A promising strategy to enhance the therapeutic effectiveness for the treatment of oncological diseases involves the development of combined therapeutic schemes. In our work, we showed the therapeutic potential of the combined action of the anticancer targeted toxin and PDT against HER2-positive breast cancer in vitro. Photodynamic treatment led to photoinduced cell death with IC50 0.64 µM, and after incubation with the toxin for 48 h, IC50 was 2.8 pM. When using two therapeutic agents at IC50 doses, significant increases in the effectiveness were observed; the viability of the combination-treated cell culture did not exceed 10%. The calculated combination index was 0.07, indicating a significant synergistic effect caused by the agents.

Bovine serum albumin nanoparticles (BSA-NPs) are widely used as model protein nanocarriers, and their physicochemical properties are strongly influenced by synthesis conditions. This study evaluated the effect of four desolvating agents (DAs), namely acetone, ethanol, isopropanol, and acetonitrile, differing in polarity and hydrogen-bonding capacity, combined with glutaraldehyde (GA) concentration, stirring speed, and DA addition rate, across 32 formulations characterized by dynamic light scattering (DLS) and scanning transmission electron microscopy (STEM). Ethanol-derived BSA-NPs were most reproducible, with hydrodynamic diameter (D_h) of 99.2 to 124.8 nm, polydispersity index (PDI) of 0.076 to 0.193, and ζ-potential of −20.78 to −23.06 mV, independent of other parameters. Acetone-derived particles were smaller but more sensitive to stirring speed, with PDI up to 0.642. Acetonitrile-derived particles showed pronounced aggregation, with PDI never below 0.404, while isopropanol-derived particles showed the strongest glutaraldehyde-dependent aggregation, with PDI up to 0.964, despite a primary size similar to ethanol. DA identity was the dominant factor governing NP properties, and its selection should precede optimization of the other parameters. DA identity further affected both resistance to trypsin digestion and drug-loading capacity. Particles produced with acetonitrile were the most resistant to proteolysis. In addition, hydrophilic Rhodamine B was better loaded into ethanol-derived carriers, and hydrophobic Nile Red was preferentially loaded into particles made via acetone desolvation.

Latest studies highlight boron-dipyrromethene (BODIPY) with meso-methyl moiety as a promising photoremovable protecting group due to its activation within the phototherapeutic window. While BODIPYs inherently generate ROS and act as photosensitizers, few studies have explored combining their photouncaging capability with photodynamic therapy (PDT). Herein, we developed novel meso-methyl-BODIPY conjugates of the DNA alkylator Boc-seco-CBI and the multikinase inhibitor cabozantinib derivative, activated by green or red light. To enhance photodecaging efficiency of conjugates, heavy atoms (Br, I) were introduced, and the boron atom was alkylated. The synthesized compounds were characterized for key photophysical and photochemical properties, including quantum yields of singlet oxygen generation, fluorescence, photolysis and cytostatic release. It was shown, that green-light irradiation of halogenated Boc-seco-CBI conjugates enabled rapid cytostatic release (<1 min), though with modest drug yields due to competing photodegradation. However, efficient uncaging of the cytostatic from the BODIPY-cabozantinib conjugate was achieved only after extended photoirradiation (~80 min) with red light. In vitro evaluation using tumor (MDA-MB-231, A431) and normal (HEK293) cell lines with various EGFR/c-Met expression demonstrated that the BODIPY-cabozantinib conjugate exhibited predominant photosensitizing effects, with minimal cytostatic contribution. During this study, we encountered significant synthetic challenges in developing red-light-absorbing conjugates, coupled with their photodegradation under prolonged irradiation. Our observations reveal key considerations for developing conjugates based on meso-methyl-BODIPY that combine PDT with light-controlled drug release toward antitumor therapy.

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.