Abstract
The wide-scale use of liposomal delivery systems is challenged by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes but are limited by low efficiencies (passive) or high drug specificities (active). Here, we present an efficient and universal loading strategy for synthesizing therapeutic liposomes. Integrating a thermal equilibration technique with our unique liposome synthesis approach, co-loaded targeting nanovesicles can be engineered in a scalable manner with potencies 200-fold higher than typical passive encapsulation techniques. We demonstrate this capability through simultaneous co-loading of hydrophilic and hydrophobic small molecules and targeted delivery of liposomal Doxorubicin to metastatic breast cancer cell line MDA-MB-231. Molecular dynamic simulations are used to explain interactions between Doxorubicin and liposome membrane during thermal equilibration. By addressing the existing challenges, we have developed an unparalleled approach that will facilitate the formulation of novel theranostic and pharmaceutical strategies.
Highlights
Decades of research have resulted in a variety of liposomal formulations for use in both therapeutic [1–3] and theranostic [4–6] applications
We have developed a novel approach to sequester small molecules rapidly and efficiently
We found that the liposomes remain stable in water and PBS without change in size for at least 24 h at 37 ◦C, whereas an increase in size of approximately 10% from 105.9 ± 10.2 nm to 117.8 ± 15.3 nm was observed when incubated with 10% Fetal Bovine Serum (FBS). (Supplementary Figure S4A)
Summary
Decades of research have resulted in a variety of liposomal formulations for use in both therapeutic [1–3] and theranostic [4–6] applications. Advances in synthesis procedure and membrane functionalization have led to targeting and stealth capabilities, which can increase bioavailability at disease sites several fold with minimal side effects, compared to systemically administered drugs [7,8]. These improvements have in turn led to the FDA approval and commercial use of several liposomal drugs, including Doxil® for cancer [9], Abelcet® for fungal infections [10], and DepoDur® for pain management [11], and more recent Moderna/Pfizer vaccines for Covid-19 [12]. Liposomes form within the media containing drug molecules, encapsulating the drug in the process This approach is typically performed with dilute solutions, and the encapsulation efficiencies are relatively low [14]. Organic solvents (e.g., chloroform and ethanol) are typically used, that can inactivate certain molecules [15]
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