome. ConclusionsIn cases where the nevus sebaceous affects larger areas, employing a short-term PDT regimen in conjunction with surgical intervention proves to be an effective strategy, reducing the extent of surgical excision and yielding superior cosmetic results for our patients.

Cannabidiol Combination Enhances Photodynamic Therapy Effects on MCF-7 Breast Cancer Cells.

Cannabis sativa is a well-known plant for its psychoactive effects; however, its many derivatives, such as Cannabidiol (CBD), contain several therapeutic applications. Tetrahydrocannabinol (THC) is the main cannabis derivative responsible for psychoactive properties, while CBD is non-psychotropic. For this reason, CBD has been more exploited in the last decade. CBD has been connected to multiple anticancer properties, and when combined with photodynamic therapy (PDT), it is possible to eradicate tumors more effectively. In this study, CBD was utilized to treat MCF-7 breast cancer cells, followed by in vitro PDT combination therapy. Conventional breast cancer treatment modalities such as chemotherapy, radiotherapy, etc. have been reported for inducing a number of undesirable side effects, recurrence of the disease, and low quality of life. In this study, cells were exposed to varying concentrations of CBD (i.e., 1.25, 2.5, 5, 10, and 20 μg/mL) and incubated 12 and 24 h after treatment. The optimal doses were then used in combination therapy. Morphology and biochemical assays, including lactate dehydrogenase (LDH) for membrane integrity, adenosine triphosphate (ATP) for viability, and trypan blue exclusion assay for viability, were used to examine cellular responses after treatments. The optimal concentration was then utilized in Hypericin-Gold nanoparticles mediated PDT combination. The results revealed that, in a dose-dependent manner, conventional morphological characteristics of cell death, such as vacuolization, blebbing, and floating were observed in treated cells. The biochemical responses demonstrated an increase in LDH, a decrease in ATP, and a reduction in viability. This study demonstrated that CBD induces cell death in MCF-7 breast cancer cells cultured in vitro. The immunofluorescence results of combination therapy indicated that cell death occurred via apoptosis. In conclusion, this study proposes that the CBD and PDT combination therapy is effective in killing MCF-7 breast cancer cells in vitro by induction of apoptosis.

Dual Functional Magnetic Nanoparticles Conjugated with Carbon Quantum Dots for Hyperthermia and Photodynamic Therapy for Cancer.

The global incidence of cancer continues to rise, posing a significant public health concern. Although numerous cancer therapies exist, each has limitations and complications. The present study explores alternative cancer treatment approaches, combining hyperthermia and photodynamic therapy (PDT). Magnetic nanoparticles (MNPs) and amine-functionalized carbon quantum dots (A-CQDs) were synthesized separately and then covalently conjugated to form a single nanosystem for combinational therapy (M-CQDs). The successful conjugation was confirmed using zeta potential, Fourier transform infrared spectroscopy (FT-IR), and UV-visible spectroscopy. Morphological examination in transmission electron microscopy (TEM) further verified the conjugation of CQDs with MNPs. Energy dispersive X-ray spectroscopy (EDX) revealed that M-CQDs contain approximately 12 weight percentages of carbon. Hyperthermia studies showed that both MNP and M-CQDs maintain a constant therapeutic temperature at lower frequencies (260.84 kHz) with high specific absorption rates (SAR) of 118.11 and 95.04 W/g, respectively. In vitro studies demonstrated that MNPs, A-CQDs, and M-CQDs are non-toxic, and combinational therapy (PDT + hyperthermia) resulted in significantly lower cell viability (~4%) compared to individual therapies. Similar results were obtained with Hoechst and propidium iodide (PI) staining assays. Hence, the combination therapy of PDT and hyperthermia shows promise as a potential alternative to conventional therapies, and it could be further explored in combination with existing conventional treatments.

Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape.

Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCTER ) is prepared to boost immunotherapy. First, PNBCTER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)-like activities, which can reshape the TME. Second, PNBCTER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by TER , PNBCTER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.

Comparison of antivascular endothelial growth factor treatment for myopia choroidal neovascularisation: a systematic review and meta-analysis of randomised controlled trials

ObjectivesTo evaluate the efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) therapy for myopia choroidal neovascularisation (CNV), and to compare the efficacy of two different anti-VEGF retreatment criteria.Data sourcesPubMed,...

