Poly(2-methyl-2-oxazoline) conjugates with doxorubicin: From synthesis of high drug loading water-soluble constructs to in vitro anti-cancer properties

Sedláček, Ondřej; Driessche, Alexandra Van; Uvyn, Annemiek; Geest, Bruno G. De; Hoogenboom, Richard

doi:10.1016/j.jconrel.2020.06.018

Cited by 31 publications

(27 citation statements)

References 65 publications

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“…However, there is still a pressing need for fewer toxic drugs formulation and presentation. In order to circumvent the adverse effects of DOX and improve its efficacy, different drug delivery systems have been developed [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Among lipid-based systems, Doxil ® and Myocet ® are liposomal commercial formulations, which improved the safety profile of DOX in comparison with free DOX.…”

Section: Introductionmentioning

confidence: 99%

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

et al. 2021

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Doxorubicin (DOX), a chemotherapy drug successfully used in the therapy of various types of cancer, is currently associated with the mucositis development, an inflammation that can cause ulcerative lesions in the mucosa of the gastrointestinal tract, abdominal pain and secondary infections. To increase the safety of the chemotherapy, we loaded DOX into nanostructured lipid carriers (NLCs). The NLC–DOX was characterized by HPLC, DLS, NTA, Zeta potential, FTIR, DSC, TEM and cryogenic-TEM. The ability of NLC–DOX to control the DOX release was evaluated through in vitro release studies. Moreover, the effect of NLC–DOX on intestinal mucosa was compared to a free DOX solution in C57BL/6 mice. The NLC–DOX showed spherical shape, high drug encapsulation efficiency (84.8 ± 4.6%), high drug loading (55.2 ± 3.4 mg/g) and low average diameter (66.0–78.8 nm). The DSC and FTIR analyses showed high interaction between the NLC components, resulting in controlled drug release. Treatment with NLC–DOX attenuated DOX-induced mucositis in mice, improving shortening on villus height and crypt depth, decreased inflammatory parameters, preserved intestinal permeability and increased expression of tight junctions (ZO-1 and Ocludin). These results indicated that encapsulation of DOX in NLCs is viable and reduces the drug toxicity to mucosal structures.

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Section: Introductionmentioning

confidence: 99%

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

et al. 2021

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“…Although similar roles are expected for FA-PEtOx-ICG, FA-PEtOx-ICG could be used for cancer theranostics (therapy + diagnosis) because the PEtOx backbone could be easily modified with various therapeutic agents (e.g., radioisotopes). Sedlacek et al recently reported poly(2-methyl-2-oxazoline) conjugated with doxorubicin (polymer-drug conjugate) for cancer therapy …”

Section: Resultsmentioning

confidence: 99%

“…Acyl groups of PEtOx can be hydrolyzed by reaction with acid . Introduced secondary amino groups in PEtOx can be modified with various substituents. , We have previously reported the PEtOx derivatives conjugated with signal emitters for the diagnosis of cancers. , Fluorescence dye (indocyanine green, ICG)-conjugated PEtOx (PEtOx-ICG) was developed for both fluorescence imaging and photoacoustic imaging of cancers . Furthermore, PEtOx labeled with both ICG and a radioisotope (indium-111, 111 In) ( 111 In-PEtOx-ICG) can be used as a fluorescence/nuclear medical dual imaging probe …”

Section: Introductionmentioning

confidence: 99%

“…15 Introduced secondary amino groups in PEtOx can be modified with various substituents. 16,17 We have previously reported the PEtOx derivatives conjugated with signal emitters for the diagnosis of cancers. 8,18 Fluorescence dye (indocyanine green, ICG)-conjugated PEtOx (PEtOx-ICG) was developed for both fluorescence imaging and photoacoustic imaging of cancers.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Poly(2-ethyl-2-oxazoline)-Based Fluorescence Imaging Probe Targeting the Folate Receptor in Tumor Tissues

Sano

Suzuno

Bao

et al. 2021

ACS Appl. Polym. Mater.

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Poly(2-ethyl-2-oxazoline) (PEtOx) is a water-soluble and biocompatible polymer. In this study, we developed a cancertargeted fluorescence imaging probe based on PEtOx by conjugating both cancer-targeting moieties and fluorescent dyes to secondary amino groups introduced by hydrolyzing the acyl groups of PEtOx. Due to the overexpression of folate receptors in tumors such as ovarian cancers, we selected folic acid (FA) as the cancer-targeting moiety in this study. After partial hydrolysis of propionyl groups in PEtOx (50 kDa) by refluxing with hydrochloric acid, the FA derivative and fluorescence dye (indocyanine green [ICG] derivative) were sequentially reacted to obtain FA-PEtOx-ICG. The hydrolysis ratio of PEtOx was approximately 8%, and the number of FA and ICG derivatives introduced into PEtOx was approximately 11 and 5, respectively. The cellular uptake of FA-PEtOx-ICG by SKOV3 (human ovarian cancer cells) overexpressing folate receptors was evaluated by fluorescence microscopy. FA-PEtOx-ICG was highly internalized by SKOV3 cells compared to control PEtOx-ICG. Moreover, the cellular uptake was significantly suppressed by the coaddition of excess FA, suggesting the specific binding of FA-PEtOx-ICG to folate receptors. For in vivo evaluation, an animal model of peritoneal metastases was prepared by intraperitoneal injection of green fluorescent protein (GFP)-transfected SKOV3 cells into female nude mice, and the mice were fed a folate-deficient diet. The submillimeter peritoneal metastasis foci (GFP-positive) were detected by FA-PEtOx-ICG with spectral fluorescence imaging. Furthermore, the fluorescence signals of FA-PEtOx-ICG in SKOV3 tumors were significantly reduced when mice were fed a folate-containing diet. These results indicate the specific binding of FA-PEtOx-ICG to the folate receptors in vivo.

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“…Another class of polymers recently introduced for the design of polymer–drug conjugates are the poly(2-oxazoline)s (PAOx), which are biocompatible, display minimal immunogenicity, and have excellent potential for customization. Over the last decade, PAOx–drug conjugates have been studied with several drug molecules, including rotigotine, , doxorubicin, , benazepril, and penicillin . The PAOx–rotigotine conjugate is a sustained-release formulation that successfully passed a preliminary phase 1A human clinical trial for treatment of Parkinson’s disease …”

Section: Introductionmentioning

confidence: 99%

Thermoresponsive Polymer–Antibiotic Conjugates Based on Gradient Copolymers of 2-Oxazoline and 2-Oxazine

et al. 2021

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A polymer–antibiotic conjugate with thermoresponsive properties near body temperature is presented. The backbone polymer is a copolymer of 2-n-propyl-2-oxazine (PropOzi) and methoxycarbonylethyl-2-oxazoline (C2MestOx) which is conjugated with the broad-spectrum antibiotic, cefazolin, via modification of the methyl ester group of C2MestOx. The resulting polymer–antibiotic conjugate has a cloud point temperature near body temperature, meaning that it can form a homogenous solution if cooled, but when injected into a skin-mimic at 37 °C, it forms a drug depot precipitate. Cleavage of the ester linker leads to quantitative release of the pristine cefazolin (with some antibiotic degradation observed) and redissolution of the polymer. When Escherichia coli were treated with polymer–antibiotic conjugate total clearance is observed within 12 h. The power of this approach is the potential for localized antibiotic delivery, for example, at a specific tissue site or into infected phagocytic cells.

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Poly(2-methyl-2-oxazoline) conjugates with doxorubicin: From synthesis of high drug loading water-soluble constructs to in vitro anti-cancer properties

Cited by 31 publications

References 65 publications

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

Development of a Poly(2-ethyl-2-oxazoline)-Based Fluorescence Imaging Probe Targeting the Folate Receptor in Tumor Tissues

Thermoresponsive Polymer–Antibiotic Conjugates Based on Gradient Copolymers of 2-Oxazoline and 2-Oxazine

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