The control of epidermal growth factor grafted on mesoporous silica nanoparticles for targeted delivery

The performance of biomaterials in a biological environment is largely influenced by the surface properties of the biomaterials. In particular, grafted targeting ligands significantly impact the subsequent cellular interactions. The utilisation of a grafted epidermal growth factor (EGF) is effective for targeted delivery of drugs to tumours, but the amount of these biological attachments cannot be easily quantified as most characterization methods could not detect the extremely low amount of EGF ligands grafted on the surface of nanoparticles. In this study, hollow mesoporous silica nanoparticles (HMSNs) were functionalized with amine groups to conjugate with EGFs via carbodiimide chemistry. Time of flight secondary ion mass spectrometry (ToF-SIMS), a very surface specific technique (penetration depth <1.5 nm), was employed to study the binding efficiency of the EGF to the nanoparticles. Principal component analysis (PCA) was implemented to track the relative surface concentrations of EGFs on HMSNs. It was found that ToF-SIMS combined with the PCA technique is an effective method to evaluate the immobilization efficiency of EGFs. Based on this useful technique, the quantity and density of the EGF attachments that grafted on nanoparticles can be effectively controlled by varying the EGF concentration at grafting stages. Cell experiments demonstrated that the targeting performance of EGFR positive cells was affected by the number of EGFs attached on HMSNs.

Development of ligand incorporated chitosan nanoparticles for the selective delivery of 5-fluorouracil to colon

Drug delivery systems with active targeting ligand provide improved therapeutic efficiency due to the selectivity towards tumor cells. In this paper we prepared drug loaded nanoparticles (NPs) using folate (FA) incorporated chitosan (FA-CS) based on ionic gelation technology. FA-CS NPs were spherical in shape with an average particle size of 100 nm, while 5-fluorouracil (5-FU) loaded NPs became less circular with average particle size of 100-500 nm. NPs made from FA-CS conjugates exhibited improved capability to encapsulate hydrophilic 5-FU. It was found 5-FU distributed in FA-CS NPs in solid solution state. In vitro release results demonstrated the release of 5-FU from FA-CS NPs was more controllable as compared to that of CS NPs.

Fabrication of high specificity hollow mesoporous silica nanoparticles assisted by Eudragit for targeted drug delivery.

Hollow mesoporous silica nanoparticles (HMSNs) are one of the most promising carriers for effective drug delivery due to their large surface area, high volume for drug loading and excellent biocompatibility. However, the non-ionic surfactant templated HMSNs often have a broad size distribution and a defective mesoporous structure because of the difficulties involved in controlling the formation and organization of micelles for the growth of silica framework. In this paper, a novel "Eudragit assisted" strategy has been developed to fabricate HMSNs by utilising the Eudragit nanoparticles as cores and to assist in the self-assembly of micelle organisation. Highly dispersed mesoporous silica spheres with intact hollow interiors and through pores on the shell were fabricated. The HMSNs have a high surface area (670m(2)/g), small diameter (120nm) and uniform pore size (2.5nm) that facilitated the effective encapsulation of 5-fluorouracil within HMSNs, achieving a high loading capacity of 194.5mg(5-FU)/g(HMSNs). The HMSNs were non-cytotoxic to colorectal cancer cells SW480 and can be bioconjugated with Epidermal Growth Factor (EGF) for efficient and specific cell internalization. The high specificity and excellent targeting performance of EGF grafted HMSNs have demonstrated that they can become potential intracellular drug delivery vehicles for colorectal cancers via EGF-EGFR interaction.

Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.

Biodegradable Eri silk nanoparticles as a delivery vehicle for bovine lactoferrin against MDA-MB-231 and MCF-7 breast cancer cells

This study used the Eri silk nanoparticles (NPs) for delivering apo-bovine lactoferrin (Apo-bLf) (~2% iron saturated) and Fe-bLf (100% iron saturated) in MDA-MB-231 and MCF-7 breast cancer cell lines. Apo-bLf and Fe-bLf-loaded Eri silk NPs with sizes between 200 and 300 nm (±10 nm) showed a significant internalization within 4 hours in MDA-MB-231 cells when compared to MCF-7 cells. The ex vivo loop assay with chitosan-coated Fe-bLf-loaded silk NPs was able to substantiate its future use in oral administration and showed the maximum absorption within 24 hours by ileum. Both Apo-bLf and Fe-bLf induced increase in expression of low-density lipoprotein receptor-related protein 1 and lactoferrin receptor in epidermal growth factor (EGFR)-positive MDA-MB-231 cells, while transferrin receptor (TfR) and TfR2 in MCF-7 cells facilitated the receptor-mediated endocytosis of NPs. Controlled and sustained release of both bLf from silk NPs was shown to induce more cancer-specific cytotoxicity in MDA-MB-231 and MCF-7 cells compared to normal MCF-10A cells. Due to higher degree of internalization, the extent of cytotoxicity and apoptosis was significantly higher in MDA-MB-231 (EGFR+) cells when compared to MCF-7 (EGFR-) cells. The expression of a prominent anticancer target, survivin, was found to be downregulated at both gene and protein levels. Taken together, all the observations suggest the potential use of Eri silk NPs as a delivery vehicle for an anti-cancer milk protein, and indicate bLf for the treatment of breast cancer.