Metal coordination micelles for anti-cancer treatment by gene-editing and phototherapy

CRISPR-Cas9 is a central focus of the emerging field of gene editing and photodynamic therapy (PDT) is a clinical-stage ablation modality combining photosensitizers with light irradiation. But metal coordination biomaterials for the applications of both have rarely been investigated. Herein, Chlorin-e6 (Ce6) Manganese (Mn) coordination micelles loaded with Cas9, termed Ce6-Mn-Cas9, were developed for augmented combination anti-cancer treatment. Manganese played multiple roles to facilitate Cas9 and single guide RNA (sgRNA) ribonucleoprotein (RNP) delivery, Fenton-like effect, and enhanced endonuclease activity of RNP. Histidine (His)-tagged RNP could be coordinated to Ce6 encapsulated in Pluronic F127 (F127) micelles by simple admixture. Triggered by ATP and endolysosomal acidic pH, Ce6-Mn-Cas9 released Cas9 without altering protein structure or function. Dual guide RNAs were designed to target the antioxidant regulator MTH1 and the DNA repair protein APE1, resulting in increased oxygen and enhanced PDT effect. In a murine tumor model, Ce6-Mn-Cas9 inhibited tumor growth with the combination therapy of PDT and gene editing. Taken together, Ce6-Mn-Cas9 represents a new biomaterial with a high degree of versatility to enable photo- and gene-therapy approaches.

Friends against the Foe: Synergistic Photothermal and Photodynamic Therapy against Bacterial Infections.

Multidrug-resistant (MDR) bacteria are rapidly emerging, coupled with the failure of current antibiotic therapy; thus, new alternatives for effectively treating infections caused by MDR bacteria are required. Hyperthermia-mediated photothermal therapy (PTT) and reactive oxygen species (ROS)-mediated photodynamic therapy (PDT) have attracted extensive attention as antibacterial therapies owing to advantages such as low invasiveness, low toxicity, and low likelihood of causing bacterial resistance. However, both strategies have notable drawbacks, including the high temperature requirements of PTT and the weak ability of PDT-derived ROS to penetrate target cells. To overcome these limitations, a combination of PTT and PDT has been used against MDR bacteria. In this review, we discuss the unique benefits and limitations of PTT and PDT against MDR bacteria. The mechanisms underlying the synergistic effects of the PTT-PDT combination are also discussed. Furthermore, we introduced advancements in antibacterial methods using nano-based PTT and PDT agents to treat infections caused by MDR bacteria. Finally, we highlight the existing challenges and future perspectives of synergistic PTT-PDT combination therapy against infections caused by MDR bacteria. We believe that this review will encourage synergistic PTT- and PDT-based antibacterial research and can be referenced for future clinical applications.

Recent advances and prospects of metal-organic frameworks in cancer therapies.

Metal-organic frameworks (MOFs) have been broadly applied in biomedical and other fields. MOFs have high porosity, a large comparative area, and good biostability and have attracted significant attention, especially in cancer therapies. This paper presents the latest applications of MOFs in chemodynamic therapy (CDT), sonodynamic therapy (SDT), photodynamic therapy (PDT), photothermal therapy (PTT), immunotherapy (IT), and combination therapy for breast cancer. A combination therapy is the combination of two different treatment modalities, such as CDT and PDT combination therapy, and is considered more effective than separate therapies. Herein, we have also discussed the advantages and disadvantages of combination therapy in the treatment of breast cancer. This paper aims to illustrate the potential of MOFs in new cancer therapeutic approaches, discuss their potential advantages, and provide some reflections on the latest research results.

PARP inhibitors diminish DNA damage repair for the enhancement of tumor photodynamic therapy

Pancreatic cancer is a lethal malignancy and only around 4% of patients will live 5 years post-diagnosis. Photodynamic therapy (PDT) is a promising strategy for treating malignant tumors because of its high selectivity. Through the colocalization of light, oxygen and photosensitizer, a large number of reactive oxygen species (ROS) are generated under excitation at a specific wavelength of a laser, which can induce DNA damage and destroy cancer cells. However, the repair mechanism of cell will repair part of the damaged DNA, which could reduce the efficiency of PDT. The poly (ADP-Ribose) polymerase (PARP) plays a wide and multifaceted role in the cellular response to DNA damage, with growing evidence for participation in multiple pathways of DNA damage repair and genome maintenance. Cells require PARP to resolve single-strand DNA breaks (SSBs) induced by chemotherapy agents. Its inhibition is thought to result in the accumulation of damage in DNA, which may eventually lead to cell death. The combination therapy of PDT and PARP inhibitors may benefit patients. In this study, we design and synthesize a zeolitic imidazolate framework-8 (ZIF-8) to co-deliver DNA damaging agent Chlorin e6 (Ce6) and PARP inhibitor Olaparib (Ola). Ce6 and Ola demonstrate strong synergistic actions, providing a novel approach for the treatment of pancreatic cancer.

