HDAC inhibitor conjugated polymeric prodrug micelles for doxorubicin delivery

Senevirathne, Suchithra A.; Washington, Katherine E.; Miller, Jason B.; Oupický, David; Siegwart, Daniel J.; Stefan, Mihaela C.

doi:10.1039/c6tb03038f

Cited by 20 publications

(32 citation statements)

References 38 publications

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“…Because of the increased number of ester linkages, a cumulative DOX release of ~90% was obtained for both pH 5 and 6 within 8 h (Figure 4), which is higher than the cumulative release obtained for the previously reported PEG- b -(PCL- ran -PPBCL) polymer. 23 The release obtained at pH 5 and 6 was significantly higher than that measured at pH 7.4. In an acidic environment, the ester linkages in the polymer backbone of PPBCL will be cleaved, and thus the NPs will no longer hold the cargo, thereby releasing the DOX into the buffer.…”

Section: Resultsmentioning

confidence: 77%

“…Only 30 mol % of PBA was incorporated in the polymer; hence, only minimal activity of HDAC inhibition was observed in vitro studies. 23 In an attempt to further increase the content of HDACi conjugated to the polymer backbone, exhaustive trials were carried out to obtain the homopolymer of γ -4-phenylbutyrate– ε -caprolactone. With the use of the commonly used catalyst, Sn(Oct) 2 , for ring-opening polymerizations, 30–32 we observed that the major product obtained was not the homopolymer but the more thermodynamically stable butyrolactone analogue (Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

“…The thermodynamic stability of the formed nanoparticles is comparable to the micelles that were reported previously with the terpolymer, PEG- b -(PCL- ran -PPBCL). 23 …”

Section: Resultsmentioning

confidence: 99%

“…This represents a significant increase in DLC and EE as compared to our previously reported value of 5.1% DLC and 52% EE which was obtained for PEG- b -(PCL- ran -PPBCL). 23 The increase in DOX loading is due to the high number of PBA units conjugated to the polymer backbone which resulted in hydrogen bonding and π -stacking interactions between DOX and the polymer backbone.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we reported PBA conjugated poly(ethylene glycol)- b -poly( γ -4-phenylbutyrate– ε -caprolactone- ran - ε -caprolactone) (PEG- b -(PCL- ran -PPBCL)) copolymer for the delivery of DOX. 23 The γ -4-phenylbutyrate– ε -caprolactone monomer was copolymerized with ε -caprolactone in the presence of PEG as the macro-initiator with tin(II) 2-ethylhexanoate (Sn(Oct) 2 ) as the catalyst. The low incorporation of the PBA, into the polymeric backbone, resulted in reduced cytotoxicity to the human cervical cancer cells (HeLa).…”

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy

et al. 2018

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The short chain fatty acid, 4-phenylbutyric acid (PBA), is used for the treatment of urea cycle disorders and sickle cell disease as an endoplasmic reticulum stress inhibitor. PBA is also known as a histone deacetylase inhibitor (HDACi). We report here the effect of combination therapy on HeLa cancer cells using PBA as the HDACi together with the anticancer drug, doxorubicin (DOX). We synthesized γ-4-phenylbutyrate–ε-caprolactone monomer which was polymerized to form poly(γ-4-phenylbutyrate–ε-caprolactone) (PPBCL) homopolymer using NdCl3·3TEP/TIBA (TEP = triethyl phosphate, TIBA = triisobutylaluminum) catalytic system. DOX-loaded nanoparticles were prepared from the PPBCL homopolymer using poly(ethylene glycol) as a surfactant. An encapsulation efficiency as high as 88% was obtained for these nanoparticles. The DOX-loaded nanoparticles showed a cumulative release of >95% of DOX at pH 5 and 37 °C within 12 h, and PBA release was monitored by 1H NMR spectroscopy. The efficiency of the combination therapy can notably be seen in the cytotoxicity study carried out on HeLa cells, where only ~20% of cell viability was observed after treatment with the DOX-loaded nanoparticles. This drastic cytotoxic effect on HeLa cells is the result of the dual action of DOX and PBA on the DNA strands and the HDAC enzymes, respectively. Overall, this study shows the potential of combination treatment with HDACi and DOX anticancer drug as compared to the treatment with an anticancer drug alone.

