Responsive chitosan-based microgels

Li, Helin; Pich, Andrij (Thesis advisor); Plamper, Felix Alois (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


Regarding the development of stimuli-responsive microgels as drug delivery systems for cancer therapies, improvements in biocompatibility, stability, and controlled release are the major challenges due to the generally limited dosages of anticancer drugs capable of being loaded, poor drug bioavailability, and non-specialized drug administration. To overcome those challenges, this Thesis presents various pH-sensitive biopolymer-based microgel systems which exhibit good biocompatibility and biodegradability (whilst producing non-toxic degradation by-products), thus demonstrating the great potential for the incorporation of various active agents including drugs and biologics. Based on these properties, microgels can be utilized as drug delivery vehicles for stimulus-triggered degradation and controlled drug delivery, thus suggesting that the presented microgel systems are good candidates for site-specific cancer therapies. This Thesis focuses on conductive polymer-based, as well as biopolymer-based microgels, for use in drug delivery systems. Chapter 1 provides an overview of different functional microgels. These microgels exhibit good biocompatibility, biodegradability, non-toxicity, pH-sensitivity, redox-activity, and adjustable chemical and mechanical properties. These properties endow them with a wide variety of applications, such as drug encapsulation, which facilitates their use as delivery systems, electrical sensors, and functional coatings, as well as their application in areas such as tissue regeneration and wastewater filtration. Chapter 2 introduces a controlled drug release system: drug-loaded biopolymer-based microgels. Due to the present problems faced with its use, such as insufficient cellular uptake as well as the numerous drug resistance mechanisms in cells, an anticancer drug, doxorubicin (DOX), has been developed to be capable of being encapsulated into nanocarriers. Moreover, this drug can also be released under the control of the microenvironment, most notably in tumor tissues. The Thesis details the preparation of cross-linked chitosan-poly(hydroquinone) (CHHQ) microgels with pH and redox sensitivity. Due to their pH-sensitivity, redox-activity, and biodegradability, CHHQ microgels have previously been exploited to load and release DOX. The loading of the active ingredient is achieved by means of physical entrapment of both π-π stacking and hydrogen bonding between chitosan, poly(hydroquinone), and DOX. The drug loading profiles were investigated and an encapsulation efficiency of 80.9% was observed. The drug release profiles show that approximately 43% of DOX is released over one hour at pH 6; contrastingly, very little DOX release is observed over the same time period at pH 7.4. These results suggest that CHHQ microgels are a promising anti-tumor drug carrier for anticancer drug delivery systems. Chapter 3 describes the development of chitosan-poly(aniline) (CH-PANI) microgels. These microgels exhibit both pH-sensitivity and redox-activity. The CH-PANI microgels are composed of chitosan and poly(aniline), using glutaraldehyde as the cross-linker. The degradation results show that CH-PANI microgels can be degraded in an acidic environment, in the presence of lysozyme. The results suggest that the prepared CH-PANI microgels hold great potential as drug delivery carriers for the selective delivery of therapeutics to acidic tissues, such as tumors. Chapter 4 details and explores how novel pH-sensitive dual-degradable dextran-chitosan (DE-CH) microgels are suitable as drug carriers for the efficient, targeted delivery of drugs to the colon. A series of DE-CH microgels were synthesized by cross-linking two modified biopolymers, alkyne-modified chitosan, and azide-modified dextran with varying azide:alkyne molar ratios from 1:0.5, 1:1, 1:1.5 to 1:2. The microgels were cross-linked via copper(II)-catalyzed azide-alkyne cycloaddition (CuAAC) without a cross-linker. By conducting dynamic light scattering (DLS) and electrophoretic mobility studies, it was demonstrated that the microgels were pH-sensitive. Under slightly acidic conditions, the microgels can be degraded in the presence of dextranase, an enzyme present in the colon. In addition, the prepared DE-CH microgels are capable of loading vancomycin hydrochloride (VM), an antibiotic effective against many gram-positive bacteria. The results showed an encapsulation efficacy of up to 93.7%, indicating a possible application for the microgels as an effective platform for site-specific targeted drug delivery (e.g., to the colon).