Trigger-responsive nanomedicines through controlled chemistry

The aim of my Ph.D. thesis is to develop trigger-responsive prodrug platform to address the nanoparticle (NP) formulation issue in cancer therapeutics. By designing a trigger-responsive camptothecin (CPT) prodrug structure, it was demonstrated for the first time that a small molecule prodrug could be encapsulated in PEGylated nanoparticles with quantitative drug loading efficiency and more than 50% drug loading. The nanoparticles were shown to have controlled release profile in response to cancer-specific trigger. A series of dimeric CPT derivatives were designed that are responsive to various in vivo applicable triggers to study the formulation mechanism. The prodrug library suggested that the dimeric prodrug structure and the flexible trigger-responsive side chain are both critical to the high drug loading formulation. A hypoxia-responsive CPT dimeric prodrug was further developed and was co-encapsulated with photodynamic sensitizer, chlorin e6, in one NP for combination therapy to combat tumor resistance to photodynamic therapy (PDT) caused by a hypoxic environment. The ultra-high drug loading nanoparticles with controllable release and defined nano-structure mark a milestone in the formulation of nanomedicine and will have significant impact on nanomedicine platform design as well as their clinical translation. In connection with the dimeric prodrug design, a trigger-responsive amphiphilic polymeric nano-assembly is also explored for cancer treatment based on thiol-responsive chain-shattering polymeric therapeutics. The polymeric therapeutics showed controlled self-assembly behavior and good in vivo anti-tumor efficacy. To develop novel polymeric biomaterials for biomedical application, I also studied dynamic aromatic hindered urea chemistry as degradable polymeric materials. The aromatic hindered ureas have hundred times higher dynamic exchange kinetics (k-1) than the reported aliphatic hindered ureas and showed fast hydrolytic degradation in polymers with pH-independent kinetics. The room temperature self-healing property of the aromatic hindered ureas in a cross-linked gel was explored as a proof of concept as a potent self-healable biomaterials.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Materials Science & Engr

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Cai, Kaimin

Contributors dc:contributor

• Lu, Yi
• Cheng, Jianjun
• Ferguson, Andrew L.
• Kilian, Kristopher A.
• Leal, Cecilia

• Trigger-responsive materials
• Nanomedicine
• photodynamic therapy
• hindered urea bond
• dynamic chemistry

Statement dc:rights

• Copyright 2017 Kaimin Cai

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/105110

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/105110