Synthesis and characterization of poly(ethylene glycol) grafted poly(L-lactide)

Cho, Kuk Young; Kim, Chang-Hyeon; Lee, Jongwoo; Park, Jung-Ki

doi:10.1002/(sici)1521-3927(19991101)20:11<598::aid-marc598>3.0.co;2-1

Cited by 33 publications

(22 citation statements)

References 13 publications

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“…-epoxy--methoxy polyethylene glycol (mPEG 400 -epoxide) was synthesized as per published procedure. 15 Tritiated methyl iodide was purchased from ARC Radiochemical (St. Louis, MO) as solution in toluene and was used directly after dilution in dimethylsulfoxide.…”

Section: Materials and Cellsmentioning

confidence: 99%

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: Materials and Cellsmentioning

confidence: 99%

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Wong¹,

Misri²,

Shenoi³

et al. 2016

j biomed nanotechnol

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“…Clearance data after intravenous administration of tritiated UHRA-4 and UHRA-4/UFH complex in female Balb/C mice. References (58,59) …”

Section: Supplementary Materialsmentioning

confidence: 99%

Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants

et al. 2014

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Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the only clinically approved antidote to heparin, has shown adverse effects and ineffectiveness against low-molecular weight heparins and fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules and recombinant proteins have several drawbacks including limited efficacy, toxicity, immunogenicity, and high cost. Thus, there is an unmet clinical need for safer, rapid, predictable, and cost-effective anticoagulant-reversal agents for all clinically used heparins. We report a design strategy for a fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use of multivalent presentation of branched cationic heparin binding groups (HBGs). Optimization of the UHRA design was aided by isothermal titration calorimetry studies, biocompatibility evaluation, and heparin neutralization analysis. By controlling the scaffold's molecular weight, the nature of the protective shell, and the presentation of HBGs on the polymer scaffold, we arrived at lead UHRA molecules that completely neutralized the activity of all clinically used heparins. The optimized UHRA molecules demonstrated superior efficacy and safety profiles and mitigated heparin-induced bleeding in animal models. This new polymer therapeutic may benefit patients undergoing high-risk surgical procedures and has potential for the treatment of anticoagulant-related bleeding problems.

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“…From the commercially available MeO–PEG–OH, 1 , MeO–PEG‐epoxide, 2 , could be prepared by etherification . The 1 H NMR of MeO–PEG‐epoxide, 2 , shows new resonances corresponding to the epoxide group at δ = 3.15, 2.78, 2.59 ppm (peak b and c, Figure S1, Supporting Information) while MALDI‐ToF MS exhibited a uniform increase of 56.04 Da (theoretical exact mass = 56.03 Da, Figure A) for each individual signal, with respect to those in the starting material.…”

Section: Resultsmentioning

confidence: 99%

Efficient Synthesis of High Purity Homo‐arm and Mikto‐arm Poly(ethylene glycol) Stars Using Epoxide and Azide–Alkyne Coupling Chemistry

Zhang

Elupula

et al. 2013

Macromol. Rapid Commun.

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High purity homo-arm and mikto-arm poly(ethylene glycol) (PEG) stars are successfully prepared by the combination of epoxide ring-openings and azide-alkyne click reactions. First, monohydroxy-PEG was modified via epoxide chemistry to bear one hydroxyl and one azide functionality at the same end. An alkyne-functionalized PEG chain was then coupled to the azide. Subsequently, the remaining hydroxyl could be reactivated to an azide again and again to enable stepwise addition of alkyne-functionalized polymer arms. The use of efficient reactions for this iterative route provides star polymers with an exact number of arms, and a tailorable degree of polymerization for each arm. Detailed characterization confirms the high purity of multi-arm polyethylene glycol products.

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Synthesis and characterization of poly(ethylene glycol) grafted poly(L-lactide)

Cited by 33 publications

References 13 publications

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants

Efficient Synthesis of High Purity Homo‐arm and Mikto‐arm Poly(ethylene glycol) Stars Using Epoxide and Azide–Alkyne Coupling Chemistry

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