Abstract:

Intravesical drug delivery (IDD) is a direct administration of chemotherapeutic agents into the urinary bladder via insertion of a catheter. The major limitations of this treatment are poor retention of the drug in the bladder due to dilution and wash out during periodical micturition, low permeability of the urothelium, and intermittent catheterisations. Additionally, frequent use of catheters is uncomfortable for the patients and has potential risks of irritation, inflammatory reactions and infections. To counteract these limitations associated with low drug permeability, mucoadhesive formulations offer great promise. A number of mucoadhesive materials have been researched, including the use of hydrophilic polymers of both natural and synthetic type, such as chitosan, carbomers and cellulose derivatives. Mucoadhesive polymers are capable of adhering to and retaining on mucosal tissues. Various chemical approaches could also be used to enhance the mucoadhesive properties of these materials by introducing specific functional groups such as thiols, acrylates, catehols and maleimides. Thus, use of chemically modified and enhanced mucoadhesive polymers could significantly improve the efficacy of IDD by prolonging the drug residence in the bladder and reduce the need for frequent catheterisations.

This study reports the design of maleimide-functionalised poly(lactide-co-glycolide)-block-poly(ethyleneglycol) (PLGA-PEG-Mal) nanoparticles (NPs) as potential mucoadhesive formulations for IDD to the urinary bladder. Four types of NPs were developed using PLGA-PEG containing 3 and 5 kDa PEG with and without maleimide terminal groups. Their physicochemical characteristics have been investigated using dynamic light scattering, transmission electron microscopy and small-angle neutron scattering techniques. It was established that the size of NPs was dependent on the solvent used in their preparation and molecular weight of PEG, for example, 105 ± 1 nm and 68 ± 1 nm particles were formed from PLGA20K-PEG5K in dimethyl sulfoxide and acetone, respectively. The hydrophobic nature of PLGA-based core of the NPs provided an excellent opportunity for formulating poorly water-soluble compound as a model drug. These NPs were loaded with lipophilic fluorescein and their retention on freshly excised lamb bladder mucosa was studied and assessed using a wash-off in vitro technique with fluorescent detection. It was demonstrated that maleimide-functionalised PLGA-PEG-Mal NPs exhibited greater retention on bladder mucosa compared to unmodified counterparts and withstand wash out effect caused by periodic irrigation with artificial urine solution. The adhesion of maleimide decorated NPs is due to their ability to form covalent linkages with thiols present in mucin layer of the bladder epithelium. Additionally, the assessment of the biocompatibility of PEG-Mal using the slug mucosal irritation in vivo test revealed that these materials are non-irritant to mucosal surfaces.