Tumor Microenvironment-Sensitive Liposomes Penetrate Tumor Tissue via Attenuated Interaction of the Extracellular Matrix and Tumor Cells and Accompanying Actin Depolymerization

Abstract

Delivery of anticancer drugs into tumor cores comprised of malignant cancer cells can result in potent therapeutic effects. However, conventional nanoparticle-based drug delivery systems used for cancer therapy often exhibit inefficient tumor-penetrating properties, thus, suggesting the need to improve the functional design of such systems. Herein, we focus on the interactions between cancer cells and the extracellular matrix (ECM) and demonstrate that liposomes modified with slightly acidic pH-sensitive peptide (SAPSp-lipo) can penetrate in vivo tumor tissue and in vitro spheroids comprised of cancer cells and ECM. We previously reported SAPSp-lipo, tumor microenvironment-sensitive liposomes, are effectively delivered to tumor tissue (Hama et al. J Control Release 2015, 206, 67-74). Compared with conventional liposomes, SAPSp-lipo could be delivered to deeper regions within both spheroids and tumor tissues. Furthermore, tumor penetration was found to be promoted at regions where actin depolymerization was induced by SAPSp-lipo and inhibited by the polymerization of actin. In addition, SAPSp-lipo attenuated the interaction between cancer cells and ECM, contributing to the penetration of SAPSp-lipo. These results suggest that SAPSp-lipo penetrates tumors via the interspace route and is accompanied by actin depolymerization. Taken together, SAPSp-lipo demonstrates potential as a novel tumor-penetrable drug carrier for induction of therapeutic effects against malignant cells that comprise tumor cores.

Multicellular Tumor Spheroids (MCTS) as a 3D In Vitro Evaluation Tool of Nanoparticles

“…The effect of surface charge on penetration can be used to control the diffusion by using surface switches such as a pH‐responsive peptide that can turn negatively charged nanoparticles to positively charged ones in slightly acidic conditions. The underlying idea is that the negatively charged nanoparticles will penetrate into the spheroid and, once surrounded by an acidic environment, the nanoparticles displayed a positive charge accelerating the uptake by cells . This required the movement of NPs in the paracellular route in contrast to the transcellular route, which the authors confirmed by observing the actin depolymerization.…”

“…While neutral liposomes did not associate with the spheroid, cationic liposomes did accumulate on the spheroid periphery. Only negative charged liposomes were found to display sufficient penetration into the B16−F1 spheroids . An important study and theoretical model to explain this behavior was published by Reddy et al Although spheroids were not used, the researchers have attempted to answer the question how size, shape and charge affect the transport in interstitial fluid.…”

Strategies to improve tumor penetration of nanomedicines through nanoparticle design

“…The high collagen level in the tumor ECM is a major barrier in the transport of NPs, while LOX could crosslink collagen and stiffens the ECM, which further deteriorates the effective transport and penetration of the NPs. Furthermore, the ECM network is composed of charged matrix polymers, such as collagen and hyaluronan, which hinder delivery of highly charged NPs on account of electrostatic interactions with these matrix polymers (Lieleg, Baumgärtel, & Bausch, ; Stylianopoulos et al, ; Suzuki et al, ).…”

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

“…However, with remarkable advancement in technology and analytical methods seen in the last decade, attention has shifted to the TM contribution towards the development of chemoresistance [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Chemotherapeutic drugs need to access all cancer cells in a solid tumor to be effective, thus components of the tumor microenvironment become important players in the response of these cells to drugs [ 33 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. The TM is a dynamic entity and is characterized by cellular heterogeneous, the amounts of oxygen, nutrients and ECM proteins [ 41 , 54 , 55 , 56 , 57 , 58 , 59 ].…”