Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

Noack, Anne-Kathrin; Lucas, Henrike; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

doi:10.3390/ijms21176029

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…However, the burst release of drugs could produce many adverse effects. Therefore, many drugs were loaded into functionalized carriers to reduce the drug release rate and achieve controlled drug release [ 5 ]. For example, Vivian F. Lotfy et al fabricated a chitosan derivative hydrogel for drug loading and investigated the drug release mechanism [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

A Double-Layer Hydrogel Dressing with High Mechanical Strength and Water Resistance Used for Drug Delivery

et al. 2023

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Hydrogel dressings provide a moist wound healing environment, absorb the exudates of the wound, and have better biocompatibility than traditional dressings. However, it is still difficult to meet the needs of modern medicine due to the defects in drug burst release, weak mechanical strength, and poor water retention. To solve these problems, we developed a double-layer (DL) hydrogel based on β-cyclodextrin polymer (β-CDP), poly(vinyl alcohol) (PVA), and carboxymethyl cellulose sodium (CMC) via a layer-by-layer method. Inspired by natural coconut, this hydrogel consisted of a drug release layer (DRL) and a mechanical support layer (MSL). In our design, the introduction of β-CDP into the DRL slowed the drug release rate of the DL hydrogel. Furthermore, the mechanical strength of the hydrogel was improved by immersing the MSL in a calcium chloride/boric acid solution. Combining these two layers, the tensile strength and elongation at break of the DL hydrogel reached 1504 kPa and 400%, respectively. More interestingly, the release mechanism of DL hydrogel conformed to the diffusion–relaxation–erosion model, which was different from traditional hydrogel dressings. Therefore, the as-prepared DL structure represents a feasible solution for fabricating high-performance mechanical hydrogel dressings with sustained drug release properties, and the DL hydrogel has potential to be used for medical dressings applied in daily life.

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Section: Introductionmentioning

confidence: 99%

A Double-Layer Hydrogel Dressing with High Mechanical Strength and Water Resistance Used for Drug Delivery

et al. 2023

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“…In particular, much research has been undertaken into the development of poly(N-(2hydroxypropyl)methacrylamide), or pHPMA, conjugated to Dox, i.e. pHPMA-Dox pro-drug systems [17,18]. Following initial reports in the 1970s which indicated the potential use of HPMA in biological applications [19,20], a variety of pHPMA conjugates have been prepared to treat multiple types of cancer [21,22].…”

Section: Introductionmentioning

confidence: 99%

Polymer Architecture Alters Tissue Distribution and Enhances Cytotoxicity Profiles in Orthotopic Models of Triple Negative Breast Cancers

Moloney

Mehradnia

Cavanagh

et al. 2023

Preprint

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The efficacy of nanomedicines is dependent on their access to target sites in the body, and this in turn is affected by their size, shape and transport properties in tissue. Although there have been many studies, the ability to design nanomaterials with optimal physicochemical properties for in vivo efficacy remains a significant challenge. In particular, it is difficult to quantify the detailed effects of cancer drug delivery systems in vivo as tumour volume reduction, a commonly reported marker of efficacy, does not always correlate with cytotoxicity in tumour tissue. Here, we studied the behaviour in vivo of two specific poly(2-hydroxypropyl methacrylamide) (pHPMA) pro-drugs, with the same chemical compositions of redox-responsive backbone components and pH-sensitive linkers to the anti-cancer drug doxorubicin but with varying architectures, in this case hyperbranched and star-shaped. Evaluation of the biodistribution of these polymers following systemic injection indicated differences in the circulation time and organ distribution of the two polymers, despite their very similar hydrodynamic radii (~ 10 and 15 nm) and underlying chemistry of backbone, side-chain and pro-drug linkers. In addition, both polymers showed improved tumour accumulation in orthotopic triple-negative breast cancers in mice, and decreased accumulation in healthy tissue, as compared to free doxorubicin. Importantly, there was a significant increase in tumour accumulation for the hyper-branched polymer compared to the star polymer, suggesting a possible role for solution conformations of these materials, rather than the chemistries, in mediating their performance. The results of haematoxylin and eosin assays, and TUNEL staining indicated a higher population of apoptotic cells in the tumours for both polymer pro-drug treatments, and in turn a lower population of apoptotic cells in the heart, liver and spleen, as compared to free doxorubicin. In particular, the hyperbranched polymer demonstrated significantly higher tumour deposition and apoptosis levels than its star shaped counterpart. Taken together, these data suggest that the penetration of both of these polymer pro-drugs was enhanced in tumour tissue relative to free doxorubicin, and that the combination of size, architecture, bioresponsive backbone and drug linker degradation yielded greater efficacy for the polymers as measured by biomarkers other than that of tumour volume.

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“…pHPMA-Dox pro-drug systems. 17,18 Following initial reports in the 1970s on the potential use of HPMA in biological applications, 19,20 a variety of pHPMA conjugates have been prepared to treat multiple types of cancer. 21,22 Furthermore, several HPMA-Dox formulations have reached clinical trials, including the candidate polymer therapeutics PK1 and PK2.…”

Section: Introductionmentioning

confidence: 99%

Chain-extension in hyperbranched polymers alters tissue distribution and cytotoxicity profiles in orthotopic models of triple negative breast cancers

Moloney¹,

Mehradnia²,

Cavanagh³

et al. 2023

Biomater. Sci.

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Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

Cited by 4 publications

References 25 publications

A Double-Layer Hydrogel Dressing with High Mechanical Strength and Water Resistance Used for Drug Delivery

A Double-Layer Hydrogel Dressing with High Mechanical Strength and Water Resistance Used for Drug Delivery

Polymer Architecture Alters Tissue Distribution and Enhances Cytotoxicity Profiles in Orthotopic Models of Triple Negative Breast Cancers

Chain-extension in hyperbranched polymers alters tissue distribution and cytotoxicity profiles in orthotopic models of triple negative breast cancers

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