A Liposome-Micelle-Hybrid (LMH) Oral Delivery System for Poorly Water-Soluble Drugs: Enhancing Solubilisation and Intestinal Transport

A novel liposome-micelle-hybrid (LMH) carrier system was developed as a superior oral drug delivery platform compared to conventional liposome or micelle formulations. The optimal LMH system was engineered by encapsulating TPGS micelles in the aqueous core of liposomes and its efficacy for oral delivery was demonstrated using lovastatin (LOV) as a model poorly soluble drug with P-gp (permeability glycoprotein) limited intestinal absorption. LOV-LMH was characterised as unilamellar, spherical vesicles encapsulating micellar structures within the interior aqueous core and showing an average diameter below 200 nm. LMH demonstrated enhanced drug loading, water apparent solubility and extended/controlled release of LOV compared to conventional liposomes and micelles. LMH exhibited enhanced LOV absorption and transportation in a Caco-2 cell monolayer model of the intestine by inhibiting the P-gp transporter system compared to free LOV. The LMH system is a promising novel oral delivery approach for enhancing bioavailability of poorly water-soluble drugs, especially those presenting P-gp effluxes limited absorption

Controlled drug delivery from self-assembled hydrogels

Peptide gelators are useful building blocks for creating diverse self- assembled nanostructures, including novel drug delivery systems. The aim of this Thesis is to understand better the key contributing factors in the drug-delivery properties of peptide-based self-assembled hydrogels.Using the archetypical peptide gelators Fmoc (9-fluorenylmethoxycarbonyl)- FF (diphenylalanine); Fmoc-FF 1, as a starting point, the effect of gel concentration, temperature and the size of the (drug) molecule encapsulated on the rate of drug release was investigated. This study was then extended to other gelator including those with different headgroups and di- and tri-peptide analogoues of Fmoc-FF 1 where other hydrophobic amino acids were introduced. The variation in the gel properties such as stiffness correlated well with changes in drug release properties. This study was then extended to longer peptides, containing 4-6 amino acids and inspired by the elastin protein. The resulting elastin-like peptide hydrogels also show good drug release properties which when combined with their elastin-like structure, makes these peptide gelators good candidate for biomedical applications. To assist the release of drugs that are poorly-soluble in water, gelation of Fmoc-FF 1 in various PEG:water mixtures was investigated. This resulted in gels with good mechanical properties. Interestingly, the secondary structures in these gels appears different from gels from 1 in water. The gelation of 1 in this system can be explained by a combination of the macromolecular crowding and hydrophobic effects. Poorly soluble drugs are readily encapsulated and then released in this gel system. Finally, gels based on Fmoc-FF 1 in a mixture of PEG 400 and biological media were used to generate a scaffold for distance- and time-depended drug release in vitro drug release studies targeting the cancer cell line HeLa. A clear relationship between distance from the drug release plug and cell viability was observed in these studies. The work presented in this Thesis has broaden the knowledge drug release from self-assembled peptide gels. The results should therefore benefit further development of these materials for clinical application, be it in the treatment of diseases such as cancer or tissue engineering

Liposome-Micelle-Hybrid (LMH) Carriers for Controlled Co-Delivery of 5-FU and Paclitaxel as Chemotherapeutics

Paclitaxel (PTX) and 5-fluorouracil (5-FU) are clinically relevant chemotherapeutics, but both suffer a range of biopharmaceutical challenges (e.g., either low solubility or permeability and limited controlled release from nanocarriers), which reduces their effectiveness in new medicines. Anticancer drugs have several major limitations, which include non-specificity, wide biological distribution, a short half-life, and systemic toxicity. Here, we investigate the potential of liposome-micelle-hybrid (LMH) carriers (i.e., drug-loaded micelles encapsulated within drug-loaded liposomes) to enhance the co-formulation and delivery of PTX and 5-FU, facilitating new delivery opportunities with enhanced chemotherapeutic performance. We focus on the combination of liposomes and micelles for co-delivery of PTX and 5_FU to investigate increased drug loading, improved solubility, and transport/permeability to enhance chemotherapeutic potential. Furthermore, combination chemotherapy (i.e., containing two or more drugs in a single formulation) may offer improved pharmacological performance. Compared with individual liposome and micelle formulations, the optimized PTX-5FU-LMH carriers demonstrated increased drug loading and solubility, temperature-sensitive release, enhanced permeability in a Caco-2 cell monolayer model, and cancer cell eradication. LMH has significant potential for cancer drug delivery and as a next-generation chemotherapeutic

Cholic Acid-Based Antimicrobial Peptide Mimics as Antibacterial Agents

There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure–activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents