Ring-Opening Polymerization of ε-Caprolactone Initiated by Ganciclovir (GCV) for the Preparation of GCV-Tagged Polymeric Micelles

Sawdon, Alicia J.; Peng, Ching‐An

doi:10.3390/molecules20022857

Cited by 13 publications

(22 citation statements)

References 25 publications

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“…In contrast, the viability of HT-29 cells was decreased to 60% when challenged with 2 mg mL −1 5’-DFUR-PCL-MPEG micelles for 72 h (Figure 8B). In prior work, it has been shown that HT-29 cells treated with polymeric micelles tagged with acyclovir (ACV) [49] or ganciclovir (GCV) [51] did not exhibit apparent toxicity. This is because ACV and GCV prodrugs are not converted to their active and toxic form by TP.…”

Section: Resultsmentioning

confidence: 99%

Enhanced Anticancer Activity of 5’-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs

et al. 2018

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The compound 5’-deoxy-5-fluorouridine (5’-DFUR) is a prodrug of the anti-tumor drug 5-fluorouracil (5-FU). Thymidine phosphorylase (TP) is an enzyme that can convert 5’-DFUR to its active form 5-FU and the expression of TP is upregulated in various cancer cells. In this study, 5’-DFUR associated with amphiphilic copolymer poly(ε-caprolactone)-methoxy poly(ethylene glycol) (5’-DFUR-PCL-MPEG) was synthesized, characterized, and self-assembled into functional polymeric micelles. To demonstrate that the prodrug 5’-DFUR could convert into cytotoxic 5-fluorouracil (5-FU) by endogenous TP, HT-29 colorectal cancer cells were treated with 5’-DFUR-PCL-MPEG polymeric micelles for various time periods. Chemotherapeutic drugs doxorubicin (DOX) and 7-ethyl-10-hydroxycamptothecin (SN-38) were also encapsulated separately into 5’-DFUR-PCL-MPEG polymeric micelles to create a dual drug-loaded system. HT-29 cells were treated with DOX or SN-38 encapsulated 5’-DFUR-PCL-MPEG polymeric micelles to examine the efficacy of dual drug-loaded micelles. As a result, HT-29 cells treated with 5’-DFUR-PCL-MPEG polymeric micelles showed up to 40% cell death rate after a 72-h treatment. In contrast, HT-29 cells challenged with DOX or SN-38 encapsulated 5’-DFUR-incorporated polymeric micelles showed 36% and 31% in cell viability after a 72-h treatment, respectively.

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Section: Resultsmentioning

confidence: 99%

Enhanced Anticancer Activity of 5’-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs

et al. 2018

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“…The synthesis of GCV–PCL–chitosan and MPEG 350 –PCL–chitosan amphiphilic polymers in this study was previously reported [ 27 ]. In brief, 50 mg of GCV was mixed with 2.25 mL of ε-caprolactone (ε-CL) for 5 min at room temperature, followed by the addition of Sn(Oct) 2 (0.5 wt% of ε-CL).…”

Section: Methodsmentioning

confidence: 99%

“…PCL is commonly synthesized by ring-opening polymerization of ε-caprolactone using alcohol (R-OH) as an initiator and stannous (II) octoate (Sn(Oct) 2 ) as a catalyst [ 25 , 26 ]. Prodrug GCV possessing hydroxyl groups was employed as the initiator to synthesize GCV–PCL by ring-opening polymerization of ε-caprolactone [ 27 ]. The reported liphophilic GCV–PCL were further grafted with hydrophilic biodegradable chitosan which has been widely accepted as an efficient vector for nonviral gene delivery by forming complexes with DNA plasmids [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Polymeric Nanovectors Incorporated with Ganciclovir and HSV-tk Encoding Plasmid for Gene-Directed Enzyme Prodrug Therapy

et al. 2021

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In the area of gene-directed enzyme prodrug therapy (GDEPT), using herpes simplex virus thymidine kinase (HSV-tk) paired with prodrug ganciclovir (GCV) for cancer treatment has been extensively studied. It is a process involved with two steps whereby the gene (HSV-tk) is first delivered to malignant cells. Afterward, non-toxic GCV is administered to that site and activated to cytotoxic ganciclovir triphosphate by HSV-tk enzyme expressed exogenously. In this study, we presented a one-step approach that both gene and prodrug were delivered at the same time by incorporating them with polymeric micellar nanovectors. GCV was employed as an initiator in the ring-opening polymerization of ε-caprolactone (ε-CL) to synthesize hydrophobic GCV-poly(caprolactone) (GCV–PCL), which was furthered grafted with hydrophilic chitosan to obtain amphiphilic polymer (GCV–PCL–chitosan) for the fabrication of self-assembled micellar nanoparticles. The synthesized amphiphilic polymer was characterized using Fourier transform infrared spectroscopy and proton nuclear magnetic resonance. Micellar prodrug nanoparticles were analyzed by dynamic light scattering, zeta potential, critical micelle concentration, and transmission electron microscopy. Polymeric prodrug micelles with optimal features incorporated with HSV-tk encoding plasmids were cultivated with HT29 colorectal cancer cells and anticancer effectiveness was determined. Our results showed that prodrug GCV and HSV-tk cDNA encoded plasmid incorporated in GCV–PCL–chitosan polymeric nanocarriers could be delivered in a one-step manner to HT-29 cells and triggered high cytotoxicity.

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“…In recent years, a number of new Cs derivatives with improved transfection efficiency and better water solubility have been synthesized and characterized for drug and gene delivery. For example, urocanic acid-modified, 5 hydrophobized, 6 , 7 glycosylated, 8 polyethylene glycol-modified (PEGylated), 9 , 10 trimethylated, 11 , 12 poly(amidoamine) (PAMAM) grafted, 13 , 14 poly(epsilon-caprolactone) grafted, 15 , 16 oligoamine grafted, 17 and glycol grafted Cs 18 , 19 have been characterized using in vitro and in vivo models. These modified Cs derivatives have distinct advantages and disadvantages when used as the drug and gene delivery systems or theranostics.…”

Section: Introductionmentioning

confidence: 99%

A study on the hemocompatibility of dendronized chitosan derivatives in red blood cells

Zhou¹,

Li²,

Lu³

et al. 2015

DDDT

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Dendrimers are hyperbranched macromolecules with well-defined topological structures and multivalent functionalization sites, but they may cause cytotoxicity due to the presence of cationic charge. Recently, we have introduced alkyne-terminated poly(amidoamine) (PAMAM) dendrons of different generations (G=2,3) into chitosan to obtain dendronized chitosan derivatives [Cs-g-PAMAM (G=2,3)], which exhibited a better water solubility and enhanced plasmid DNA transfection efficiency. In this study, we attempted to examine the impact of Cs-g-PAMAM (G=2,3) at different concentrations (25 μg/mL, 50 μg/mL, and 100 μg/mL) on the morphology, surface structure, and viability of rat red blood cells (RBCs). The results showed that treatment of RBCs with Cs-g-PAMAM (G=2,3) at 50 μg/mL and 100 μg/mL induced a slightly higher hemolysis than Cs, and Cs-g-PAMAM (G=3) caused a slightly higher hemolysis than Cs-g-PAMAM (G=2), but all values were <5.0%. Optical microscopic and atomic force microscopic examinations indicated that Cs-g-PAMAM (G=2,3) caused slight RBC aggregation and lysis. Treatment of RBCs with 100 μg/mL Cs-g-PAMAM (G=3) induced echinocytic transformation, and RBCs displayed characteristic irregular contour due to the folding of the periphery. Drephanocyte-like RBCs were observed when treated with 100 μg/mL Cs-g-PAMAM (G=3). Erythrocytes underwent similar shape transition upon treatment with Cs-g-PAMAM (G=2) or Cs. The roughness values (Rms) of RBCs incubated with Cs-g-PAMAM (G=2,3) were significantly larger than those for RBCs incubated with physiological saline (P<0.01), but the Rms showed no difference for Cs and Cs-g-PAMAM (G=2,3) (P>0.05). Furthermore, Cs-g-PAMAM (G=2,3) exhibited a lower cytotoxicity in human kidney 293T cells. These results indicate that Cs-g-PAMAM (G=2,3) are hemocompatible but may disturb membrane and lipid structures at higher concentrations. Further safety and biocompatibility evaluations are warranted for Cs-g-PAMAM. Our findings prove helpful for a better understanding of the advantages of combining PAMAM dendrimers and chitosan to design and develop new, safe, and effective drug delivery vehicles.

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Ring-Opening Polymerization of ε-Caprolactone Initiated by Ganciclovir (GCV) for the Preparation of GCV-Tagged Polymeric Micelles

Cited by 13 publications

References 25 publications

Enhanced Anticancer Activity of 5’-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs

Enhanced Anticancer Activity of 5’-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs

Polymeric Nanovectors Incorporated with Ganciclovir and HSV-tk Encoding Plasmid for Gene-Directed Enzyme Prodrug Therapy

A study on the hemocompatibility of dendronized chitosan derivatives in red blood cells

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