Softness confers chemotherapeutic microparticle better killing

Tumor-repopulating cells confer their released microparticles a mechanical softness that facilitates those microparticles to efficiently deliver chemotherapeutic drugs for a better cancer treatment.

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May 20, 2019
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Nanotechnology-based drug delivery systems (NDDS), despite their advantages in cancer treatment, still face challenges from insufficient accumulation at tumor sites, suboptimal extravasation and subsequent penetration into tumor parenchyma, making NDDS insufficient to target tumor cells, especially for those highly tumorigenic tumor-repopulating cells (TRCs) which are soft and preferably located within the hypoxic compartment far from tumor vessels in solid tumors.

In response to exogenous or endogenous stimuli, cells may rearrange their cytoskeleton, leading to a mechanical force imbalance on the local plasma membrane and the subsequent encapsulation of cytosolic contents within the membrane to form large-sized vesicles, which are then released into extracellular spaces. Such specialized subcellular vesicles of 100-1000 nm in size are termed microparticles. Due to their high biocompatibility and intrinsic targeting properties, MPs hold a great potential as drug delivery carriers. Previously, we developed a novel drug-delivering system using tumor cell-derived MPs (2D-MPs), which possess high anticancer efficacy without adverse side effects.1 Moreover, the drug-loaded 2D-MPs are preferentially taken up by TRCs rather than by differentiated tumor cells. This is because the softness confers TRCs the virtue of more deformability to take up large-size vesicles.2 Despite these, the anticancer activity of 2D-MP-based drug delivery systems might be compromised by the stiffness of 2D-MPs, which hinders large-size MPs to cross blood vessels and penetrate tumor parenchyma.

Different cell types display differential stiffness, which matches the local extracellular matrix stiffness in order for the cells to properly sense and respond to the surrounding mechanical microenvironments.3 Based on this understanding, we have developed a mechanics-based culture system using 3D soft fibrin gels that can selectively amplify TRCs from primary tumor tissues and cancer cell lines in both murine and human settings.4 In this study, we aim to develop softer MPs as drug carriers and use their deformability to improve drug distribution in tumor mass. Considering the softness of TRCs,2,4 we hypothesize that TRC-derived MPs (3D-MPs) might be softer than bulk tumor cell-derived 2D-MPs. In this study, we cooperated with Professors Xiangliang Yang and Lu Gan at the Huazhong University of Science and Technology to develop 3D-MPs, which indeed are much softer than 2D-MPs. Doxorubicin (DOX)-loaded 3D-MPs (DOX@3D-MPs) exhibited much better anticancer efficacy and efficiency than their 2D-MPs counterparts (DOX@2D-MPs), even better than Doxil (pegylated liposomal doxorubicin, a FDA-approved anticancer nanodrug). This excellent anticancer activity of drug-loaded 3D-MPs is also verified by loading different anticancer drugs and using different tumor models. Jasplakinolide (Jasp) is an agent for actin polymerization and stability, but latrunculin A (LatA) acts for actin depolymerization and instability. In line with the notion that the softness of MPs contributes to highly efficient drug delivery, we demonstrate that Jasp-stiffened 3D-MPs reduced the ability of tumor accumulation, blood vessel extravasation and tumor penetration, while LatA-softened 2D-MPs enhanced the ability to deliver drugs into tumor. Finally, we identify a cytoskeleton-related protein cytospin-A critically affects the stiffness of MPs. The expression of cytospin-A in TRCs and 3D-MPs is much lower than that in differentiated tumor cells and 2D-MPs, respectively. Cytospin-A knockdown results in the generation of softer MPs, which exhibit the enhanced tumor accumulation, extravasation and tumor penetration, as well as the uptake by tumor cells and TRCs. Thus, cytospin-A is involved in the regulation of softness of MPs, and affects the in vivo drug delivery process and the subsequent anticancer activity.

In this study, we clearly show that TRC-derived 3D-MPs, by virtue of their mechanical softness, can effectively modulate the in vivo transport process of anticancer drug, generating an excellent anticancer activity without obvious side effects (Figure 1). These findings reveal a new aspect of microparticle biology, thus providing better strategies for chemotherapeutic drug delivery in cancer therapy.

Figure 1. Schematic illustration of 3D-MPs as an effective anticancer drug delivery carrier. Drug-packaging 3D-MPs with less cytospin-A expression exhibit enhanced tumor accumulation, extravasation from tumor vessels and penetration into deep tumor parenchyma, and efficient cellular uptake by TRCs due to their softness and deformability compared with drug-packaging 2D-MPs, resulting in excellent anticancer activity.

 

Our paper: Liang Q et al.The softness of tumour-cell-derived microparticles regulates their drug-delivery efficiency. Nat. Biomed. Eng. DOI: 10.1038/s41551-019-0405-4.

 

References:

1. Tang, K. et al. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat. Commun.        3, 1282 (2012).

2. Ma, J. et al. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived                          chemotherapeutic microparticles. Cell Res. 26, 713–727 (2016).

3. Discher, D. E.et al. Growth factors, matrices, and forces combine and control stem cells. Science 324,          1673–1677 (2009).

4. Liu, J. et al. Soft fibrin gels promote selection and growth of tumorigenic cells. Nat. Mater. 11, 734–741        (2012).

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Bo Huang

Professor, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College

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