Abstract
Simple SummaryA new approach of combined optoacoustic (OA) and fluorescence (FL) imaging for in vivo real-time tracing photosensitizer (PS) kinetics and functional vascular effects in the treated area was developed. FL monitoring using a photoactivatable multi-inhibitor liposomal (PMILs) platform, demonstrates enhancement of PS accumulation in tumor, 24 h post-treatment. OA monitoring revealed the alterations of the tumor vasculature structure after treatment, which is in good agreement with the histological data that shows five times higher percentage of hemorrhages in PMIL treated mice compared to the untreated group.The newly developed multimodal imaging system combining raster-scan optoacoustic (OA) microscopy and fluorescence (FL) wide-field imaging was used for characterizing the tumor vascular structure with 38/50 μm axial/transverse resolution and assessment of photosensitizer fluorescence kinetics during treatment with novel theranostic agents. A multifunctional photoactivatable multi-inhibitor liposomal (PMILs) nano platform was engineered here, containing a clinically approved photosensitizer, Benzoporphyrin derivative (BPD) in the bilayer, and topoisomerase I inhibitor, Irinotecan (IRI) in its inner core, for a synergetic therapeutic impact. The optimized PMIL was anionic, with the hydrodynamic diameter of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01, and the zeta potential between −14.9 ± 1.04 to −16.9 ± 0.92 mV. In the in vivo studies on BALB/c mice with CT26 tumors were performed to evaluate PMILs’ therapeutic efficacy. PMILs demonstrated the best inhibitory effect of 97% on tumor growth compared to the treatment with BPD-PC containing liposomes (PALs), 81%, or IRI containing liposomes (L-[IRI]) alone, 50%. This confirms the release of IRI within the tumor cells upon PMILs triggering by NIR light, which is additionally illustrated by FL monitoring demonstrating enhancement of drug accumulation in tumor initiated by PDT in 24 h after the treatment. OA monitoring revealed the largest alterations of the tumor vascular structure in the PMILs treated mice as compared to BPD-PC or IRI treated mice. The results were further corroborated with histological data that also showed a 5-fold higher percentage of hemorrhages in PMIL treated mice compared to the control groups. Overall, these results suggest that multifunctional PMILs simultaneously delivering PDT and chemotherapy agents along with OA and FL multi-modal imaging offers an efficient and personalized image-guided platform to improve cancer treatment outcomes.
Highlights
Imaging plays a major role in the development of effective cancer therapies
The Photoactivatable multi-inhibitor liposomes (PMILs) exhibited an average hydrodynamic size of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01 demonstrating that a narrow size distribution and monodispersity were well maintained in all nanoconstructs. ζ
-potential of PMILs was recorded between −14.9 ± 1.04 to −16.9 ± 0.92 mV, which was suggestive of an anionic charge in all PMILs prepared (Table 1). ζ-potential prevents the aggregation of nanoliposomes and charged liposomes offer great stability on storage
Summary
Imaging plays a major role in the development of effective cancer therapies. monitoring drug delivery, and dynamic changes in physical parameters, such as blood flow, tumor oxygenation, and vessel structure, is key for evaluating therapeutic efficacy. Amongst several therapies being developed, Photodynamic therapy (PDT) is a therapeutic approach that is gaining wide recognition in clinical practice It is based on irradiation of photosensitizers (PS) with the light of a certain wavelength in the presence of oxygen in a tissue resulting in the formation of cytotoxic reactive oxygen species (ROS) [1,2,3]. Vascular PDT has been shown to be efficient for cancer treatment [11,12,13,14,15] It can be implemented by a short drug-to-light interval when the irradiation is carried out at the time when the photosensitizer is predominantly located in the blood and has not yet been or minimally distributed to the surrounding tissues
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