A promise of nose to brain delivery of bevacizumab intranasal sol-gel formulation substantiated in rat C6 glioma model.

Glioblastoma is one of the rapidly spreading cancers, with its potent malignancy often linked to pronounced angiogenesis within tumors. To mitigate this vascularization profile, bevacizumab (Avastin®), a monoclonal antibody, has been utilized for its antiangiogenic activity. However, its effectiveness is hindered by challenges in crossing the blood-brain barrier and the risk of off-target organ toxicity. Delivering drugs directly from the nose to the brain through the olfactory or trigeminal nerves bypassing the blood-brain barrier offers enhanced bioavailability and a more precise targeting strategy. To overcome these challenges, we aimed to develop bevacizumab in situ gel loaded mesoporous silica nanoparticles for intranasal delivery and further examine their pharmacokinetic and pharmacodynamic characteristics. The intranasal gel of mesoporous silica nanoparticles loaded with bevacizumab was optimized and formulated using a factorial and quality by design approach. In the case of bevacizumab mesoporous silica nanoparticles, lower particle size and most negative zeta potential were selected as quality target product profiles which is important for drug loading on the mesoporous silica nanoparticles and also transport of these nanoparticles across the nasal mucosa to the brain. A design space with a multidimensional combination of input variables and process parameters has been demonstrated to assure quality. To optimize the design space and achieve the desired quality standards, the base catalyst and surfactant concentration were chosen as the critical process parameters, while particle size and zeta potential were identified as the critical quality attributes. The novel formulation was assessed for physicochemical parameters such as particle size, zeta potential, entrapment efficiency, appearance, color, consistency, and pH. Additionally, studies on in vitro release, ex vivo permeation, stability, nasal toxicity, organ safety, and bioavailability were conducted. The efficacy study was conducted in an orthotopic murine glioblastoma rat model in which C6 Luc cells were instilled in the striatum of the rat's brain. In vivo, bioluminescence imaging of brain tumors was carried out to observe the tumor regression after treatment with the intranasal and intravenous bevacizumab formulation. Biochemical parameters and histopathology were performed for organ safety studies. The optimized intranasal formulation exhibited an average particle size of 318.8 nm and a zeta potential of - 14.7 mV for the mesoporous silica nanoparticles. The formulation also demonstrated an entrapment efficiency of 91.34% and a loading capacity of 45.67%. Further pharmacokinetic studies revealed that the optimized intranasal bevacizumab formulation achieved a significantly higher brain concentration Cmax = 147.9 ng/ml, indicating improved bioavailability compared to rats administered with intravenous bevacizumab formulation (BEVATAS®), which had a Cmax of 127.2 ng/ml. Moreover, this nanoparticle formulation entirely mitigated systemic exposure to bevacizumab. Organ safety evaluation of different biochemical parameters and histopathological analyses revealed that the intranasal bevacizumab-treated group was showing less off-target organ toxicity compared to the group treated with intravenous bevacizumab formulation. Subsequently, the efficacy of this nanosystem was evaluated in an orthotopic glioblastoma rat model, monitoring tumor growth over time through in vivo bioluminescence imaging and assessing anti-angiogenic effects. Twenty-one days post-induction, mesoporous silica nanoparticles loaded with bevacizumab in situ gel exhibited a marked reduction in average bioluminescence radiance (4.39 × 10³) from day 7 (1.35 × 10⁷) emphasizing an enhanced anti-angiogenic effect compared to the group treated with intravenous bevacizumab formulation which showed a gradual decrease in average bioluminescence radiance (4.82 × 10⁴) from day 7 (1.42 × 10⁷). These results suggest that the proposed novel formulation of mesoporous silica nanoparticles loaded bevacizumab in situ gel could serve as a promising avenue to enhance glioblastoma treatment efficacy, thereby potentially improving patient quality of life and survival rates significantly. Furthermore, the success of this delivery method could open new avenues for treating other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. By providing effective brain-targeted therapies, this approach has the potential to revolutionize treatment options and improve outcomes for a broad spectrum of neurological conditions.