Microfluidic platforms for the production of nanoliposomes for cancer therapy

This thesis investigates the manufacturing and development of nanoliposomes as delivery systems for chemotherapeutic drugs by applying the microfluidic technique. The research emphasises the advantages of using microfluidic technology over traditional methods in the formulation of the paclitaxel-loaded nanoliposomes and carboplatin-loaded nanoliposomes, highlighting its ability to produce size-controlled, monodispersed, and stable nanoformulations.

It aims to harness the control and precision microfluidic systems offer to create various kinds of nanoliposomes, including conventional, PEGylated, and elastic nanoliposomes. The primary focus is utilising the microfluidics technique to achieve nanoliposomes with diameters below 200 nm, low polydispersity index <0.25, high encapsulation efficiency, and good stability. In the first experimental chapter, an investigation was conducted to examine a wide range of lipid compositions and ratios, alongside varying the microfluidic parameters, such as total flow ratio and/or flow rate ratio, to optimise the physiochemical properties of the nanoliposomes and determine the optimum formulation for paclitaxel encapsulation.

Additionally, the research investigates the effect of PEGylation on nanoliposomes, revealing that PEGylated liposomes show improved stability compared to conventional liposomes. The studies examine the impact of altering the DSPE-PEG2000 to DPPC to cholesterol ratio and microfluidic parameters that influence the resulting nanoliposomes' particle size, polydispersity index, and stability. Afterwards, the non-PEGylated and PEGylated optimised formulations were utilised to conduct a comparative study examining the efficacy of encapsulating hydrophilic chemotherapies.

These nanoliposomes were loaded with carboplatin throughout the study, and their physicochemical characteristics and encapsulation efficiency were compared. After all, a unique and novel study was conducted to explore the capability of the microfluidic in manufacturing elastic nanoliposomes—an evaluation of the microfluidic system efficiency to optimise the characteristics of the elastic nanoliposomes for dermal drug delivery.

The unloaded nanoliposome analysis was conducted using several techniques, including dynamic light scattering, fourier-transform infrared spectroscopy, and atomic force microscopy, and the optimum formulations were utilised for chemotherapy encapsulation. Further examination was conducted on the chemotherapy-loaded nanoliposomes to determine the encapsulation efficiency and in vitro release. The results demonstrate that multiple parameters can impact the characteristics of the nanoliposomes, including the lipid type and ratio, the surface modification, and the manufacturing method parameters.

The results of the first experimental chapter showed an impact of the lipid type and ratio on the nanoliposome size, polydispersity index, and encapsulation effectiveness. The DPPC and DMPC lipids with a 2:1 lipid-to-cholesterol ratio produced liposomes with optimal size < 180 nm, improved polydispersity index < 0.2, high encapsulation efficiency > 90% and good stability. Moreover, the effect of the microfluidic parameters was highly noticeable, specifically the flow rate ratio; increasing the FRR decreases the aggregation and produces smaller nanoliposomes.

The exact impact of the FRR was reported for PEGylated nanoliposomes; the results show a significant effect of the FRR and PEG lipid ratio on the liposomes' physicochemical characteristics. Among the prepared formulations, two were size-controlled, had low polydispersity, and had good stability. The average encapsulation efficiency was >90% for both formulations, and the drug release was sustained.

However, the PEGylated nanoliposomes were ineffective as drug carriers for hydrophilic molecules; the PEGylated liposomes demonstrated smaller diameters and more excellent stability, while conventional liposomes showed better homogeneity and higher encapsulation efficiency for carboplatin. The results showed that the microfluidic system enhanced the encapsulation efficiency of carboplatin significantly compared to the traditional methods.

Moreover, the microfluidic showed a revolutionary addition to elastic liposome manufacturing. The results reveal the microfluidics' significant impact in enhancing the elastic liposome size, polydispersity, and encapsulation efficiency. Likewise, the edge activator type and concentration, Tween 80 formulations with optimised concentration, provide the most suitable size and higher encapsulation efficiency.

The release profile of the formulations showed more immediate release from the EL with higher edge activator concentration and a higher % of the released dug from the Tween 80 formulations.<br><br>