Investigation of hydrophobically derivatized hyperbranched polyglycerol with PEGylated shell as a nanocarrier for systemic delivery of chemotherapeutics

Misri, Ripen; Wong, Nelson K.Y.; Shenoi, Rajesh A.; Lum, Christine M.W.; Chafeeva, Irina; Tóth, Károly; Rustum, Youcef M.; Kizhakkedathu, Jayachandran N.; Khan, Mohamed K.

doi:10.1016/j.nano.2015.04.016

Cited by 14 publications

(19 citation statements)

References 36 publications

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“…43 Our observation with DTX/HPG-C 10 -HPG may offer a contributing factor as to how a NP lowers anticancer drug toxicity-by alteration of the interactions between anticancer drugs and non-cancerous normal cells or cancer cells. We have also made a similar observation with DTX loaded into a PEGylated HPG NP, 17 and we are actively investigating the mechanism of this phenomenon. Together, these results suggest that HPG NPs may be able to widen the therapeutic index of anticancer drugs through alteration of cellular interactions.…”

Section: Discussionsupporting

confidence: 53%

“…It is also noteworthy that HPG-C 10 -HPG displayed lower toxicity to these cells when compared to a PEGylated version of HPG NP that we reported previously. 17 HPG-C 10 -HPG is capable of encapsulating DTX in its hydrophobic pocket. Similar to previously reported polymeric micelles, 29-31 the release of DTX from HPG-C 10 -HPG displays a two-phase mechanism, exhibiting an initial burst release and a subsequent sustained release.…”

Section: Discussionmentioning

confidence: 99%

“…17 The maximum stable drug loading achieved was 1 wt% of HPG-C 10 -HPG. Incorporated 3 H-DTX was released with an initial burst phase and with a subsequent sustained release at 37 C in PBS (Fig.…”

Section: Drug Release Assaymentioning

confidence: 92%

“…Calculations of cell viability with reference to untreated cells were reported before. 17 IC 50 values were computed with Graphpad ® .…”

Section: Proliferation (Xtt) Assaymentioning

confidence: 99%

“…17 Briefly, the tissues were incubated in Solvable ® (Perkin Elmer) at 50 C overnight. After the digestion of the tissues, the vials were allowed to cool before the addition of 50 L 200 mM EDTA, 200 L 30% H 2 O 2 , and 25 L 10 M HCl.…”

Section: Biodistribution Studies In Tumor-bearing Micementioning

confidence: 99%

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Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Wong¹,

Misri²,

Shenoi³

et al. 2016

j biomed nanotechnol

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PEGylation is commonly used to increase the plasma residence time of anticancer drug nanocarriers. However, PEGylation may trigger antibody production and lead to accelerated blood clearance in subsequent administrations. Moreover, the presence of PEG shells on nanocarriers may also hamper endosomal escape and decrease drug payload release. To avoid these shortcomings, we synthesized and evaluated a non-PEGylated, hyperbranched polyglycerol nanoparticle (HPG NP) with a hydrophobic core and a hydrophilic HPG shell, HPG-C10-HPG, as a candidate for systemic delivery of anticancer drug. In vitro studies with primary human cell lines revealed that HPG-C10-HPG possesses low cytotoxicity. The presence of long chain alkyl groups (C1o) in the core as the hydrophobic pocket in the NP enabled the binding and sustained release of the hydrophobic drug docetaxel. Remarkably, the docetaxel-loaded HPG-C10-HPG formulation also confers preferential protection to primary cells, when compared to cancer cells, potentially widening the therapeutic index. HPG-C10-HPG, however, accumulated at higher levels in the liver and spleen when administered intravenously in mice. Comparing the biodistribution patterns of HPG-C10-HPG, PEGylated HPG-C10-PEG, and unmodified HPG in a xenograft model reveals that the accumulation pattern of HPG-C10-HPG was attributed to insufficient shielding of the hydrophobic groups by the HPG shell. Our results revealed the influence of the nature of the hydrophilic shell and the presence of hydrophobic groups on the tumor-to-tissue accumulation specificities of these HPG NP variants. Therefore, the present study provides insights into the structural considerations of future HPG NP designs for systemic drug delivery.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Drug Release Assaymentioning

confidence: 92%

“…Calculations of cell viability with reference to untreated cells were reported before. 17 IC 50 values were computed with Graphpad ® .…”

Section: Proliferation (Xtt) Assaymentioning

confidence: 99%

Section: Biodistribution Studies In Tumor-bearing Micementioning

confidence: 99%

See 3 more Smart Citations

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Wong¹,

Misri²,

Shenoi³

et al. 2016

j biomed nanotechnol

Self Cite

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Co‐Delivery of siNRF2 and Sorafenib by a “Click” Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma

Tong,

Feng,

Sun

et al. 2023

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In the course of antitumor therapy, the complex tumor microenvironment and drug‐mediated changes in cell signaling and biological processes lead to drug resistance. The effect of sorafenib is greatly limited by the specific tumor microenvironment induced by antiangiogenic therapy and ferroptosis resistance induced by the upregulation of nuclear factor erythroid‐2 related factor 2 (NRF2). In this study, a pH responsive and amphiphilic hyperbranched polyglycerol, HDP, is synthesized based on a co‐graft click chemistry pathway. This nano‐scale carrier provides excellent drug‐loading capacity, storing stability and pH responsibility, and effectively co‐delivery of sorafenib and siRNA. Sorafenib and siNRF2 plays a greatly synergistic effect in inducing reactive oxygen species (ROS), iron overloading, depleting glutathione (GSH), and promoting lipid peroxidation. Importantly, verified in two different animal experiments, HDP‐ss (HDP loaded with both siNRF2 and sorafenib) presents a superior anti‐tumor effect, by achieving a tumor inhibition rate of ≈94%. Thus, HDP can serve as an excellent targeted delivery nanocarrier with good biocompatibility in antitumor therapy, and combined application of siNRF2 effectively improves the antitumor effect of sorafenib by overcoming NRF2‐mediated ferroptosis resistance. Taken together, this study provides a novel therapeutic strategy to combat the drug resistance in antiangiogenic therapy and ferroptosis.

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Protonated Montmorillonite Clay Used as Green Non-toxic Catalyst for the Synthesis of Biocompatible Polyglycidol

2015

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Investigation of hydrophobically derivatized hyperbranched polyglycerol with PEGylated shell as a nanocarrier for systemic delivery of chemotherapeutics

Cited by 14 publications

References 36 publications

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Co‐Delivery of siNRF2 and Sorafenib by a “Click” Dual Functioned Hyperbranched Nanocarrier for Synergistically Inducing Ferroptosis in Hepatocellular Carcinoma

Protonated Montmorillonite Clay Used as Green Non-toxic Catalyst for the Synthesis of Biocompatible Polyglycidol

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