Synthesis of a gemcitabine-modified phospholipid and its subsequent incorporation into a single microbubble formulation loaded with paclitaxel for the treatment of pancreatic cancer using ultrasound-targeted microbubble destruction

Making waves: how ultrasound-targeted drug delivery is changing pharmaceutical approaches

“… 94 They combined a solution of chloroform and 1,2-dibehenoyl- sn-glycero -3-phosphocholine (DBPC) with another solution of gemcitabine, phospholipase D, and calcium chloride to generate a gemcitabine-carrying phospholipid complex that can be used to form the shell of a lipid microbubble. 94 The final microbubble consisted of the lipid-gemcitabine molecule, DSPE-PEG2000, and paclitaxel (5 : 1.43 : 2.5 weight ratio) surrounding a perfluorobutane core, and resulted in a 40% reduction in tumor growth in a BxPC-3 pancreatic cancer mouse model when administered in conjunction with ultrasound (1 MHz, 3.5 W cm −2 , 0.48 MPa). 94 In another approach, Dwivedi et al designed a DOX-loaded magneto-liposome-ligated microbubble complex, where the iron oxide nanoparticles were loaded with DOX then encapsulated within oligolamellar vesicles, which were then covalently conjugated to lipid-based microbubbles (1,2-distearoyl- sn-glycero -3-phosphocholine (DSPC))/cholesterol/DSPE-PEG2000-maleimide (60 : 20 : 20 molar ratio) with a perfluorooctane gas core.…”

“… 94 The final microbubble consisted of the lipid-gemcitabine molecule, DSPE-PEG2000, and paclitaxel (5 : 1.43 : 2.5 weight ratio) surrounding a perfluorobutane core, and resulted in a 40% reduction in tumor growth in a BxPC-3 pancreatic cancer mouse model when administered in conjunction with ultrasound (1 MHz, 3.5 W cm −2 , 0.48 MPa). 94 In another approach, Dwivedi et al designed a DOX-loaded magneto-liposome-ligated microbubble complex, where the iron oxide nanoparticles were loaded with DOX then encapsulated within oligolamellar vesicles, which were then covalently conjugated to lipid-based microbubbles (1,2-distearoyl- sn-glycero -3-phosphocholine (DSPC))/cholesterol/DSPE-PEG2000-maleimide (60 : 20 : 20 molar ratio) with a perfluorooctane gas core. 95 The resulting magneto-liposome-ligated microbubble complex improved pancreatic tumor targeting and tumoricidal activity (approximately 80% reduction in tumor volume) in a pancreatic cancer xenograft mouse model.…”

“…92,93 Recently, Logan et al developed a novel approach to loading a combination of drugs within a lipid-based microbubble by creating a drug-laden phospholipid molecule for use in a one-pot synthesis of a dual-loaded UCA. 94 They combined a solution of chloroform and 1,2-dibehenoyl-sn-glycero-3phosphocholine (DBPC) with another solution of gemcitabine, phospholipase D, and calcium chloride to generate a gemcitabine-carrying phospholipid complex that can be used to form the shell of a lipid microbubble. 94 The final microbubble consisted of the lipid-gemcitabine molecule, DSPE-PEG2000, and paclitaxel (5 : 1.43 : 2.5 weight ratio) surrounding a perfluorobutane core, and resulted in a 40% reduction in tumor growth in a BxPC-3 pancreatic cancer mouse model when administered in conjunction with ultrasound (1 MHz, 3.5 W cm À2 , 0.48 MPa).…”

The Effective Combination between 3D Cancer Models and Stimuli-Responsive Nanoscale Drug Delivery Systems

“…Several articles have reported investigations into US-responsive DDSs in 3D models [ 80 , 81 , 82 ]. Logan et al observed a significant reduction in MCF-7 spheroid volume, along with an increase in the number of necrotic cells when MCF-7 cells, which were organized into a 3D model, were treated with a combination of rose bengal, PTX, and doxorubicin, which were all loaded into a drug-delivery microbubble for the chemo-sonodynamic therapy of breast cancer [ 80 ].…”

“…Indeed, Logan et al developed human pancreatic cancer (PANC-1) spheroids to study a gemcitabine-modified phospholipid, which was formed into a single PTX-loaded microbubble formulation, and the responsiveness to US. They performed these in vitro experiments before investigating the US-triggered DDSs on a human pancreas adenocarcinoma (BxPC-3) tumor that was ectopically implanted into a mouse model [ 82 ]. Their data once again confirmed the usefulness of 3D cancer spheroids in providing predictive results before investigations move to in vivo models, as the 3D model is characterized by a lower level of uncertainty than 2D cell-cultures, at least in regard to experimental setups in the field of sonodynamic therapy.…”