Comparison of 3-year outcomes of photodynamic therapy combined with intravitreal ranibizumab or aflibercept for polypoidal choroidal vasculopathy in a European cohort

PurposeCombined use of photodynamic therapy (PDT) with intravitreal anti-vascular endothelial growth factors (anti-VEGF) agents, such as ranibizumab (IVR) or aflibercept (IVA), has been shown to be effective for treating polypoidal choroidal vasculopathy (PCV). However, it is currently not well established which anti-VEGF agent provides superior outcomes for performing combination therapy. The present study compares the visual outcomes and re-treatment burden of combination therapy of PDT with either IVR or IVA in a European cohort of patients with PCV.MethodsA retrospective analysis was done on PCV patients who had received combination therapy of PDT with either IVR or IVA. The demographic characteristics, visual outcome, and anti-VEGF re-treatment exposures were analysed and compared.ResultsA total of forty-four eyes (n = 11 male, 25%) were included in the analysis: 7 patients received IVR, 19 started with IVR but switched to IVA (IVS), and 18 received IVA, in combination with PDT. The BCVA improved in all three groups at 6-, 12-, 18-, 24-, 30-, and 36-month follow-ups after PDT, although the improvement was not statistically significant in the IVR group. The number of intravitreal anti-VEGF injections required/year after PDT was significantly fewer than before PDT. Significantly less eyes in the IVS group attained a good visual acuity of more than 70 ETDRS letters at the final visit.ConclusionBoth IVR and IVA combined with PDT were effective treatments for the European cohort of patients with PCV. In eyes refractory to IVR, performing PDT promptly may be more beneficial than switching to IVA.

One-Year Outcome of Combination Therapy with Full or Reduced Photodynamic Therapy and One Anti-Vascular Endothelial Growth Factor in Pachychoroid Neovasculopathy.

This paper evaluates a one-year treatment outcome after full or reduced photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) combination therapy for pachychoroid neovasculopathy (PNV). After the initial combination therapy, a total of 29 eyes from 29 patients (16 for full treatment and 13 for reduced treatment), exhibited reduced, central retinal thickness and central choroidal thickness, and the improvements were maintained for 1 year after the initial combination therapy. Twenty-two eyes (75.9%) required no additional treatments for 1 year. The recurrence rate was 31.3% in the full treatment and 15.4% in the reduced treatment, with no significant differences between them. One shot of anti-VEGF and full or reduced PDT combination therapy had similar efficacy in treating PNV. Further prospective, large-scale, and long-term studies are required to determine a better treatment for PNV.

Effectiveness of Current Treatments for Wet Age-Related Macular Degeneration in Japan: A Systematic Review and Pooled Data Analysis.

PurposeWe conducted a systematic review to investigate the effectiveness of clinical treatments for wet age-related macular degeneration (wAMD) in Japanese patients in the decade since anti-vascular endothelial growth factor (VEGF) therapies were introduced.MethodsPubMed was searched for articles published in English between 1 January 2008 and 30 September 2018 using a multistring search strategy. Reviews were scanned for additional relevant studies and select gray literature was evaluated. Mean and/or median for the logarithm of the minimum angle of resolution (logMAR) visual acuity (VA), central retinal thickness (CRT), and the number of injections after 12 months of treatment were calculated using extracted data. Data were stratified by disease type and treatment modality.ResultsOf 335 studies identified, 94 were selected for data extraction (147 treatment arms; typical AMD, n = 25; polypoidal choroidal vasculopathy [PCV], n = 85). Mean (median) logMAR VA was 0.44 (0.32) for typical AMD and 0.34 (0.31) for PCV; the respective mean number of anti-VEGF injections was 5.6 and 4.6. The mean CRT was approximately 220 μm for both groups. For typical AMD, anti-VEGF monotherapy resulted in better VA outcomes than photodynamic therapy (PDT) alone. For PCV, anti-VEGF monotherapy or anti-VEGF plus PDT combination therapy resulted in better VA and CRT outcomes than PDT monotherapy. Combination therapy required fewer injections than anti-VEGF monotherapy (PCV, 3.2 versus 5.3).ConclusionwAMD treatment has advanced dramatically in the years since anti-VEGF drugs were introduced in Japan. Discrete patient populations may benefit from differing management regimens, including the fewer injections required with combination therapy.