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Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

“…The thermodynamic stability of the formed nanoparticles is comparable to the micelles that were reported previously with the terpolymer, PEG- b -(PCL- ran -PPBCL). 23 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy

et al. 2018

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Enhanced DOX loading in star‐like benzyl functionalized polycaprolactone micelles

Karmegam

Kuruppu

Gedara

et al. 2021

Journal of Polymer Science

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The self-assembly of functionalized polycaprolactone amphiphilic diblock copolymers is explored for carrier-mediated doxorubicin delivery for cancer treatment. In this report, functionalized polycaprolactone-based amphiphilic block copolymers with controlled branching architecture are investigated. Star-like copolymers, namely 4-arm and 6-arm poly(γ-benzyloxy-εwere synthesized by living ring-opening block copolymerization (ROP) of γ-(2-benzyloxy)-ε-caprolactone and γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-εcaprolactone using multifunctional initiators. A systematic investigation of the effect of branching points on polymer properties and micellar carrier properties was carried out. The star-like PBCL-b-PMEEECL micelles displayed better thermodynamic stability, size reduction, and enhanced doxorubicin encapsulation than the linear PBCL-b-PMEEECL. Furthermore, the π-π stacking between the benzyl group of the hydrophobic PBCL core and the doxorubicin, the anti-cancer drug, also increases the stability and loading capacity of the micelles. The star-polymers dis-

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Polymeric Micelles Employing Platinum(II) Linker for the Delivery of the Kinase Inhibitor Dactolisib

Shi

Lou

Steenbergen

et al. 2019

Part & Part Syst Charact

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Polymeric micelles are attractive nanocarriers for hydrophobic drug molecules such as the kinase inhibitor dactolisib. Two different poly(ethylene glycol)–poly(acrylic acid) (PEG‐b‐PAA) block‐copolymers are synthesized, PEG(5400)‐b‐PAA(2000) and PEG(10000)‐b‐PAA(3700), respectively. Polymeric micelles are formed by self‐assembly once dactolisib is conjugated via the ethylenediamine platinum(II) linker (Lx) to the PAA block of the block copolymers. Dactolisib micelles with dactolisib loading content of 17% w/w show good colloidal stability and display sustained release of Lx‐dactolisib over 96 h in PBS at 37 °C, while media containing reagents that compete for platinum coordination (e.g., glutathione (GSH) or dithiothreitol (DTT)) effectuate release of the parent inhibitor dactolisib at similar release rates. Dactolisib/lissamine‐loaded micelles are internalized by human breast adenocarcinoma cells (MCF‐7) in a dose and time‐dependent manner as demonstrated by confocal microscopy. Dactolisib‐loaded micelles inhibit the PI3K/mTOR signaling pathway at low concentrations (400 × 10−9 m) and exhibit potent cytotoxicity against MCF‐7 cells with IC50 values of 462 ± 46 and 755 ± 75 × 10−9 m for micelles with either short or longer PEG‐b‐PAA block lengths. In conclusion, dactolisib loaded PEG‐b‐PAA micelles are successfully prepared and hold potential for nanomedicine‐based tumor delivery of dactolisib.

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HDAC inhibitor conjugated polymeric prodrug micelles for doxorubicin delivery

Cited by 20 publications

References 38 publications

Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy

Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy

Enhanced DOX loading in star‐like benzyl functionalized polycaprolactone micelles

Polymeric Micelles Employing Platinum(II) Linker for the Delivery of the Kinase Inhibitor Dactolisib

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