Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy

Abstract

To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as ‘micelle pool’ drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML-shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre-loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention.

Micelle-in-Liposomes for Sustained Delivery of Anticancer Agents That Promote Potent TRAIL-Induced Cancer Cell Apoptosis

“…Zhang et al and Franzè et al both demonstrated a more sustained drug release from MIL than from micelles as we found in our research. However, neither of these two other papers provided a cryo-TEM image or other direct evidence to verify that the micelles were actually inside the aqueous core of the liposomes [ 33 , 34 ]. While Romana et al did provide a cryo-TEM image of a single liposome containing worm-like micelles inside, no ratio of liposomes containing micelles over all liposomes was reported [ 35 ].…”

Evaluation of the Physicochemical Properties, Pharmacokinetics, and In Vitro Anticancer Effects of Docetaxel and Osthol Encapsulated in Methoxy Poly(ethylene glycol)-b-Poly(caprolactone) Polymeric Micelles

“…Then, 20 μL of drug-loaded mPEG- b -PCL micelle solution was dissolved in 180 μL of ACN. The encapsulation efficiency (EE, %) and drug loading (DL, %) of DTX and OTH were calculated by using the equation below [ 54 , 55 , 56 ]: DL% = Weight of drug in micelles/weight of feeding drug and polymer × 100 EE% = Weight of drug in micelles/weight of feeding drug × 100 …”

Tumor Microenvironment‐Related Sonodynamic Therapy Mediates Tumor Therapy

“…Collagenase (CLG) can effectively destroy collagen and destroy dense ECM. [ 143 ] In an oxygenated nanosystem containing CLG (FePO 2 @HC), under the action of GSH, FePO 2 @HC can release CLG, destroy the dense structure of the ECM, promote FePO2 into the deep part of the tumor, release oxygen to alleviate hypoxia and promote the formation rate of ROS. [ 144 ] It has been proven that destroying the dense structure of the ECM can enhance the therapeutic effect of SDT, and this result mainly comes from the improvement of the penetration of the nanodrug delivery system.…”

“…Collagenase (CLG) can effectively destroy collagen and destroy dense ECM. [143] In an oxygenated nanosystem containing CLG (FePO 2 @HC), under the action of GSH, FePO 2 @HC can release CLG, destroy the a-c) Reproduced with permission. [124] Copyright 2020, American Chemical Society.…”