A tumor multicomponent targeting chemoimmune drug delivery system for reprograming the tumor microenvironment and personalized cancer therapy

Abstract

Nanoparticle library engineered with tunable size, shape, and geometry will provide a better idea of targeting multicomponent of tumor microenvironment consisting of epithelial cells, tumor hypoxia, tumor immune cells and angiogenic blood vessels.

Figure 1

Strategy for universal nanothernaostic delivery systems to target all major components of cancer cells and cancer-associated cells. The tumor microenvironment has been divided into six major components: tumor epithelial cells, tumor blood vessel, tumor hypoxia, cancer stem cells, tumor stroma and tumor immune cells. The epithelial cells function as a generator of tumor mass and proliferation, the tumor blood vessel is responsible for angiogenesis and supplying nutrients to the tumor, tumor hypoxia represents a drug-resistant population and works for tumor acidosis, cancer stem cells maintain stemness of the tumor environment and is responsible for metastasis and invasion. Tumor stroma is a dense layer of extracellular matrix and fibroblasts that prevents drug penetration, and tumor immune cells help to fight against antitumor immune surveillance.

Figure 2

Hit selection criteria and lifecycle of a targeted delivery system for cancer therapy. An example of combinatorial screening and optimization of DTXL-TNPs. (a) The PSMA targeting PLGA-PEG nanoparticle (BIND-014) encapsulated with deocetaxel and a 50 nm nanoparticle is suitable for internalizing tumor by the EPR effect. (b) Combinatorial library nanoparticle with various shape, size and drug loading. (c) The screeninig of a library at the cellular level and an animal tumor model to find a best hit for clinical tranlation. (d) The importatnt parameter and FDA requirements that need to be monitored for achieving efficient nanoparticle hits for human trials. Images reproduced, with permission, from [34].

Figure 3

Library synthesis of tumor multicomponent targeting ligands and various types of drug and gene delivery systems, coupling them using reagent-free click reaction (azide and DBCO) for selective cancer therapy and imaging. Different size-, shape- and material-based nanoparticles will be used so that they can be multimodal agents, for example flagella-like nanomicelles will be used for lowering macrophage-associated liver and spleen uptake. Thus, the need is obvious for the development of an approach to design universal nanothernaostic delivery systems that aim at particular receptor targets on the cancer cells and cancer-associated cells containing drug, dye and a cargo carrier and, hence, include the most important aspects of any therapy into one system: diagnosis, targeting and drug delivery.

Figure 4

The functional outcome of nanoparticle (NP) immune modulation depends on numerous factors that are intrinsic to NPs, such as composition, size and charge, as well as extrinsic factors such as route of administration. These concepts and how they relate to manipulating immune responses are described in this figure. Reproduced, with permission, from [140].

Figure 5

The enhanced permeability retention effect (EPR) in primary and metastatic tumors is described. The mechanistic pathway indicates that nanoparticles diffuse from leaky blood vessels to the distal area of the tumor. The EPR effect depends on molecular weight of the nanoparticles, pH of the tumor environment, expression of transporter proteins and cellular endocytosis. Reproduced, with permission, from [3].

Figure 6

The multi-pronged activity of nanoparticles to target cancer cells and regulate their uptake into tumor-specific compartments. Nanoparticles serve as therapeutic agents by modulating tumor-associated immune cells, inducing toxicity locally and blocking the tumor survival pathway. The naoparticles contained with an imaging agent can be engineered with tumor-biomarker-specific antibody and agonist to detect the tumor early for imaging and diagnostics. For receptor-mediated tumor targeting, nanoparticles are tailored with a wide variety of ligads, such as peptides, lipids and antibodies. Reproduced, with permission, from [141].