Cancer Bioenergetics and Tumor Microenvironments-Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

Abstract

Cancer is an impending bottleneck in the advanced scientific workflow to achieve diagnostic, prognostic, and therapeutic success. Most cancers are refractory to conventional diagnostic and chemotherapeutics due to their limited targetability, specificity, solubility, and side effects. The inherent ability of each cancer to evolve through various genetic and epigenetic transformations and metabolic reprogramming underlies therapeutic limitations. Though tumor microenvironments (TMEs) are quite well understood in some cancers, each microenvironment differs from the other in internal perturbations and metabolic skew thereby impeding the development of appropriate diagnostics, drugs, vaccines, and therapies. Cancer associated bioenergetics modulations regulate TME, angiogenesis, immune evasion, generation of resistant niches and tumor progression, and a thorough understanding is crucial to the development of metabolic therapies. However, this remains a missing element in cancer theranostics, necessitating the development of modalities that can be adapted for targetability, diagnostics and therapeutics. In this challenging scenario, nanomaterials are modular platforms for understanding TME and achieving successful theranostics. Several nanoscale particles have been successfully researched in animal models, quite a few have reached clinical trials, and some have achieved clinical success. Nanoparticles exhibit an intrinsic capability to interact with diverse biomolecules and modulate their functions. Furthermore, nanoparticles can be functionalized with receptors, modulators, and drugs to facilitate specific targeting with reduced toxicity. This review discusses the current understanding of different theranostic nanosystems, their synthesis, functionalization, and targetability for therapeutic modulation of bioenergetics, and metabolic reprogramming of the cancer microenvironment. We highlight the potential of nanosystems for enhanced chemotherapeutic success emphasizing the questions that remain unanswered.

Keywords: bioenergetics; cancer chemotherapy; metabolic regulation; metabolic reprogramming; mitochondria; nanoparticles; theranostics; tumor microenvironment.

Figure 1

Tumor microenvironment landscape and targetable niches: Tumors are highly heterogeneous in the cellular and non-cellular milieu. The interplay among the tumor microenvironment components and crosstalk with the tumor and non-tumor components facilitates tumor growth and metastasis. The major tumor niches that modulate tumor infiltration and growth are depicted by metabolic, hypoxic, and acidic niches that create a distinct metastatic and immune microenvironment.

Figure 2

Mitochondria play a crucial role as decision makers of cancer progression. Inherent to their capabilities as a powerhouse of the cells, mitochondria control cellular biosynthesis, bioenergetics, calcium and redox homeostasis, biogenesis, and cell death. Mitochondrial function is ingrained in each stage of cancer progression spanning tumor initiation development, metastasis, and therapeutic responses.

Figure 3

A schematic representation of smart nanosystem to target resistant cancer niches, especially the CSC niche. The flow diagram integrates the multifactorial approach using Nanoparticles (NP) for pan-cancer theranostics, aimed to obtain specific targeting.

Figure 4

Smart nanocarriers based TME and bioenergetics modulation. Small molecular weight nanoparticles are targeted to metabolic pathways including lactic acid, kynurenine, prostaglandin E2, ROS pathways, and other metabolic targets. Nanoparticles functionalized or encapsulated with drugs demonstrate precise targeting to the destined location due to their small size and physiochemical properties. This advanced technology has enabled the integration of nano-based drug targeting systems with imaging modalities to follow the chemotherapeutics and diagnostic track. Upon localization to the precise location, the drug effect is initiated to induce desired response with reduced toxicity.