Tumor microenvironment and nanotherapeutics

Abstract

Recent studies delineate a predominant role for the tumor microenvironment in tumor growth and progression. Improved knowledge of cancer biology and investigation of the complex functional interrelation between the cellular and noncellular compartments of the tumor microenvironment have provided an ideal platform for the evolution of novel cancer nanotherapies. In addition, multifunctional "smart" nanoparticles carrying imaging agents and delivering multiple drugs targeted preferentially to the tumor/tumor microenvironment will lead to early diagnosis and better treatment for patients with cancer. The emerging knowledge of the tumor microenvironment has enabled rational designing of nanoparticles for combinatorial treatment strategies that include radiotherapy, antiangiogenesis and chemotherapy. This multimodality approach is thus expected to achieve therapeutic efficacy and enhance the quality of life of cancer patients. This review highlights the unique characteristics of the tumor microenvironment that are exploited by nanotechnology to develop novel drug delivery systems aimed to target the tumor/tumor microenvironment.

Keywords: Tumor microenvironment; endothelial cells; enhanced permeability and retention (EPR) effect; multiple drug resistance (MDR); nanoparticles.

Figure 1

The primary tumor microenvironment. The primary tumor microenvironment consists of tumor cells surrounded by normal epithelial cells, mesenchymal stem cells (MSC), endothelial progenitor cells (EPCs) and various bone marrow derived cells (BMDC). Presence of heterogeneous cells and their secreted soluble factors, signaling molecules, extracellular matrix and mechanical cues with in the tumor microenvironment promote neoplastic transformations, support tumor growth and invasion (Modified from www.Cernostics.com)

Figure 2

Phenotyping the tumor reactive stroma in Cholangiocarcinoma (CCA). Immunohistochemistry of different markers to characterize cells and structural components of the tumor reactive stroma in CCA: A. cancer-associated fibroblasts [CAFs] (α-SMA); B. extracellular matrix [ECM] (fibronectin); C. inflammatory cells (CD45); D. tumor-associated macrophages [TAM] (CD206, arrows); E. lymphatic endothelial cells (Podoplanin); F. vascular endothelial cells (CD34). Histological specimens were derived from surgical liver resection of patients with Intrahepatic cholangiocarcinoma (iCCA). Original magnification: 200×, adapted from (5)

Figure 3

Stimuli responsive nanopreparations as emerging drug delivery and controlled drug release systems. The various stimuli are applied as following: (I) External stimulus such as temperature (T) and pH is utilized to facilitate formation of nanoparticles; (II) External stimuli such as magnetic field, ultrasonic, light, and temperature allows for remotely controlling the precision of spatial and temporal drug release; (III) acidic tumor pH (6.5–7.2) is utilized to trigger drug release and/or reverse shielding of nanoparticles at tumor site thereby enhancing tumor cell uptake of nanoparticulate drugs; and (IV) intracellular environments such as low pH in endo/lysosomal compartments and high redox potential in cytoplasm are utilized to improve intracellular drug release inside tumor cells adapted from (8)

Figure 4

Vascular pathophysiology and EPR effect in nanoparticle delivery. Scheme representing the microvasculature of normal (A) and tumor (B) tissue. Poorly developed leaky vasculature allows 10–100 nm sized nanoparticles to extravasate and gets accumulated with in solid tumor. Within tumor depending on their sustained drug release properties, nanoparticles keep releasing active drug for significantly longer time point. Nanoparticles cannot leak through the intact blood vessels, so it considerably decreases the systemic toxicity. Scanning electron microscopic (SEM) imaging showing simple, organized arrangement of arterioles, capillaries, and venules in normal rat carotid sinus (C), on the contrary xenograft of human tumor in nude mice depicts abundant microvasculature lacking the hierarchy of blood vessels (D) SEM adapted from (21,22)

Figure 5

A comparison of the effect of Chemotherapy and metronomic therapy in cancer. A schematic representation elucidating the importance of metronomic dosing over traditional maximum tolerated dosing (MTD) in intermittent chemotherapy. Traditional chemotherapeutic regimen is often associated with systemic toxicity and recurrence of tumor after several days of treatment. However, in metronomic therapy, fractionated MTD for a period of time, is less toxic and is effective in tumor growth inhibition and results in remission of the disease

Figure 6

Scheme of Multifunctional nanoparticles used in cancer nanotherapeutics. The multifunctional nanocarriers are able to carry multiple therapeutic agents that may have a biological or non-biological origin. Impregnation of the nanocarrier with poly ethylene glycol termed PEGylation prolongs circulation time and reduces immunogenicity of nanoparticles, and impregnation of contrast agent/imaging agent makes this nanoparticulate formulation more traceable with in solid tumors. Conjugating targeting agents like antibodies and ligands is an approach to actively target tumor and endothelial cells within tumor microenvironment with minimum toxicity to other cell types. Hence, advances in the design of multifunctional nanoparticles is focused on developing the ideal nanocarrier that can effectively carry optimal drug to solid tumor, bring about tumor growth inhibition and prevent it’s progression