Size shrinkable drug delivery nanosystems and priming the tumor microenvironment for deep intratumoral penetration of nanoparticles

Niu, Yimin; Zhu, Jiaan; Yang, Li; Shi, Huihui; Gong, Yongsheng; Li, Rui; Huo, Qiang; Ma, Tao; Liu, Yang

doi:10.1016/j.jconrel.2018.03.012

Cited by 120 publications

(76 citation statements)

References 141 publications

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“…[ 4 ] NPs, which are small in size or size shrinkable in tumor tissues, are generally considered to have better intra‐deep penetration characteristics. [ 5 ] However, they are easily cleared during the blood circulation and failed to retain at the tumor site. [ 6 ] Therefore, controlling the size of NPs alone is not the optimal way to resolve the contradiction between penetration and retention.…”

Section: Methodsmentioning

confidence: 99%

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

et al. 2020

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The complex tumor microenvironment constitutes a variety of barriers to prevent nanoparticles (NPs) delivery and results in extremely low accumulation of nanomedicines in solid tumors. Here, a newly developed size-changeable collagenase-modified polymer micelle is employed to enhance the penetration and retention of nanomedicine in deep tumor tissue. The TCPPB micelle is first formed by self-assembly of maleimideterminated poly(ethylene glycol)-block-poly(β-amino ester) (MAL-PEG-PBAE) and succinic anhydride-modified cisplatin-conjugated poly(ε-caprolactone)block-poly(ethylene oxide)-triphenylphosphonium (CDDP-PCL-PEO-TPP). Next, Col-TCPPB NPs are prepared through a "click" chemical combination of thiolated collagenase and maleimide groups on TCPPB micelle. Finally, biocompatible chondroitin sulfate (CS) is coated to obtain CS/Col-TCPPB NPs for avoiding collagenase inactivation in blood circulation. In tumor acidic microenvironment, the hydrophobic PBAE segments of the resultant micelles become hydrophilic, leading to a dissociation and subsequent dissolution of partial collagenase-containing components (Col-PEG-PBAE) from NPs. The dissolved Col-PEG-PBAE promotes the digestion of collagen fibers in tumor tissue like a scavenger, which enhances the NPs penetration. Simultaneously, the increased hydrophilicity of residual Col-PEG-PBAE in the micellar matrix causes an expansion of the NPs, resulting in an enhanced intratumoral retention. In tumor cells, the NPs target to release the cisplatin drugs into mitochondria, achieving an excellent anticancer efficacy.Engineered nanoparticles (NPs), which are capable of improving drug solubility, overcoming pharmacokinetic limitations, and reducing toxic side effects over systemic chemotherapy drugs, perform as a promising nanoplatform for delivering drugs

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Section: Methodsmentioning

confidence: 99%

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

et al. 2020

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“…Tumor heterogenicity and poor tumor penetration remain huge challenges for nanoparticles (NPs) to deliver anti-cancer drugs. 1 Compared with normal tissues, solid tumors tend to display dense extracellular matrix (ECM), abnormal tumor vasculature and lymphatic system, as well as elevated tumor interstitial fluid pressure (IFP), which intrinsically hinders the transport of NPs to the deeper regions of tumors and restrict the treatment options of NPs. Moreover, the poor treatment capacity of tumor cells in the internal region of the tumor may further lead to tumor recurrence and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Han

Song

et al. 2020

IJN

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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.

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“…Among all of these properties, particle size is one of the key factors that affect the blood circulation time, tumor accumulation and tumor penetration of nanoparticles, as well as the enzyme activity or imaging effect . The diameter of the recently reported PBTA was mainly among 4–300 nm 1a.…”

Section: Introductionmentioning

confidence: 99%

“…The diameter of the recently reported PBTA was mainly among 4–300 nm 1a. The particles with smaller size exhibited higher surface to volume ratio, resulting in the more water molecules coordinated to the metal ions (Gd, Fe, or Mn), obtaining enhanced T 1 ‐weighted magnetic resonance imaging (MRI) effect 9b. In addition, it was demonstrated that the nanoparticles with smaller particle size could achieve deeper tumor penetration because of the reduced diffusional obstacle .…”

Section: Introductionmentioning

confidence: 99%

Size Switchable Nanoclusters Fueled by Extracellular ATP for Promoting Deep Penetration and MRI‐Guided Tumor Photothermal Therapy

Zhou

Liu

Zhang

et al. 2019

Adv Funct Materials

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Protein-based theranostic agents (PBTAs) exhibit superior performance in the diagnosis and therapy of cancers. However, the in vivo applications of PBTA are largely limited by undesired accumulation, penetration, or selectivity. Here, an ATP-supersensitive protein cluster is fabricated for promoting PBTA delivery and enhancing magnetic resonance imaging (MRI)-guided tumor photothermal therapy. Gd 3+ -and CuS-coloaded small bovine serum albumin nanoparticles (GdCuB) are synthesized as the model protein with a size of 9 nm and are encapsulated into charge switchable polycations (DEP) to form DEP/ GdCuB nanoclusters of 120 nm. In blood circulation, DEP/GdCuB significantly extends the half-lifetime and thereby enhances the tumor accumulation of GdCuB. When the clusters reach the tumor site, the extracellular adenosine triphosphate (ATP) can effectively trigger the release of GdCuB, resulting in tumoral deep penetration as well as the activation of T 1 -weighted MRI (r 1 value switched from 2.8 × 10 −3 to 11.8 × 10 −3 m −1 s −1 ). Furthermore, this delivery strategy also improves the tumoral photothermal therapy efficacy with the MRI-guided therapy. The study of ATP-activated nanoclusters develops a novel strategy for tumor deep penetration and on/off imaging of PBTA by size switchable technology, and reveals the potential for MRI-guided therapy of cancers.

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Size shrinkable drug delivery nanosystems and priming the tumor microenvironment for deep intratumoral penetration of nanoparticles

Cited by 120 publications

References 141 publications

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

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

Size Switchable Nanoclusters Fueled by Extracellular ATP for Promoting Deep Penetration and MRI‐Guided Tumor Photothermal Therapy

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