Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Dr. Sandro R.P. da Rocha

Second Advisor

Dr. Dennis Ohman

Third Advisor

Dr. Qingguo Xu

Fourth Advisor

Dr. Masahilo Sakagami

Fifth Advisor

Dr. Hu Yang


Pseudomonas aeruginosa (PA) is the predominant pathogen in chronic lung infections of cystic fibrosis (CF) patients. The most important mechanism of adaptation of PA to host defense and antibiotic treatment is the formation of biofilms within the mucus layer covering the lung bronchi. The effectiveness of antibiotics such as aminoglycosides is significantly attenuated by their limited penetration through thick mucus and embedded biofilm matrix in patients’ lung. Inhaled tobramycin (Tobra), which is the most commonly used antibiotics in the treatment of PA infections for CF patients, is usually found to be in very high concentration in patients’ lung, and yet still cannot prevent CF pulmonary exacerbation.

The purpose of this study was to develop biodegradable dendrimer nanocarriers (DNCs) with appropriate physicochemical characteristics that would promote carrier diffusion/penetration through PA biofilms and pulmonary mucus. We investigated the effect of surface charge of DNCs on their pentation and diffusion. The positive charge of amine-modified, fluorescently-tagged (FITC), generation 4 polyester dendrimers (G4OH-(NH2-FITC)) led to slower mobility in PA biofilms and model mucus layer compared to their PEG 1000Da-modified negatively charged analogs (G4OH-(NH2-FITC)-(PEG)) as measured by fluorescence recovery after photobleaching (FRAP). The enhanced penetration of the PEGylated analogs was attributed to the fact that PEG can act to modulate the interactions between DNCs and the negatively charged biopolymers in biofilm and mucus matrix upon shielding the surface of the otherwise positively charged carrier. The effectiveness of Tobra-dendrimer conjugates either modified with PEG (neutral, G4OH-(Tobra)-(PEG)) and non-PEGylated (positive charge, G4OH-(Tobra)) was assessed in planktonic and biofilms of non-mucoid (PAO1) and mucoid (FRD1) PA strains. The minimum inhibitory concentration (MIC) of Tobra hydrolyzed from the DNCs was of similar magnitude as to free Tobra, indicating that the conjugation and release of Tobra leads to bioactive drug as the non-released analog and G4OH themselves have MIC >> then free drug. By contrast, in an established PA biofilm model, PEGylated dendrimer-drug conjugates demonstrated a significantly stronger bioactivity in eliminating biomass at relatively higher concentration (8, 16 µg/mL) compared to free Tobra and the positively charged G4OH-(Tobra) in mucoid PA strain. Our results demonstrate a correlation between the surface characteristics of the dendrimer nanocarriers and their ability to efficiently penetrate PA biofilms, and also that those negatively charged dendrimer nanocarriers can lead to enhanced efficacy in reducing biofilm in relevant mucoid PA strains. Biodegradable dendrimer nanocarriers with appropriate design of surface chemistry can thus be a promising approach to overcome the antibiotic resistance in the treatment of biofilms in CF infections.

As our dendrimer-based antibiotics have the potential to be designed as an inhaled dosage form for CF patients in the future, we are also interested in the fate of aerosol particles after inhalation, including drug deposition and dissolution. Thus, we reviewed the most recent in vitro dissolution methodologies for oral inhaled drug products (OIDPs), along with whatever limited regulatory considerations exist for their dissolution study. From industry perspective, the dissolution testing of OIDPs for both innovative and generic drugs plays critical role in the context of bioequivalence assessment and quality assurance during formulation development.


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