Nucleus-Targeted, Echogenic Polymersomes for Delivering a Cancer Stemness Inhibitor to Pancreatic Cancer Cells

Abstract

Chemotherapeutic agents for treating cancers show considerable side effects, toxicity, and drug resistance. To mitigate the problems, we designed nucleus-targeted, echogenic, stimuli-responsive polymeric vesicles (polymersomes) to transport and subsequently release the encapsulated anticancer drugs within the nuclei of pancreatic cancer cells. We synthesized an alkyne-dexamethasone derivative and conjugated it to N-polyethylene glycol (PEG)-polylactic acid (PLA) copolymer employing the Cu catalyzed "Click" reaction. We prepared polymersomes from the dexamethasone-PEG-PLA conjugate along with a synthesized stimuli-responsive polymer PEG-S-S-PLA. The dexamethasone group dilates the nuclear pore complexes and transports the vesicles to the nuclei. We designed the polymersomes to release the encapsulated drugs in the presence of a high concentration of reducing agents in the nuclei of pancreatic cancer cells. We observed that the nucleus-targeted, stimuli-responsive polymersomes released 70% of encapsulated contents in the nucleus-mimicking environment in 80 min. We encapsulated the cancer stemness inhibitor BBI608 in the vesicles and observed that the BBI608 encapsulated polymersomes reduced the viability of the BxPC3 cells to 43% in three-dimensional spheroid cultures. The polymersomes were prepared following a special protocol so that they scatter ultrasound, allowing imaging by a medical ultrasound scanner. Therefore, these echogenic, targeted, stimuli-responsive, and drug-encapsulated polymersomes have the potential for trackable, targeted carrier of chemotherapeutic drugs to cancer cell nuclei.

Dexamethasone Conjugates: Synthetic Approaches and Medical Prospects

“…Click chemistry is a product synthesis procedure that combines small modular units and is characterized by "green" one-pot synthesis conditions, high specificity, and high product yield, as well as minimal and non-toxic by-products [85]. Therefore, click reactions, including Cu(I)-catalyzed azide-alkyne cycloaddition and Cu(II)-catalyzed [3 + 2] azidealkyne cycloaddition, have been used for the synthesis of DEX conjugates [86][87][88][89][90].…”

“…An in vivo study comparing the conjugate to the equivalent dose of free DEX showed that a single administration of the DEX-PEG conjugate provided a long-term (>15 days) reduction in ankle joint inflammation in a rat model of adjuvant-induced arthritis. Karandish et al [87] used Cu(II)-catalyzed azide-alkyne cycloaddition to design nucleus-targeted, stimuli-responsive polymersomes for the delivery of anticancer drugs to the nuclei of pancreatic cancer cells. In this case, the DEX group was used to improve the transport of the drug carriers to the nuclei via dilation of the nuclear pore.…”

“…The nuclear uptake studies showed that the targeted DEX-containing polymersomes were present in pancreatic cancer cell nuclei after 3 h of incubation, while non-targeted DEX free polymersomes did not penetrate the cells. Karandish et al [87] used Cu(II)-catalyzed azide-alkyne cycloaddition to design nucleus-targeted, stimuli-responsive polymersomes for the delivery of anticancer drugs to the nuclei of pancreatic cancer cells. In this case, the DEX group was used to improve the transport of the drug carriers to the nuclei via dilation of the nuclear pore.…”

“…Figure 8. Scheme for the synthesis of a dexamethasone conjugate with N 3 -polyethylene glycolpolylactic acid copolymer by Cu(II)-catalyzed cycloaddition[87].…”

Echogenic exosomes as ultrasound contrast agents

“…Exosomes were thawed at room temperature. 49 Once the exosomes reached room temperature, 210 mL of exosomes were added dropwise to 1.5 mL of 320 mM mannitol-HEPES buffer (pH 7.4) while stirring. Aer 10 minutes of stirring, pressurized ltered ambient air was bubbled in for 45 minutes.…”