Ratiometrically Designed Nanocarrier to Impact Major Cancer Pathways for Effective Pancreatic Cancer Treatment
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doi: 10.1007/s40242-020-0288-7
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Ratiometrically Designed Nanocarrier to Impact Major Cancer Pathways for Effective Pancreatic Cancer Treatment JI Jian* Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, P. R. China Abstract To achieve secured in vivo drug synergy in stroma-rich pancreatic cancer(PDAC) is not an easy task. Ji and Liu et al. demonstrate the rational development of a ratiometrically designed nanocarrier to co-package a CDK4/6 cell cycle inhibitor palbociclib(PAL) plus an autophagy inhibitor hydroxychloroquine(HCQ) for efficient PDAC treatment. The lead formulation was obtained using a computer software aided in vitro screening, followed by a remote drug co-import into a lipid-coated mesoporous silica nanoparticle. The ratiometric nanocarrier led to the synchronized pharmacokinetic(PK) profile and effective intratumoral buildup of the drug pair post intravenous injection, which otherwise exhibited distinctly different biodistribution characteristics. The treatment using PAL/HCQ co-delivery nanoparticles yielded the most effective shrinkage of PDAC in subcutaneous and orthotopic PANC1 mouse models. The mechanistic investigation also demonstrated the activation of anti-apoptosis pathway after repetitive nanoparticle injection in mice, which promoted the authors to introduce a small molecule anti-apoptosis inhibitor to further improve the performance of their already potent nanoparticle in the PDAC mouse model. This work has been published online in Nature Communications on August 25, 2020. Pancreatic cancer(PDAC) is a highly lethal cancer, which is resistant to almost all the available therapies[1]. It has become popular to identify pharmacologically novel drug combination with the hope to improve PDAC therapeutic outcome. While a list of innovative combinations emerged in tissue cultures, i.e., a CDK4/6 cell cycle inhibitor plus an autophagy inhibitor in this case, a major obstacle to prevent the in vivo utilization of paired drugs partially comes from the presence of thick dysplastic stroma, a physical and functional barrier that prevents drug access in PDAC. Given this background, Ji and Liu et al.[2] hypothesized that it was possible to design a co-encapsulated nanocarrier to concurrently interfere the non-redundant cancer pathways at PDAC site[Fig.1(A)]. The beauty of using nanocarrier also includes the possibility of ratiometric drug design, which provides a safeguard for synchronized pharmacokinetic(PK) and abundant intratumoral drug access, a feature that cannot be achieved using free drug combo. With respect to cancer biology, the uniqueness of this study is the co-targeting of CDK4/6 cell cycle and autophagy pathways. While the recent emergence of CDK4/6 inhibitor has generated great success in breast cancer(BC), it is a natural evolution to investigate the extended use of these new compounds(i.e., palbociclib, PAL) beyond BC, such as PDAC that is famous for abe
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