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Abstract Breast cancer is a widespread, intricate, and diverse disease.The incidence of cancer is rising in both industrialized and developing nations, making rendering it a leading global source of death. Due to the intimate relationship between lifestyle variables and cancer, cancer prevention may be both more effective and less expensive. In addition finding novel and effective cancer therapies is a significant issue on a global scale. Natural remedies have been utilized to cure a variety of illnesses, and they are now a significant focus of drug development research. Numerous cascades, as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis, are modulated by these products, notably phytochemicals, which have received significant research and have proven to have anti-carcinogenic properties. The majority of effective anti-cancer medications already on the market are phytochemicals or their equivalents, and some are even being tested on humans. Sono-photodynamic therapy (SPDT) is a breakthrough and a modern technology to eliminate tumor and affected tissues without affecting the healthy tissue adjacent to and away from the tumor. This requires the use of a so-called sonophotosenstiser, which is highly concentrated in the tumor area, which responds ideally to photonic energy and ultrasonic waves, which works to stop tumor growth and elimination, which is a promising technique to eliminate superficial and deep cancer tumors. Transdermal drug delivery (TDD) is considered as a perfect alternative to conventional drug administration. The drug or macromolecules can be delivered through the skin into the bloodstream at a set rate using this delivery technique without causing any discomfort.Hydrophilic, heavy-weight, charged substances cannot easily pass through the stratum corneum into the systemic circulation due to the skin’s high lipophilicity. However, many therapeutically effective pharmacological compounds have high molecular weights and are hydrophilic, such as peptides.Many diverse strategies have been employed to get over this barrier, including chemical and physical permeation enhancers including iontophoresis, electroporation, and microneedles to encourage the skin absorption of medications. The present work aimed to study of microneedle-iontophoresis transdermal delivery of Goniothalamus macrophyllus for activated cancer therapy using light and ultrasound. An IR laser and US (in both puls.and cont. modes) were used as energy sources. The underlying work was conducted with the goal of obtaining favourable results on applying the SPDT in combination with transdermaly delivered SPDT sensitizer G. macrophyllus as an advanced cancer treatment modality for the aiming of treatment EAC bearing mice. We employed EP (5sec) with three different arrays of microneedle MN electrodes (parallel, triangular, and circular) followed by Ip (5min) with different (6, 9, 12) volts, and infrared laser with an ultrasound were used as our two energy sources (pulsed and continuous wave). In the current study, 120 male Swiss albino mice, 60–65 days aged and 205 gm weighing were obtained. Only after EAC cancer was implanted upon subcutaneous injection of Ehrlich ascites carcinoma cells the treatment trial launched. The Medical Research Institute at Alexandria University’s ethical criteria was followed when using experimental animals in the study methodology. In vivo study groups were as follow; group 1: (50 mice); group 1a: 10 mice received only saline and were kept without any treatment. group 1b: 10 EAC bearing mice received only saline and were kept without any treatment. group 1c: 40 EAC bearing mice were subjected to 6:12 volt EP (5 sec) + array MN electrodes IP (5 min) with (G. macrophyllus) only. group 2: (laser irradiated group) 10 EAC bearing mice of this group were exposed to Laser, for 3 min. group 3: (G. macrophyllus, laser group): 10 EAC bearing mice of this group were subjected to 6 volt EP (5 sec) + array MN electrodes IP (5 min) with (G. macrophyllus), then the tumor site was irradiated to laser light at same conditions of group 2. group 4: (ultrasound group): 10 EAC bearing mice of this group were exposed to continuous/pulsed ultrasound for 3 min. group 5: (G. macrophyllus, ultrasound group): 10 EAC bearing mice of this group were subjected to 6 volt EP (5 sec) + array MN electrodes IP (5 min) with (G. macrophyllus), then the tumor site was irradiated to ultrasound at same conditions of group 4. group 6: (combined group): 10 EAC bearing mice of this group were exposed to laser light for 3 min, followed by ultrasound for 3 min. group 7: (G. macrophyllus, combined group): 10 EAC bearing mice of this group were subjected to 6volt EP (5 sec) + array MN electrodes IP (5 min) with (G. macrophyllus), then the tumor site was irradiated to laser light followed by ultrasound at same conditions of group 5. The TDD and SPDT treatment evaluation: Estimation mean of G. macrophyllus pore diameter penetrated through (µm), transported (µg/cm2 ), absorbed (µg/mg tissue), flux rate (µg/cm2 /5min) and penetration depth (µm) at 5 sec electroporation microneedle (parallel, circular and triangular) assisted TDD followed by DC-Iontophoresis (Square wave, 0.5 mA for 5min) at different volts (6, 9 and 12 volt) to Evaluate the effective TDD system. Biochemical examinations were applied to detect serum ALT, AST, urea and creatinine levels to detect effect of G. macrophyllus in combination with laser and / or ultrasound on liver and kidney functions. Activities of some antioxidants were measured, namely; (GST, SOD, GR, Cat, TAC) and (MDA) to detect the effect of G. macrophyllus in combination with laser and / or ultrasound on antioxidant system and oxidative stress. Molecular detection of P53, Caspase 3,9, Bax, Bcl2, TNFα and VEGF gene expression using qRt-PCR to detect the effect of G. macrophyllus to detect the effect of G. macrophyllus in combination with laser and / or ultrasound on pro and anti-apoptotic as well as necrosis and angiogensis. Evaluating the histological modifications in the tumour tissues after various therapies using Hematoxylin and Eosin (H&E) stain using light microscope to detect the effect of G. macrophyllus in combination with laser and / or ultrasound on EAC tissue. |