Yolk-shell polyphosphazenes nanotheranostics for multimodal imaging guided effective phototherapy

A critical issue of photodynamic therapy (PDT) is the hypoxia feature in tumor microenvironment and the PDT-caused continuous oxygen consumption, which suppresses the effect of tumor treatment. Though the perfluorocarbon-based microbubbles with high oxygen affinity have been utilized to supply endogenous oxygen to improve PDT, some risks are wished to be addressed including oxygen leakage and storage issues. Herein, perfluorohexane (PFH) and Fe3O4 nanoparticles were encapsulated in biocompatible polyphosphazenes (PPZ) and polydopamine (PDA) shells were further grown to prevent the leakage of PFH. After loading chlorine e6 (Ce6) and modifying with polyethylene glycol (PEG), a multimodal nanotheranostic (PFH–Fe3O4@PPZ@PDA-PEG-Ce6) were successfully constructed for ultrasonic (US), magnetic resonance (MR) and fluorescence imaging guided photothermal therapy (PTT) and enhanced PDT. PFH can not only bind and delivery oxygen but also be used as contrast agent for US imaging. While PDA is a frequently used PTT agent and Ce6 is PDT agent as well as fluorescent agent. The yolk-shell nanoplatform showed good biocompatibility, biostability and well cellular uptake. Importantly, strengthened PDT efficiency has also been greatly improved due to high oxygen-rich PFH. Furthermore, the nanoplatform efficiently generated hyperthermia to kill tumor upon 808 nm illumination. Remarkably, the PTT/enhanced PDT combination therapy can be realized under the guidance of US/MR/fluorescence imaging. This nanoplatform could dramatically inhibit tumor growth by PTT and improved PDT, demonstrating great promising for multimodal imaging guided phototherapy.

A Supramolecular Photosensitizer System Based on Nano-Cu/ZIF-8 Capped with Water-Soluble Pillar[6]arene and Methylene Blue Host-Guest Complexations.

Photodynamic therapy (PDT) as a safe, non-invasive modality for cancer therapy, in which the low oxygen and high glutathione in the tumor microenvironment reduces therapeutic efficiency. In order to overcome these problems, we prepared a supramolecular photosensitive system of O2-Cu/ZIF-8@ZIF-8@WP6–MB (OCZWM), which was loaded with oxygen to increase the oxygen concentration in the tumor microenvironment, and the Cu2+ in the system reacted with glutathione (GSH) to reduce the GSH concentration to generate Cu+. It is worth noting that the generated Cu+ can produce the Fenton reaction, thus realizing the combination therapy of PDT and chemodynamic therapy (CDT) to achieve the purpose of significantly improving the anti-cancer efficiency.

Potential of Photodynamic Therapy Based on Sugar-Conjugated Photosensitizers.

In 2015, the Japanese health insurance approved the use of a second-generation photodynamic therapy (PDT) using talaporfin sodium (TS); however, its cancer cell selectivity and antitumor effects of TS PDT are not comprehensive. The Warburg effect describes the elevated rate of glycolysis in cancer cells, despite the presence of sufficient oxygen. Because cancer cells absorb considerable amounts of glucose, they are visible using positron emission tomography (PET). We developed a third-generation PDT based on the Warburg effect by synthesizing novel photosensitizers (PSs) in the form of sugar-conjugated chlorins. Glucose-conjugated (tetrafluorophenyl) chlorin (G-chlorin) PDT revealed significantly stronger antitumor effects than TS PDT and induced immunogenic cell death (ICD). ICD induced by PDT enhances cancer immunity, and a combination therapy of PDT and immune checkpoint blockers is expected to synergize antitumor effects. Mannose-conjugated (tetrafluorophenyl) chlorin (M-chlorin) PDT, which targets cancer cells and tumor-associated macrophages (TAMs), also shows strong antitumor effects. Finally, we synthesized a glucose-conjugated chlorin e6 (SC-N003HP) that showed 10,000–50,000 times stronger antitumor effects than TS (IC50) in vitro, and it was rapidly metabolized and excreted. In this review, we discuss the potential and the future of next-generation cancer cell-selective PDT and describe three types of sugar-conjugated PSs expected to be clinically developed in the future.

