Combination of Pt-Based Chemotherapy with Immunotherapy or Photodynamic Therapy for Advanced Cancer Treatment In Vitro and In Vivo

基於鉑類藥物的化療與免疫或光動力聯合治療的體內外抗腫瘤活性研究

Student thesis: Doctoral Thesis

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Award date4 Jun 2020

Abstract

As the widely used first-line chemotherapeutic agents, cisplatin, carboplatin, and oxaliplatin play pivotal roles in various malignant cancers with strong anticancer activity. The therapeutic effects, however, are hampered by drug resistance and many serious side-effects. With the development of platinum(IV) prodrugs, these two major issues associated with chemotherapeutic drugs and their use have become manageable. The improvements have been accomplished by functionalizing chemotherapeutic agents with other bioactive ligands or small molecules to get “dual-action” or “multi-action” complexes. Besides, chemotherapeutic agents can be delivered by nanocarriers to achieve stronger anticancer effects while being less harmful to normal tissues. Recent discoveries indicate that the tumor microenvironment also plays a key role in the development of cisplatin-resistant tumor cells. The strategies associated with the design of platinum(IV) prodrugs, including Pt-loaded nanoplatforms, therefore, should be zoomed on the tumor microenvironment for drug development instead of isolated cancer cells in vitro. This thesis aims to develop combinations of platinum(IV) prodrugs with other therapies for cancer treatment. The combinatorial therapy can increase the tumor-targeting properties while also overcome the pressing issues, like drug resistance, an obstacle to the efficacy of all existing chemotherapeutic options. The anticancer effects of those designed complexes were evaluated in vitro and in vivo during the course of this study.

In chapter II, we deal with the construction of an effective immuno-chemotherapeutic nanohybrid for the treatment of cervical cancer. This nanohybrid is established by ratiometrically co-loading cisplatin prodrug with an immune checkpoint inhibitor, an IDO inhibitor (IDOi), into layered double hydroxide (LDH) nanoparticles. The nanohybrid exhibits stronger anticancer effects and leads to enhanced apoptosis with more binding of Pt on DNA in cervical cancer specimens as compared to cisplatin. Meanwhile, the IDO inhibitor in the nanohybrid blocks the synthesis of kynurenine and revives the immunosuppressed T cells. The activated T cells ultimately increase the death of cancer cells by stimulating effector T cells in vitro and in vivo. This work indicates that a combined therapeutic approach using a nanocarrier is favorable for advanced cancer treatment.

In chapter III, an oxaliplatin-based Pt(IV) prodrug with controllable activation property is loaded on core-shell-shell upconversion nanoparticles (UCNPs) for specific binding to red blood cells (RBCs). To achieve a long-term circulation in the bloodstream, the bio-carrier RBC is incorporated to improve the accumulation of nanosystems at tumor sites efficiently. Upon irradiation with 808 nm near-infrared (NIR) light, the synergistic immunopotentiation action is further stimulated to impede the growth of tumors in the mouse model and verified by the highest frequency of CD4+ and CD8+ T cells in tumor tissues. Compared with other individual therapies, the laser-induced antitumor outcome of the nanosystem presents effective tumor inhibition with minimal harm caused to normal tissues on the murine breast cancer-tumor-bearing BALB/c mouse model. The enhanced anticancer effect achieved from our nanosystem highlights the clinical viability of the combinatorial therapeutic option.

In the following two chapters, we focus on in vivo pharmacology and safety assessments for a series of novel platinum(IV) complexes and a PDT-based nanoplatform. In chapter IV, a cisplatin-based platinum(IV) prodrug, containing a (4-formylphenoxy)acetic acid in the axial position, was evaluated in vivo with pharmacology and pharmacokinetic tests. The prodrug exhibits significant anticancer activity in three different tumor-bearing mouse models, including the cisplatin-resistant cancer model. Strikingly, an excellent antimetastatic property is noticed in the platinum(IV) prodrug-treated groups. Once the prodrug is injected into the tail vein of the tumor-bearing mouse, the cancer cells can be killed by efficient Pt accumulation and Pt-DNA binding in the tumor sites with negligible side-effects.

Despite the rational design of anticancer complexes in mind, those ideas, at least, have to be verified by the demonstration of expectable efficacy in experimental animal models with human or relevant cancer cells before further explorations, like clinical trials. In chapter V, anticancer evaluations of platinum(IV) complexes and a PDT-based nanoplatform were explored in various xenograft tumor models after maximum tolerated dose (MTD) tests. Platinum(IV) complexes show stronger anticancer effects than the origin Pt(II) drugs. Besides, the PDT-based nanoplatform exhibits a strong PDT effect for cancer treatment. The tested complexes include monochalcoplatin, ruthplatin, phorbiplatin, and an upconversion nanoplatform pHLIP-Ppa-UCNP. For monochalcoplatin and ruthplatin, complexes are designed with other biological binding ligands to activate other pathways for cancer treatment simultaneously. Besides, phorbiplatin and the PDT-based nanoplatform are designed to trigger cancer therapy by laser irradiation. Although all the complexes have different mechanisms, in vivo tests prove the robust anticancer activity of the complexes in specific tumor models with pharmacology or pharmacokinetic assessments, etc.