<p>Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect</p>

Abstract

Background: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors. Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidasecombined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo. Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth. Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.

Photoreactive-proton-generating hyaluronidase/albumin nanoparticles-loaded PEG-hydrogel enhances antitumor efficacy and disruption of the hyaluronic acid extracellular matrix in AsPC-1 tumors

“…In more than 90% of pancreatic tumors HA formation is significant, especially in ductal/mucinous adenocarcinomas [ 30 ]. Although HepG2 secretes HA [ 46 ], the HA amount seemed a bit lower for the degradation study in our study. Therefore, extra HA was added to the HepG2 spheroids in our experiments in order to better mimic the in vivo tumor ECM environment.…”

Bioenzyme-based nanomedicines for enhanced cancer therapy

“…Although these recent promising progresses of bioenzyme-based nanomedicines in the field of cancer therapy Mesoporous silica Ribonuclease A Catalyze RNA degradation [37] Large-pore mesoporous silica Ribonuclease A Degrade mRNA and tRNA [38] Polymer-based nanoparticles Ribonuclease A Degrade cellular RNA [39] Hollow organosilica Glucose oxidase Consume glucose [40] Mesoporous polydopamine Glucose oxidase Consume glucose [41] Liposomes Glucose oxidase Consume glucose [42] Porous silica nanoparticles Hyaluronidase Decompose HA-DOX to produce toxic dissociative DOX [43] Micelles Collagenase Digest collagen fibers in tumor ECM [45] Nanogels Collagenase Digest tumor ECM [46] Heavy-chain ferritin nanocages Collagenase Degrade the collagen in tumor ECM [47] PCL-PEG nanoparticles Collagenase IV Degrade the collagen component of ECM [48] Chitosan nanoparticles Bromelain Digest tumor ECM [49] Hierarchical nanoparticles Hyaluronidase Degrade hyaluronic acid in tumor ECM [51] Micelles Hyaluronidase Degrade hyaluronic acid in tumor ECM [52] PTT Ultrasmall platinum nanoparticles Glucose oxidase Catalyze glucose to produce H 2 O 2 and D-glucono-δ-lactone [58] Semiconducting polymer nanoparticles Bromelain Digest collagen in tumor ECM [59] Gold/mesoporous polydopamine nanoparticles Papain Degrade tumor ECM [60] Liquid metal nanoparticles Glucose oxidase Inhibit ATP and HSP levels [61] Porous hollow Prussian blue nanoparticles…”

“…These self-degradable nanoparticles with dualredox and pH responsivity showed the highest tumor inhibition ratio (93.71%) in MDA-MB-231 tumor-bearing mouse models. In another study, Sun and coworkers developed a HAase-combined multistage nanoparticle to increase solid tumor penetration and antitumor efficacy [52]. Anionic HAase was attached onto the surface of cationic epirubicin-loaded nanoparticles via electrostatic interaction.…”

Nanoparticle-Mediated Targeted Drug Delivery to Remodel Tumor Microenvironment for Cancer Therapy

“…NPs-EPI/HAase was able to effectively degraded the HA and promoted deeper penetration and better accumulation of NPs into HepG2 tumors, resulting in enhanced tumor growth inhibition. 27 Another approach is to inhibit and prevent HA synthesis and formation. 4-Methylumbelliferone (4-MU) is a derivative of coumarin that was firstly reported to suppress the synthesis of HA in cultured human skin fibroblasts in 1995.…”