Sialic acid-modified mesoporous polydopamine induces tumor vessel normalization to enhance photodynamic therapy by inhibiting VE-cadherin internalization

Tumor hypoxia do harm to the therapeutic efficiency of photodynamic therapy (PDT) since sufficient local O2 concentration is necessary for the generation of toxic singlet O2 (1O2). Herein, a sialic acid-PEG-modified mesoporous polydopamine nanoparticle dual loaded with indocyanine green and 3PO-loaded (SPMI/3) was fabricated. Owing to the specific combination between sialic acid and E-selectin overexpressed on the inflammatory endothelial cells around tumors, SPMI/3 demonstrated a 1.39-fold higher accumulation than that of the PMI/3-treated group. After laser irradiation, SPMI/3 revealed a potent anti-tumor efficacy due to the combination therapy of PDT and photothermal therapy in the early stage of treatment. Later, thanks to the overexpression of vascular endothelial growth factor induced by PDT, the slowly released 3PO from SPMI/3 reduced by 65.20% endocytosis of VE-cadherin compared to the PBS group. Accordingly, SPMI/3 normalized tumor vessels by increasing laminin and pericyte coverage, contributing to the decreased vascular permeability and improved tissue hypoxia. All these improvements contributed to the normalized tumor vasculature and inhibition of metastasis. In conclusion, this finding provides a novel strategy to enhance PDT therapy via tumor vessel normalization.

Application of phototherapeutic-based nanoparticles in colorectal cancer.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death, which accounts for approximately 10% of all new cancer cases worldwide. Surgery is the main method for treatment of early-stage CRC. However, it is not effective for most metastatic tumors, and new treatment and diagnosis strategies need to be developed. Photosensitizers (PSs) play an important role in the treatment of CRC. Phototherapy also has a broad prospect in the treatment of CRC because of its low invasiveness and low toxicity. However, most PSs are associated with limitations including poor solubility, poor selectivity and high toxicity. The application of nanomaterials in PSs has added many advantages, including increased solubility, bioavailability, targeting, stability and low toxicity. In this review, based on phototherapy, we discuss the characteristics and development progress of PSs, the targeting of PSs at organ, cell and molecular levels, and the current methods of optimizing PSs, especially the application of nanoparticles as carriers in CRC. We introduce the photosensitizer (PS) targeting process in photodynamic therapy (PDT), the damage mechanism of PDT, and the application of classic PS in CRC. The action process and damage mechanism of photothermal therapy (PTT) and the types of ablation agents. In addition, we present the imaging examination and the application of PDT / PTT in tumor, including (fluorescence imaging, photoacoustic imaging, nuclear magnetic resonance imaging, nuclear imaging) to provide the basis for the early diagnosis of CRC. Notably, single phototherapy has several limitations in vivo, especially for deep tumors. Here, we discuss the advantages of the combination therapy of PDT and PTT compared with the single therapy. At the same time, this review summarizes the clinical application of PS in CRC. Although a variety of nanomaterials are in the research and development stage, few of them are actually on the market, they will show great advantages in the treatment of CRC in the near future.

An Alternating Irradiation Strategy‐Driven Combination Therapy of PDT and RNAi for Highly Efficient Inhibition of Tumor Growth and Metastasis

Hypoxia and hypoxia induced overexpression of vascular endothelial growth factor (VEGF) not only seriously affects the treatment effects of photodynamic therapy (PDT) but also promotes tumor metastasis. Herein, an alternating irradiation strategy (referred to as alternate use of low/high dose of light [ALHDL] irradiation)-driven combination therapy of PDT and RNA interference (RNAi) is developed to synergistically inhibit tumor growth and metastasis. A cationic amphipathic peptide (ALS) served as a carrier in the co-delivery system of photochlor (HPPH) and siVEGF (ALSH/siVEGF). At the beginning of ALHDL-driven ALSH/siVEGF treatment, short-term LDL irradiation can facilitate the tumor penetration, cellular uptake, and endosome escape of ALSH/siVEGF. Moreover, accompanied by HDL-mediated rapid cell apoptosis and LDL-mediated efficient VEGF silencing, the joint use of PDT and RNAi achieved remarkable antitumor effects both in vitro and in vivo. Importantly, benefited from the excellent performance of ALHDL in slowing the rapid deterioration of the anoxic environment of tumors, and ALSH/siVEGF treatment-mediated highly improved VEGF silencing efficacy and inhibitory effect on angiogenesis, the liver and lung metastases of HeLa cells have been successfully suppressed. Together, this study clearly indicates that ALHDL-driven combination therapy of PDT and RNAi is a highly effective modality for inhibition of tumor growth and metastasis.