THE ROLE OF TUMOR DESMOPLASIA IN NANOPARTICLE DELIVERY OF DRUGS AND GENES

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  • March 19, 2019
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  • Miao, Lei
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • In desmoplastic tumors, stroma cells capture nanoparticles (NPs), preventing them from reaching tumor cells, resulting in compromised anti-tumor efficacy. This dissertation focuses on understanding the basis role of tumor associated fibroblasts (TAFs), one of the major stroma cells constituting desmoplasia, in NP delivery and tumor resistance, as well as proposing strategies to overcome the TAF-elicited barriers and improve efficacy. While the capture of therapeutic NPs in TAFs interferes tumor-stroma crosstalk and inhibits tumor progression, we found that the chronic exposure of NPs paradoxically induced the secretion of survival factors (e.g., Wnt16) from the damaged TAFs, facilitating tumor proliferation and metastasis. Therefore, we proposed the delivery of siRNA against Wnt16 to TAFs via the off-target capture, to downregulate this survival factor. The priming of damaged fibroblasts could synergize with a nanoformulation of cisplatin, and benefit the treatment of a desmoplastic bladder cancer xenograft (UMUC3/3T3). Since the off-target delivery of NPs have been verified, we further utilized the same rationale to generate a group of tumor-suppressive TAFs through transfecting TAFs with a plasmid encoding highly secretable TNF-related apoptosis-inducing ligand (sTRAIL). The production of sTRAIL from TAFs bypassed the stroma barrier and resulted in efficient killing of tumor cells. Furthermore, we also proposed a stroma depletion method via combination therapy of cisplatin NPs and gemcitabine NPs. This combination was not only detrimental to tumor cells, but induced superior apoptosis in TAFs of the UMUC3/3T3 model. To ensure the sufficient synergy, we further designed a nano-formulation with ratiometric co-loading and co-delivery of these two regimens. The design of converting these two drugs with totally different physicochemical properties into nano-cores with similar hydrophobic surface and particle size, allows for their simultaneously and ratiometric loading in a single PLGA NPs. This combinatory NPs showed potent anti-cancer efficacy compared to each regimens in separate NPs. In summary, the stroma modulating strategies proposed in the current dissertation provide new paradigms for the treatment of desmoplastic tumors. Combined with cancer immunology, a more prolonged and efficient outcome can be anticipated. The ratiometric combination nano-platform also provides a promising approach for encapsulating agents with different physicochemical properties.
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  • In Copyright
Advisor
  • Smith, Philip
  • Huang, Leaf
  • Batrakova, Elena
  • Kim, William
  • Xiao, Xiao
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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