Noncovalent Surface Locking of Mesoporous Silica Nanoparticles for Exceptionally High Hydrophobic Drug Loading and Enhanced Colloidal Stability

Abstract

Advances in water-insoluble drug delivery systems are limited by selective delivery, loading capacity, and colloidal and encapsulation stability. We have developed a simple and robust hydrophobic-drug delivery platform with different types of hydrophobic chemotherapeutic agents using a noncovalent gatekeeper's technique with mesoporous silica nanoparticles (MSNs). The unmodified pores offer a large volume of drug loading capacity, and the loaded drug is stably encapsulated until it enters the cancer cells owing to the noncovalently bound polymer gatekeeper. In the presence of polymer gatekeepers, the drug-loaded mesoporous silica nanoparticles showed enhanced colloidal stability. The simplicity of drug encapsulation allows any combination of small chemotherapeutics to be coencapsulated and thus produce synergetic therapeutic effects. The disulfide moiety facilitates decoration of the nanoparticles with cysteine containing ligands through thiol-disulfide chemistry under mild conditions. To show the versatility of drug targeting to cancer cells, we decorated the surface of the shell-cross-linked nanoparticles with two types of peptide ligands, SP94 and RGD. The nanocarriers reported here can release encapsulated drugs inside the reducing microenvironment of cancer cells via degradation of the polymer shell, leading to cell death.

Spatiotemporally and Sequentially-Controlled Drug Release from Polymer Gatekeeper–Hollow Silica Nanoparticles

“…Unmodified pores of the HMSN shell with a large surface area can hold CPT by physical adsorption29303132, and Dox·HCl can be entrapped into the unmodified pores and hollow inner core44. Our previous work highlighted the importance of unmodified pores to hold an exceptionally large mass of a drug and to release it upon specific stimuli3334. Consistent with the previous investigation, the Dox·HCl -loading efficiency up to 36 wt%, while the CPT-loading efficiency reached 80 wt%, with the proportional feeding ratio (Table 1).…”

“…To overcome these issues, polymer gatekeepers have been used in MSNs, which was shown to result in stable colloidal properties3334. Consistently, no meaningful change in the PHMSN size was observed upon incubation with phosphate-buffered saline (PBS), pH 7.4, RPMI medium with 10% fetal bovine serum (FBS), and sodium acetate buffer, pH 5.5, for up to 72 h, indicating stable colloidal properties under physiological conditions, which may prevent undesired drug leakage before reaching target sites (Figure S3).…”

“…The mass of CPT loaded into the nanoparticles were calculated from the supernatant and washed supernatant solution. The amount of CPT loaded were calculated using the UV-Vis absorption spectra using a molar absorption coefficient of 42,282 M −1 cm −1 with λ max  = 365 nm34. Then the nanoparticles dispersed in 1 mL of DI water under gentle vortexing, to this solution, 2.5 mg, 5.0 mg and 7.5 mg of Dox·HCl were added, dissolved and allowed to stir for a period of 24 h in RT.…”

“…1). Polymer gatekeepers, non-covalently attached to the surface of HMSNs, safely retain the cargos in storage until reaching the target site and successfully deliver the cargos into cancer cells via suitable release ways3334. Furthermore, a stimuli-responsive charge reversal component was incorporated in HMSNs to accomplish programmable specific targeting of the tumour site.…”

Protein-gold clusters-capped mesoporous silica nanoparticles for high drug loading, autonomous gemcitabine/doxorubicin co-delivery, and in-vivo tumor imaging

“…[55] Insulin molecules were grafted on the MSN surface capped with a glucose-responsive system, while the pores were loaded with the second cargo. Palanikumar and coworkers very recently demonstrated than the loading capacity of MSN could reach 80 wt% through higher drug concentrations in loading solutions, [56,57] unlike the typical 10 wt% threshold of previous reports. Building on this discovery, they loaded Gold nanoclusters (AuNCs) bioconjugated with proteins are highly attractive for bio-imaging as they are easily and reproducibly prepared, biocompatible, and have an intense red-NIR emission with high photo-stability, long fluorescence lifetime, and two photon excitation.…”