Mesoporous Silica Nanocarriers for triggered drug delivery in the treatment of cancer
Citation:
Toselli, Sara, Mesoporous Silica Nanocarriers for triggered drug delivery in the treatment of cancer, Trinity College Dublin, School of Pharmacy & Pharma. Sciences, Pharmacy, 2024Download Item:
Abstract:
Cancer is the second leading cause of death globally, accounting for 10 million deaths in 2020.
Cancer chemotherapy is currently limited by a high systemic toxicity that occurs as a result of high systemic dosing and the failure of non-targeted drugs to reach therapeutic doses at the target site. There is an urgent need for improved carrier systems able to deliver diagnostic agents and anti-cancer drugs to the tumour. One of the most promising approaches is based on the design of site-specific and stimuli-responsive controlled drug delivery systems (DDSs), which is of major interest for researchers worldwide. Basically, a DDS is a formulation that controls the rate and period of drug delivery and targets specific areas in the body. Mesoporous silica nanocarriers (MSNs) have received growing attention as drug carriers. Due to their stable and rigid framework under extreme conditions compared to organic DDSs, silica carriers may not suffer from uncontrollable drug release owing to an accelerated degradation in a physiological environment but release the drugs in a sustained way when suitably functionalised.
The overall aim of this research project is to develop biocompatible nanoparticles based on mesoporous silica for the delivery of contrast agent(s) and/or chemotherapeutic drug(s) for the diagnosis and/or therapy of lung cancer, that can serve as a starting step to build libraries of nanoparticles for improving the diagnosis and treatment of multiple cancers.
The objective is to detect abnormal cells with high specificity and sensitivity. The MSNs will respond promptly to the presence of known specific biomarker(s), by releasing the contrast agent(s) and consequently providing a warning signal. In a similar fashion, the MSNs could be loaded with chemotherapeutic agent(s) to provide a stimuli-responsive release triggered by the presence of the tumour biomarker(s).
The present work focused on the development of MSNs using a sol-gel method, resulting in nanoparticles (NPs) with typical features of MCM-41 type MSNs, including a spherical shape and uniform size distribution of around 100 nm, hexagonal mesopore order, and pores with a size of 2-3 nm. The NPs were loaded with paclitaxel, which showed higher toxicity towards human and murine lung cancer cells (A549 and LLC1, respectively), when compared to doxorubicin hydrochloride. To achieve selective release in the tumour environment and protect the loaded drug from premature release, the NPs were functionalized by coating their surface with two different polymers: one type had a layer of poly- (ethylene glycol) methyl ether thiol (PEG), and another type a gelatine shell (GEL). The surface functionalization improved the particles' colloidal stability and dispersibility, as well as their biocompatibility towards cancer cells (when unloaded). Moreover, it allowed for a controlled release of the payload in response to specific stimuli (glutathione for PEG-functionalised MSNs, and metalloproteinases for GEL-functionalised MSNs).
In vitro release assays and cytotoxicity studies with A549 and LLC1 lung cancer cells confirmed the ability of the functionalized NPs to protect the payload from premature release and selectively deliver to the cancer cells. Flow cytometry and confocal analysis demonstrated that the PEG- and GEL-functionalised MSNs were taken up by lung cancer cells after only one hour. Preliminary hemocompatibility studies showed low toxicity of the synthesised NPs towards red blood cells and platelets.
PEG- and GEL-functionalised MSNs loaded with DOX were tested in vitro on a well-established 3D cell model of glioblastoma multiforme in order to analyse their toxicity and internalization capabilities in a system that better mimics the complexity and three-dimensional (3D) architecture of a tumour found in vivo. This study provided evidence of the successful penetration and distribution of the NPs within the spheroids structure, and the effectiveness of both PEG- and GEL-functionalised MSNs in delivering DOX.
In vivo studies in C57/BL6 male mice bearing lung cancer demonstrated that MSNs-PEG were well tolerated, as opposed to MSNs-GEL which accumulated in liver, spleen and lungs causing tissue inflammation and a possible increase in oxidative stress. Efficacy studies with the PTX loaded NPs demonstrated an improved delivery of the drug to the tumour site, as opposed to the free drug in cremophor/ethanol (CrEL).
In summary, the present study aimed to create a stimuli-responsive nanoparticle-based system that can enhance the detection and treatment of cancer, while minimizing the impact on healthy cells. This approach could have significant implications for improving cancer therapy by mitigating the issue of non-targeted cytotoxic drug release.
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European Research Council (ERC)
Wellcome Trust
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:TOSELLISDescription:
APPROVED
Author: Toselli, Sara
Advisor:
Ruiz-Hernandez, EduardoSantos-Martinez, Maria J
Publisher:
Trinity College Dublin. School of Pharmacy & Pharma. Sciences. Discipline of PharmacyType of material:
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