Delivery of cancer therapeutics to extracellular and intracellular targets: Determinants, barriers, challenges and opportunities

Abstract

Advances in molecular medicine have led to identification of worthy cellular and molecular targets located in extracellular and intracellular compartments. Effectiveness of cancer therapeutics is limited in part by inadequate delivery and transport in tumor interstitium. Parts I and II of this report give an overview on the kinetic processes in delivering therapeutics to their intended targets, the transport barriers in tumor microenvironment and extracellular matrix (TME/ECM), and the experimental approaches to overcome such barriers. Part III discusses new concepts and findings concerning nanoparticle-biocorona complex, including the effects of TME/ECM. Part IV outlines the challenges in animal-to-human translation of cancer nanotherapeutics. Part V provides an overview of the background, current status, and the roles of TME/ECM in immune checkpoint inhibition therapy, the newest cancer treatment modality. Part VI outlines the development and use of multiscale computational modeling to capture the unavoidable tumor heterogeneities, the multiple nonlinear kinetic processes including interstitial and transvascular transport and interactions between cancer therapeutics and TME/ECM, in order to predict the in vivo tumor spatiokinetics of a therapeutic based on experimental in vitro biointerfacial interaction data. Part VII provides perspectives on translational research using quantitative systems pharmacology approaches.

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

“…For the development of immune therapies against HGSOC, it is essential to understand the network of tumor microenvironment. If we could destroy the adipose tissue and the ECM around tumors, the accessibility of immune cells and other therapeutics might be increased and thus the therapy efficacy might be improved, an issue that has already drawn the attention of scientists (36).…”

Biocompatible polymeric coatings do not inherently reducethe cytotoxicity of iron oxide nanoparticles

“…Several authors have shown that positively charged serum proteins are adsorbed on positively charged NPs, which often causes a shielding or protective effect on cell viability (Nafee et al, 2009;Schulze et al, 2009). These high-affinity proteins constitute the first layer of the biocorona, usually called the "hard corona" Tenzer et al, 2013;Au et al, 2016), and this corona basically determines the binding/internalization, as well as the following functionality of the NP. The significant cytotoxic effect of CS-IONPs can be explained by the high proteinabsorbing capacity of CS-coated surfaces, which might alter the conformation of absorbed proteins and lead to the disruption of physiological processes Xu et al, 2016).…”

Light‐Triggered Genome Editing: Cre Recombinase Mediated Gene Editing with Near‐Infrared Light

“…The delivery of genome‐editing proteins, such as Cas9, zinc finger nucleases, and recombinases, is particularly exciting as the “conditional” nature of their activity makes direct protein transduction a valuable alternative to integrating transgene technologies . However, intracellular protein transduction remains problematic due to poor membrane permeability, endosomal entrapment, and proteolytic degradation . Recent advances have delivered enzymes to the cytosol by nanoparticle assemblies, mechanical insertion through electroporation, microfluidic squeeze technology, or by achieving endosomal escape by membrane fusing .…”