Lipid-Coated Mesoporous Silica Particles for pHSensitive Tumor-Targeted Paclitaxel: Development, Characterization

Abstract

Nanoparticle carriers can selectively deliver the drug cargo to tumor cells, thus having the ability to prevent early drug release, reduce non-specific cell binding, and prolong in vivo drug retention. We constructed paclitaxel (PTX)-loaded lipid-shell mesoporous silica nanoparticles (LMSNs) for targeted anti-cancer drug delivery. The physical properties of PTX-LMSNs were analyzed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The drug loading (DL%) and entrapment efficiency (EE%) of PTX-LMSNs were measured by high performance liquid chromatography (HPLC). In vitro drug release test, in vivo imaging, tissue distribution and pharmacokinetics of PTX LMSNs were also evaluated. The SEM examination showed that MSNs were sphere, whereas TEM showed that they were rich in fine pores. The uniform core-shell structure of PTX-LMSNs was also verified by TEM. The DL capacity of PTX-LMSN was as high as 21.75%, and PTX was released from the nanoparticles in vitro in a pH-dependent manner. The cumulative amount of free PTX increased at lower pH, which is conducive to selective drug release from LMSNs in the acidic tumor tissues. In vivo imaging showed prolonged retention of PTX-LMSNs, which is beneficial to their therapeutic efficacy. In addition, PTX-LMSNs were primarily concentrated in the liver. Pharmacokinetic experiments showed that the half-life of PTX-LMSNs was 23.21% longer and 79.24% higher than that of Taxol. Together, LMSNs are a highly promising antineoplastic drug carrier system.

Introduction

Chemotherapy is still an indispensable tool for treating advanced cancer. However, the inability of traditional anti-cancer drugs to specifically target tumor cells not only leads to serious systemic side effects but also limits their therapeutic effects. In recent years, nanoparticle drug delivery systems, such as liposomes, polymeric micelles, and multimers, have attracted extensive research attention in the field of antitumor drug carriers due to their unique drug loading capacity, targeted delivery characteristics, and controllable release performance [1-3]. Nanoscale carriers achieve passive tumor targeting by enhancing the osmotic retention effect (EPR), significantly increasing the accumulation concentration of drugs in tumor tissues, and improving the solubility and stability of hydrophobic drugs [4,5]. However, traditional carriers prepared by nano-preparations such as liposomes are unstable in body fluids and also release the drug cargo before reaching the tumor, resulting in serious adverse effects [6, 7].

Particle size is an important parameter for efficient delivery of nanocarriers to tumor sites, as well as for their high adsorption on the tumor cell surface, cellular uptake and intracellular transport, which eventually determine the efficacy of chemotherapy [8-10]. Stimuli-responsive drug delivery systems dynamically adjust the particle size in response to changes in pH, enzyme, heat or magnetic field of the tumor microenvironment, prolong the cycle and enhance the EPR effect in the early stage, and promote tumor penetration in the later stage, which can significantly improve the ability to penetrate deep tumor tissues, thereby optimizing the efficiency of drug delivery and balancing the contradiction between permeability and retention [11-13].Therefore, stimuli-responsive drug delivery systems can enhance the targeted accumulation of drugs at the lesion site, thereby improving the therapeutic effect and possibly reducing damage to normal tissues [14-16]. Stimulus-responsive drug delivery systems are designed to respond to a variety of physical and chemical stimuli such as temperature, electric field, pH, magnetic field, and ionic strength, with pH and temperature being widely used because they do not require additional lasers and cause less damage to normal tissues [17].

Mesoporous silica is biodegradable, and the degradation product, silicic acid, can be absorbed and excreted through the urinary system. Lee [18] reported that 0.1 mg/mL mesoporous silica nanoparticles (MSNs) could be completely degraded within 7 days in simulated body fluids in vitro. Although mesoporous silica nanoparticles (MSNs) have good biocompatibility, they still have two major limitations in practical applications: first, the drug is easy to leak in advance during delivery, and it is difficult to achieve precise targeted and controlled release; Second, the uptake efficiency is low in some specific cell types, such as primary cells and non-phagocytic cells, which directly affects the delivery and therapeutic efficacy of the drug. These deficiencies limit the wide application of MSN in clinical treatment to a certain extent [19]. Nevertheless, owing to their high surface area, pore volume, uniformity, biocompatibility and biodegradability, MSNs are highly promising inorganic drug carriers [20-22].

Lipid-shell and mesoporous silica core nanoparticles (LMSNs) combine the characteristics of nanoparticles and liposomes. The dual vesicular and particulate structure is associated with high biocompatibility, stability and favorable pharmacokinetic profile [23, 24]. Furthermore, drugs can be efficiently encapsulated within the polymer core or between the lipid bilayers of LMSNs, thus allowing LMSNs to have high loading capacity [25]. The polymer core might also delay drug diffusion and increase the stability of the lipid shell, thereby enhancing the encapsulation efficiency (EE) and system stability [26]. In contrast, polymer micelles are relatively less stable because they are thermodynamic self-assembled structures formed by reversible stabilizing forces such as hydrophobic effects and electrostatic interactions, which will inevitably be disintegrated by multiple instability mechanisms in complex in vivo environments, resulting in drug leakage, protein adsorption, and dilution below critical micelle concentrations [27]. However, it is challenging to achieve high EE and optimal particle size when LMSNs is incorporated into hydrophilic drugs. To this end, we are committed to the development of a high-efficiency paclitaxel (PTX) delivery system based on mesoporous silica nanoparticles (LMSNs), PTX-LMSNs. PTX-LMSNs makes full use of the advantages of high drug loading capacity and small particle size of mesoporous silica nanoparticles, and significantly improves the encapsulation efficiency and tumor targeting of the drug through careful surface modification and stimulus response design, effectively overcoming the defects of traditional polymer micelle drugs that are easy to leak and insufficient targeting, thereby greatly enhancing the anti-tumor effect and treatment accuracy of paclitaxel. LMSNs were prepared using a modified method, and PTX-LMSNs were comprehensively characterized. The distribution of the nanovehicles in mice was observed by real time in vivo imaging. The in vivo pharmacokinetics of the drug was also evaluated.

Download the full article as PDF here Lipid-Coated Mesoporous Silica Particles for pHSensitive

or read it here

Materials

Paclitaxel (PTX) was purchased from Hainan Yayuan Pharmaceutical Co. Ltd. (Hainan, China), ethyl orthosilicate (TEOS) was from Aladdin Chemical Reagent Co. Ltd. (Shanghai, China), cetyltrimethyl ammonium bromide (CTAB) was from McLean Chemical Reagent Co. Ltd. (Shanghai, China), NaHCO3 was from Tianjin Zhiyuan Chemical Reagent Factory (Tianjin, China), and 15-hydroxy stearic acid polyethylene glycol (Solutol HS-15) was from BASF Company. Egg yolk lecithin (PL100M) was purchased from Shanghai AVT Pharmaceutical Technology Co. Ltd. (Shanghai, China). Other chemicals and solvents were of analytical grade.

Lipid-Coated Mesoporous Silica Particles for pHSensitive Tumor-Targeted Paclitaxel: Development, Characterization, Journal of Cancer 2025, Vol. 16, Yingyue Deng, Tao Zhang, Jiaru Zhou, Zhihao Su, Yingsong Cao, Junxi Luo, Leming Zhao, Junjie Hua, Guoqiang Wang, Min Xiao, Junfeng Ban, Yan Zhang and Hongcai Liang, DOI 2025; 16(13): 3842-3850. doi: 10.7150/jca.117433