光敏剂的转化与创新

Translation and Innovation of Photosensitizers

以光敏剂为基础的光动力疗法已被确定为许多肿瘤、皮肤性疾病、血管性疾病等适应证的安全治疗方式。在近些年的研究中,卟啉类光敏剂、二氢卟吩类光敏剂等均投入临床使用,酞菁类光敏剂、稠环醌类光敏剂等均已开展临床研究。但是,光动力疗法在临床转化中还面临着诸多问题,如有限的穿透深度、较低的溶解度、暗毒性、对氧气浓度的高度依赖等,新型的安全高效的光敏剂亟待被进一步开发,以实现高度特异性微创治疗。目前,新型光敏剂的研发主要聚焦于靶向修饰和智能纳米药物递送体系以及可激活/响应型光敏剂、耐乏氧肿瘤微环境的Ⅰ型光敏剂、适应深层实体瘤治疗的光敏剂等。此外,超声激发的声动力治疗也为光敏剂的临床应用开辟了新思路。随着新型光敏剂的开发与转化,将会有更多的光敏剂药物被应用于临床实践,为癌症和其他疾病患者带来福音。

Significance Photodynamic therapy(PDT)is a novel treatment for superficial skin diseases and tumors.The basic treatment involves administering a photosensitizing agent through intravenous injection or other methods,and then stimulating the lesion with a specific wavelength of light.This photodynamic reaction,facilitated by the photosensitizing agent,effectively cures the lesion.PDT uses the photodynamic effect for diagnosing and treating diseases.Its mechanism is based on a photosensitization reaction accompanied by biological effects that includes the participation of oxygen molecules.This process involves irradiating a laser of a specific wavelength to excite a photosensitizer that has been absorbed by tissues,causing it to enter an excited state.Then the photosensitizer in the excited state transfers energy to the surrounding oxygen,resulting in the generation of highly active singlet oxygen.This singlet oxygen undergoes an oxidative reaction with adjacent biological macromolecules,inducing cytotoxicity,and ultimately,causing cell damage and death.Over the past 20 years,PDT has emerged and developed as a new treatment technology for diseases such as esophageal cancer,lung cancer,condyloma acuminatum,acne,and nevus.Compared to traditional tumor therapies such as surgery,chemotherapy,and radiotherapy,PDT offers unique and irreplaceable advantages.It is non-resistant,allowing for repeated treatment.PDT exhibits high therapeutic selectivity towards the lesion,causing little to no damage to healthy tissues,and has only a few toxic side effects.Consequently,PDT is especially suitable for elderly and frail patients who are unable to undergo surgical resection or chemotherapy.In particular,for patients with advanced tumors who have not responded effectively to or are at risk with traditional treatments,PDT is an extremely ideal treatment option.Different types of molecules can be used as photosensitizers;however,many of them face challenges in clinical application.including limited penetration depth,low solubility,dark toxicity,and a high dependence on oxygen concentration.Therefore,more efficient and safer photosensitizers need to be further studied and developed.Currently,the focus of research and development of novel photosensitizers lies in target modification and smart nanomedicine delivery systems to achieve minimally invasive and specific therapy.An excellent photosensitizer should be capable of achieving precise lesion killing at low doses while having a minimal effect on other parts of the body.In the context of PDT,the application of novel photosensitizers is undoubtedly a key factor in further improvingthetherapeuticeffect.Progress The earliest photosensitizers used in PDT were hematoporphyrin derivatives,with the main component being dihematoporphyrin ether(DHE).Sodium porphyrinum,marketed by Canadian company QLT(Quadra Logic Technologies Phototherapeutics Inc.),has received approval for the treatment of bladder,esophageal,and lung cancers.It has become the most frequently used photosensitizer in the PDT of non-cutaneous solid tumors.However,it still has certain disadvantages,such as longlasting skin photosensitivity and low selectivity for lesion tissues.Subsequently,a wider variety of photosensitizers have been developed for treating various diseases(Table 1).There have been many studies on both traditional and novel photosensitizers.Porphyrins,chlorins,phthalocyanines,and bacteriochlorin derivatives have been employed as photosensitizers in clinical use(Table 2).Viscous cycloquinone and metal-ligand anthapurpurin derivatives have entered the clinical research stage as photosensitizers(Table 3).Meanwhile,research focusing on the development of new photosensitizers is also in full swing.Researchers are developing photosensitizers on the nano platform and achieving better drug delivery effects through surface modifications of the photosensitizer.They are also aiming to achieve more accurate PDT through the design of activatable and responsive photosensitizers.Furthermore,they are attempting to overcome the oxygen-depleted microenvironments at tumor sites by developing novel type I photosensitizers and creating photosensitizers more suitable for the treatment of deep solid tumors.Additionally,the combination of PDT with other drugs or therapies,to achieve a better therapeutic effect and reduce drug toxicity and side effects,has also garnered researchers'interest.Sonodynamic therapy,a derivative of PDT,exhibits higher therapeutic efficiency for deep lesions due to its superior tissue penetration ability.Research on acoustic sensitizer and sonodynamic therapy is also underway.Conclusions and Prospects PDT is playing an increasingly important role in the treatment of many superficial lesions and cancers.The development of photosensitizers with better treatment effects and fewer toxic side effects has been receiving extensive attention.Researchers have made significant efforts in developing more delicately designed photosensitizers.Many photosensitizers with excellent properties,such as high reactive oxygen quantum yield,high molar extinction coefficient,high maximum absorption wavelength,high targeting ability,low in vivo toxicity,and rapid in vivo clearance,have been advanced to clinical research.Simultaneously,more photosensitizers have received marketing approval,benefiting patients.The development of photosensitizers has advanced the diagnosis and precise regulation of diseases,contributing to the development of precision medicine.With the continuous development of novel photosensitizers,PDT will play a greater role in multiple indications and bring benefits to a larger numberofpatients.