Enhancing Doxorubicin Delivery in Solid Tumor by Superhydrophobic Amorphous Calcium Carbonate–Doxorubicin Silica Nanoparticles with Focused Ultrasound

Abstract

The current approach of delivering chemotherapy via pH-sensitive amorphous calcium carbonate−doxorubicin silica nanoparticles (ADS NPs) faces the challenge of insufficient drug dose due to drug instability within the bloodstream and poor tumor penetration. To overcome these long-standing obstacles, we proposed a superhydrophobic coating on the surface of the ADS NPs that could be easily modified via fluorination (ADSF NPs). The surface of fluorinated ADS NPs was further modified with a phospholipid layer to reduce aggregation and improve biocompatibility (ADSFL NPs). The contact angle and mean size of ADSFL NPs were 30.2 ± 4.4°and 353.1 ± 54.2 nm, respectively. The superhydrophobic layer generated interfacial nanobubbles on the outer shell of the NPs that reduced waterinduced leakage of doxorubicin (DOX) sevenfold compared with the uncoated group and induced a cavitation effect upon ultrasound (US) sonication. Moreover, release of DOX from the ADSFL NPs could be triggered by US, and this release was further improved 1.6-fold in acidic aqueous conditions, indicating that the ADSFL NPs retained pH responsiveness. Enhanced sonography contrast and histological examination demonstrated that US could trigger cavitation activities from ADSFL NPs in vivo to induce vessel disruption and enhance the fluorescence intensity of DOX within the tumor region threefold under US imaging guidance compared with the ADSFL NPs-only group.

Efficient ultrasound-mediated drug delivery to orthotopic liver tumors – Direct comparison of doxorubicin-loaded nanobubbles and microbubbles

“…Prior research has primarily examined MBs and NBs in flank tumor models (84)(85)(86), where human cell lines are implanted in the subcutaneous region of animals, allowing easy tumor monitoring. However, these models can differ immunologically and phenotypically from orthotopic models, where tumors naturally form (87,88).…”

Calcium Carbonate-Based Nanoplatforms for Cancer Therapeutics: Current State of Art and Future Breakthroughs

“…In ultrasound imaging, the CaCO 3 -based contrast agent showed strong echo signals and excellent echo persistence in tumor tissue . In order to solve the low penetration efficiency of drugs in tumors, Chiang et al constructed CaCO 3 -DOX silica NPs by surface modification with fluorination . A phospholipid layer (ADSFL NPs) was used to coat the surface of fluorinated CaCO 3 -DOX silica NPs to attenuate aggregation and enhance the biocompatibility.…”

“… 67 In order to solve the low penetration efficiency of drugs in tumors, Chiang et al constructed CaCO 3 -DOX silica NPs by surface modification with fluorination. 68 A phospholipid layer (ADSFL NPs) was used to coat the surface of fluorinated CaCO 3 -DOX silica NPs to attenuate aggregation and enhance the biocompatibility. Compared with the uncoated group, the outer shell of ADSFL NPs could generate interfacial nanobubbles induced by the superhydrophobic layer, which reduced the chance of DOX leakage into water by 7-fold and induced cavitation upon ultrasonic treatment.…”

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring

“…4 The invasive glioma cells rapidly infiltrate and conceal themselves within the brain tissue, making it impossible to completely eliminate the malignant cells through surgery, chemotherapy, and radiotherapy. 5 Although chemotherapy has been used extensively for the treatment of brain tumors, most chemotherapeutics do not effectively cross the BBB. 6 This is attributed to the overexpression of P-glycoprotein efflux pumps in the tumor cells, resulting in the emergence of multidrug resistance.…”

“…Astrocytes, oligodendrocyte progenitor cells, and neural stem cells may all be the cell of origin of this disease . The invasive glioma cells rapidly infiltrate and conceal themselves within the brain tissue, making it impossible to completely eliminate the malignant cells through surgery, chemotherapy, and radiotherapy . Although chemotherapy has been used extensively for the treatment of brain tumors, most chemotherapeutics do not effectively cross the BBB .…”