Combined Antitumor Therapy Using In Situ Injectable Hydrogels Formulated with Albumin Nanoparticles Containing Indocyanine Green, Chlorin e6, and Perfluorocarbon in Hypoxic Tumors

Combined therapy using photothermal and photodynamic treatments together with chemotherapeutic agents is considered one of the most synergistic treatment protocols to ablate hypoxic tumors. Herein, we sought to fabricate an in situ-injectable PEG hydrogel system having such multifunctional effects. This PEG hydrogel was prepared with (i) nabTM-technique-based paclitaxel (PTX)-bound albumin nanoparticles with chlorin-e6 (Ce6)-conjugated bovine serum albumin (BSA-Ce6) and indocyanine green (ICG), named ICG/PTX/BSA-Ce6-NPs (~175 nm), and (ii) an albumin-stabilized perfluorocarbon (PFC) nano-emulsion (BSA-PFC-NEs; ~320 nm). This multifunctional PEG hydrogel induced moderate and severe hyperthermia (41−42 °C and >48 °C, respectively) at the target site under two different 808 nm laser irradiation protocols, and also induced efficient singlet oxygen (1O2) generation under 660 nm laser irradiation supplemented by oxygen produced by ultrasound-triggered PFC. Due to such multifunctionality, our PEG hydrogel formula displayed significantly enhanced killing of three-dimensional 4T1 cell spheroids and also suppressed the growth of xenografted 4T1 cell tumors in mice (tumor volume: 47.7 ± 11.6 and 63.4 ± 13.0 mm3 for photothermal and photodynamic treatment, respectively, vs. PBS group (805.9 ± 138.5 mm3), presumably based on sufficient generation of moderate heat as well as 1O2/O2 even under hypoxic conditions. Our PEG hydrogel formula also showed excellent hyperthermal efficacy (>50 °C), ablating the 4T1 tumors when the irradiation duration was extended and output intensity was increased. We expect that our multifunctional PEG hydrogel formula will become a prototype for ablation of otherwise poorly responsive hypoxic tumors.

Phototheranostics of Cervical Neoplasms with Chlorin e6 Photosensitizer

(1) Purpose: Improving the treatment effectiveness of intraepithelial neoplasia of the cervix associated with human papillomavirus infection, based on the application of the method of photodynamic therapy with simultaneous laser excitation of fluorescence to clarify the boundaries of cervical neoplasms. (2) Methods: Examination and treatment of 52 patients aged 22 to 53 years with morphologically and cytologically confirmed mild to severe intraepithelial cervix neoplasia, preinvasive, micro-invasive, and squamous cell cervix carcinoma. All patients were carriers of human papillomavirus infection. The patients underwent photodynamic therapy with simultaneous laser excitation of fluorescence. The combined use of video and spectral fluorescence diagnostics for cervical neoplasms made it possible to control the photodynamic therapy process at all stages of the procedure. Evaluation of the photodynamic therapy of intraepithelial cervical neoplasms was carried out with colposcopic examination, cytological conclusion, and morphological verification of the biopsy material after the photodynamic therapy course. The success of human papillomavirus therapy was assessed based on the results of the polymerase chain reaction. (3) Results. The possibility of simultaneous spectral fluorescence diagnostics and photodynamic therapy using a laser source with a wavelength of 660 nm has been established, making it possible to assess the fluorescence index in real-time and control the photobleaching of photosensitizers in the irradiated area. The treatment of all 52 patients was successful after the first photodynamic therapy procedure. According to the PCR test of the discharge from the cervical canal, the previously identified HPV types were not observed in 48 patients. Previously identified HPV types were absent after repeated PDT in four patients (CIN III (n = 2), CIS (n = 2)). In 80.8% of patients, regression of the lesion was noted. (4) Conclusions. The high efficiency of photodynamic therapy with intravenous photosensitizer administration of chlorin e6 has been demonstrated both in relation to eradication therapy of human papillomavirus and in relation to the treatment of intraepithelial lesions of the cervix.

