Abstract
Mesoporous silica (MS) particles have been explored for various healthcare applications, but universal data about their safety and/or toxicity are yet to be well-established for clinical purposes. Information about general toxicity of hollow MS (HMS) particles and about immunotoxicity of MS particles are significantly lacked. Therefore, acute toxicity and immunotoxicity of HMS particles were experimentally evaluated. A systematic and objective literature study was parallelly performed to analyze the published in vivo toxicity of MS particles. Lethal acute toxicity of MS particles is likely to arise from their physical action after intravenous and intraperitoneal administrations, and only rarely observed after subcutaneous administration. No clear relationship was identified between physicochemical properties of MS particles and lethality as well as maximum tolerated dose with some exceptions. At sub-lethal doses, MS particles tend to accumulate mainly in lung, liver, and spleen. The HMS particles showed lower inflammation-inducing ability than polyinosinic-polycytidylic acid and almost the same allergy-inducing ability as Alum. Finally, the universal lowest observed adverse effect levels were determined as 0.45, 0.81, and 4.1 mg/kg (human equivalent dose) for intravenous, intraperitoneal, and subcutaneous administration of MS particles, respectively. These results could be helpful for determining an appropriate MS particle dose in clinical study.
Highlights
These authors contributed : Lue Sun, Yu Sogo
The results show that Mesoporous silica (MS) and hollow MS (HMS) particles are promising immunoadjuvants for cancer therapy owing to superior depot and immune-activating effects [26, 27]
To evaluate the toxicity of s.c.-administered HMS particles, 250, 500, 1000, or 2000 mg/kg of HMS were administered by s.c. injection into mice
Summary
2.1 Synthesis of HMS particlesHMS particles were synthesized by hydrolysis of tetraethyl orthosilicate in an ethanol aqueous solution containing hexadecyltrimethylammonium bromide and ammonia followed by structure transformation in hot ultrapure water, according to a previously published protocol [26]. 2.2 Preparation of HMS particle suspension for administration in mice. After dry sterilization at 180 °C, the HMS particles were aseptically suspended in physiological saline by ultrasonication using an UT-105S (SHARP, Osaka, Japan) for over 4 h. 2.3 Single-dose toxicity testing as part of the safety evaluation of HMS particles. Page 3 of 15 102 randomly grouped into s.c., i.p., and i.v. groups (n = 5–10), and administered with 250–2000, 23–260, or 1–71 mg/kg of HMS particles, respectively, as a single-dose. The MTD was defined referring to previous papers [34, 35], as the maximum dose causing neither death nor serious adverse reactions (e.g., irregular breathing, over 10% weight loss and sluggish movement) in mice over 14 days postadministration
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