Preclinical Evaluation of Lymph Node Targeted Therapy in Mouse Models of Cancer

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博 士 学 位 論 文
論文題目

提 出 者

Preclinical Evaluation of Lymph
Node Targeted Therapy in Mouse
Models of Cancer
(がんモデルマウスにおけるリンパ
節標的治療の前臨床的評価)

東北大学大学院医工学研究科
医工学専攻
学籍番号

C0WD9006

氏

Radhika Mishra

名

Preclinical evaluation of lymph node targeted therapy in mouse models of cancer
Treatment of metastatic lymph nodes (MLNs) is challenging. Intranodal delivery of anti-cancer
agents using a lymphatic drug delivery system (LDDS) ensures lymph node (LN)-specific drug
delivery and thus elicits superior therapeutic responses in comparison to systemic drug delivery
methods. Herein we verified the therapeutic efficacy of intranodal delivery of different therapeutic
interventions.
First, the potency of carboplatin, delivered using LDDS for the treatment of MLNs was explored.
Carboplatin was co-administered with formulations of varying physicochemical parameters to identify
an optimal range that enhanced therapeutic efficacy. The following range was found to elicit maximal
tumor suppressive effect when co-administered with carboplatin using LDDS: Osmotic pressure (π):
1177 kPa ≤ π ≤ 2785 kPa, Viscosity (µ): 6 mPa·s ≤ µ ≤ 55 mPa·s.
Subsequently, the therapeutic efficacy of an immune checkpoint inhibitor (ICI), anti-CTLA4 was
investigated. Robust and consistent therapeutic response was observed upon intranodal delivery to
tumor-positive LN, whereas delivery to tumor-negative LN or intraperitoneal delivery was found to be
detrimental as it was frequently associated with the development of interstitial pneumonia and poor
overall survival.
Combination approaches, using doxorubicin and anti-CTLA4 were also interrogated. A pronounced
therapeutic response was observed only upon sequential delivery of doxorubicin to tumor-negative
LN and anti-CTLA4 to tumor-positive LN. In summary, intranodal delivery of anti-cancer agents is a
potent drug delivery methodology that enhances the therapeutic efficacy of a wide range of anticancer agents. ...

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