Transurethral Resection of Non-Muscle Invasive Bladder Tumors Combined with Fluorescence Diagnosis and Photodynamic Therapy with Chlorin e6-Type Photosensitizers

Bladder cancer is a common disease with a high recurrence rate. In order to improve the treatment of superficial bladder tumors, we evaluated the efficacy and safety of transurethral resection (TURB) followed by fluorescence diagnosis (FD) and photodynamic therapy (PDT) with chlorin e6 photosensitizers (PSs), viz. “Fotoran e6” and “Fotoditazin”. It was found that both PSs generated singlet oxygen and revealed moderate affinity toward the lipid-like compartment. Between November 2018 and October 2020, 12 patients with verified non-muscle invasive bladder cancer (NMIBC) were treated by TURB combined with FD and PDT. Eight patients received “Fotoran e6” intravenously, while four patients received intravesical PSs. The patient ages were between 31 and 79 years, with a median age of 64.5 years (mean 61.3 ± 14.2). The total light dose was 150 J/cm2 for the local irradiation of the tumor bed with a red light at the λ = 660 nm wavelength, and 10–25 J/cm2 were additionally delivered for diffuse irradiation of the entire bladder mucosa. At the median follow-up period of 24 months (mean 24.5 ± 5.4 months, range 16–35 months), 11 patients remained tumor-free. One 79-year-old patient developed a recurrence without progression to the muscle layer. This pilot study shows that the TURB + FD + PDT technique is an effective and safe option for the first-line treatment of superficial bladder tumors.

Highly Purified Conjugates of Natural Chlorin with Cobalt Bis(dicarbollide) Nanoclusters for PDT and BNCT Therapy of Cancer

To combine the neutron-capturing and photodynamic properties of boron nanoclusters and derivatives of natural chlorins, respectively, in one molecule, conjugate of chlorin e6 methyl ester with cyclen and dioxane and nitrile derivatives of cobalt bis(dicarbollide) were synthesized. The conditions for the purification of compounds by HPLC were selected since the work with natural compounds is complicated by the production of closely related impurities.

Chlorin E6-photodynamic therapy basal cell carcinoma

Purpose of the study. Evaluation of the therapeutic efficacy of chlorin E6-photodynamic therapy (PDT) with photosensitizers (PS) photoditazine, photolone and photoran in patients suffering basal cell skin carcinoma.Materials and methods. The efficacy of chlorin E6-PDT was studied in 532 patients with basal cell skin cancer (BCC) aged 28 to 93 years. PhS Photoditazine was used in 72 (13,5 %) patients at a dose of 0.5-1.0 mg/kg, PhS Photolon - in 281 (52,8 %) patients at a dose of 1.1-1.6 mg/kg and PhS Photoran - in 179 (33,6 %) people at a dose of 1.1-1.6 mg/kg.Sessions of local irradiation of tumor foci were performed on a laser device "Latus-2" (662 nm) with a power density of 200-500 mW/cm2, light energy was applied to the tumors at a dose of 100-300-600 J/cm2.Results. During the follow-up period from 6 months to 5 years, 16.2 % of cases of relapse were diagnosed in the study group. When analyzing the results, it was found that the percentage of relapses was minimal when using all PhS in patients who underwent PDT for the first time established BCC of the initial stages (neoplasms up to 2.0 cm) and amounted to 2.2 % (4 patients out of 183), and with a prevalence of the process of more than 2.0 cm and up to 4.0 cm, 9.5 % (10 patients out of 105) of relapses were found. In the results of treatment of recurrent skin malignancies with PDT using derivatives of chloride E6, depending on the prevalence of the process, a similar trend was observed: with the size of tumor foci up to 2.0 cm, the percentage of repeated relapses was less and amounted to 17.1 % (18 patients out of 105) than in the treatment of neoplasms more than 2.0 cm and up to 4.0 cm (28.8 % of relapses - 21 patients out of 73).Conclusions. Chlorin E6-PDT makes it possible to effectively treat primary and recurrent BCC in an independent variant, and the results of treatment depend on a number of factors, including the prevalence of the disease and the presence or absence of previous treatment.