This thesis presents the design and optimization of a dendrimer-based cationic nanoparticle system tailored for versatile applications, ranging from anti-inflammatory scavenging to targeted pain relief through endosomal delivery. By harnessing the unique attributes of this platform, various strategies were devised to overcome hurdles in drug delivery, offering promising avenues for nanomedicine in anti-inflammatory and nociceptive treatments.
In our scavenging screening project, we rigorously screened various materials to find the best universal anti-inflammatory carrier. We started by exploring the potential of dendrimer-based materials as scavengers of inflammatory signals and studied how they could be used to develop therapeutic carriers. With intrinsic therapeutic properties and the ability to create tunable nanocarriers, dendrimer-based delivery systems are powerful multimodal delivery systems. The dendrimer base of our delivery system, cationic PAMAM Generation 3 dendrimer (PAMAM-G3), was selected due to its efficient scavenging ability and low biotoxicity. Conjugation with cholesterol facilitated the formation of polymeric micelles, exhibiting a cationic and hydrophilic exterior coupled with a hydrophobic interior, resulting in a high drug-loading capacity. Among the developed scavengers, PAMAM-Cholesterol (PAMAM-Chol) nanoparticles demonstrated a potent reduction in toll-like receptor activation with minimal toxicity and extended endosomal retention.
We then exploited the endosomal retention of PAMAM-Chol nanoparticles to target the activated PAR2 receptor within endosomes of relevant cancer cells, aiming to alleviate oral cancer-induced nociception. Extensive characterization confirmed the platform's stability, physical attributes, and ability to encapsulate PAR2 inhibitor, AZ3451. The platform exhibited high drug loading capacity and sustained release profiles across various pHs. Cellular uptake studies demonstrated efficient endosomal targeting, with subsequent modulation of PAR2 signaling pathways. Preclinical studies in oral cancer pain models revealed a significant and prolonged reduction in nociception for over 24 hours, surpassing the efficacy of free drugs.
Further diversification of the PAMAM-Chol platform explored its potential as a "Push" chemotherapy carrier and a "Pull" cfDNA scavenger against chemotherapy-induced neurological and neuropathic side effects. Evaluation in wild-type mice demonstrated the platform's effectiveness in mitigating chemobrain and chemotherapy-induced peripheral neuropathy, highlighting its translational potential for multimodal cancer therapy. We found that NPs loaded with chemotherapy significantly reduced the painful effects of chemotherapy-induced peripheral neuropathy and decreased recovery times.
Collectively, this body of work underscores the potential of PAMAM-Chol as a versatile tool in drug delivery and endosome-localized pain therapeutics. It contributes to the evolving landscape of precision medicine through tailored therapeutic approaches for minimizing side effects and enhancing patient well-being. The innate therapeutic properties coupled with efficient and sustained drug delivery mechanisms position the PAMAM-Chol platform as a foundational element for the development and delivery of next-generation therapeutics.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/zgyk-b392 |
| Date | January 2024 |
| Creators | Bhansali, Divya |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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