| 1. |
- Andrade, Fernanda, et al.
(author)
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Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo
- 2021
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In: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 331, s. 198-212
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Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NC S), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NC S-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.
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| 2. |
- Berg, Staffan, et al.
(author)
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Evaluation in pig of an intestinal administration device for oral peptide delivery
- 2023
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In: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 353, s. 792-801
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Journal article (peer-reviewed)abstract
- The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.
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| 3. |
- Borsa, Baris Ata, First Research Engineer, et al.
(author)
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Therapeutic-oligonucleotides activated by nucleases (TOUCAN) : A nanocarrier system for the specific delivery of clinical nucleoside analogues.
- 2023
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In: Journal of Controlled Release. - : ELSEVIER. - 0168-3659 .- 1873-4995. ; 361, s. 260-269
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Journal article (peer-reviewed)abstract
- Nucleoside analogues have been in clinical use since 1960s and they are still used as the first therapeutic option for several cancers and viral infections, due to their high therapeutic efficacy. However, their wide clinical acceptance has been limited due to their high toxicity and severe side effects to patients. Herein, we report on a nanocarrier system that delivers nucleosides analogues in a target-specific manner, making nucleoside-based therapeutics safer and with the possibility to be used in other human conditions. This system, named, Therapeutic OligonUCleotides Activated by Nucleases" (TOUCAN) combines: i) the recognition power of oligonucleotides as substrates, ii) the use of nucleases as enzymatic biomarkers and iii) the clinical efficacy of nucleoside analogues, in a single approach. As a proof-of-concept, we report on a TOUCAN that is activated by a specific nuclease produced by bacteria and releases a therapeutic nucleoside, floxuridine. We demonstrate, for the first time, that, by incorporating a therapeutic nucleoside analogue into oligonucleotide probes, we can specifically inhibit bacterial growth in cultures. In this study, Staphylococcus aureus was selected as the targeted bacteria and the TOUCAN strategy successfully inhibited its growth with minimal inhibitory concentration (MIC) values ranging from 0.62 to 40 mg/L across all tested strains. Moreover, our results indicate that the intravenous administration of TOUCANs at a dose of 20 mg/kg over a 24-h period is a highly effective method for treating bacterial infections in a mouse model of pyomyositis. Importantly, no signs of toxicity were observed in our in vitro and in vivo studies. This work can significantly impact the current management of bacterial infections, laying the grounds for the development of a different class of antibiotics. Furthermore, it can provide a safer delivery platform for clinical nucleoside therapeutics in any human conditions, such as cancer and viral infection, where specific nuclease activity has been reported.
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| 4. |
- Campos Pacheco, Jesús Enrique, et al.
(author)
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Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis
- 2024
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In: Journal of Controlled Release. - : Elsevier B.V.. - 0168-3659 .- 1873-4995. ; 369, s. 231-250
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Journal article (peer-reviewed)abstract
- Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 μm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 μm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9–10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.
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| 5. |
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| 6. |
- Gannimani, Ramesh, et al.
(author)
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Acetal containing polymers as pH-responsive nano-drug delivery systems
- 2020
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 328, s. 736-761
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Research review (peer-reviewed)abstract
- Utilization of unique acidic environment in various disease sites has been quite advantageous in targeted drug delivery. Among the widely explored pH-sensitive moieties such as hydrazone, orthoester, imine, vinylether, etc., the acetal bearing compounds are one of the most explored entities in targeted and improved drug delivery to treat disease conditions at the preclinical stage. This review addresses the design and synthesis of various acetalbased polymers as pH-responsive nano-drug delivery systems in the form of micelles, polymersomes, nanoplexes and polymeric and solid lipid nanoparticles for biomedical applications. The review will identify potential advantages, key challenges and future prospects of acetal-based pH-responsive drug delivery systems. The novel developments, strategies and suggestions described may guide the formulation scientists to optimize acetalbased pH-responsive drug delivery systems as an approach to treat various diseases.
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| 7. |
- Handl, Verena, et al.
(author)
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Continuous iontronic chemotherapy reduces brain tumor growth in embryonic avian in vivo models
- 2024
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In: Journal of Controlled Release. - : ELSEVIER. - 0168-3659 .- 1873-4995. ; 369, s. 668-683
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Journal article (peer-reviewed)abstract
- Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat tumors such as the most lethal brain tumors, glioblastomas (GBM). However, despite high toxicity for GBM cells, potent chemotherapeutics such as gemcitabine (Gem) cannot be widely implemented as they do not efficiently cross the blood brain barrier (BBB). As an alternative method for continuous administration of Gem, we here operate freestanding iontronic pumps - "GemIPs" - equipped with a custom-synthesized ion exchange membrane (IEM) to treat a GBM tumor in an avian embryonic in vivo system. We compare GemIP treatment effects with a topical metronomic treatment and observe that a remarkable growth inhibition was only achieved with steady dosing via GemIPs. Daily topical drug administration (at the maximum dosage that was not lethal for the embryonic host organism) did not decrease tumor sizes, while both treatment regimes caused S-phase cell cycle arrest and apoptosis. We hypothesize that the pharmacodynamic effects generate different intratumoral drug concentration profiles for each technique, which causes this difference in outcome. We created a digital model of the experiment, which proposes a fast decay in the local drug concentration for the topical daily treatment, but a long-lasting high local concentration of Gem close to the tumor area with GemIPs. Continuous chemotherapy with iontronic devices opens new possibilities in cancer treatment: the long-lasting and highly local dosing of clinically available, potent chemotherapeutics to greatly enhance treatment efficiency without systemic side-effects. Significance statement: Iontronic pumps (GemIPs) provide continuous and localized administration of the chemotherapeutic gemcitabine (Gem) for treating glioblastoma in vivo. By generating high and constant drug concentrations near the vascularized growing tumor, GemIPs offer an efficient and less harmful alternative to systemic administration. Continuous GemIP dosing resulted in remarkable growth inhibition, superior to daily topical Gem application at higher doses. Our digital modelling shows the advantages of iontronic chemotherapy in overcoming limitations of burst release and transient concentration profiles, and providing precise control over dosing profiles and local distribution. This technology holds promise for future implants, could revolutionize treatment strategies, and offers a new platform for studying the influence of timing and dosing dependencies of already -established drugs in the fight against hard -to -treat tumors.
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| 8. |
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| 9. |
- Kis, Nikolett, et al.
(author)
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The effects of glycols on molecular mobility, structure, and permeability in stratum corneum
- 2022
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659. ; 343, s. 755-764
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Journal article (peer-reviewed)abstract
- The skin provides an attractive alternative to the conventional drug administration routes. Still, it comes with challenges as the upper layer of the skin, the stratum corneum (SC), provides an efficient barrier against permeation of most compounds. One way to overcome the skin barrier is to apply chemical permeation enhancers, which can modify the SC structure. In this paper, we investigated the molecular effect of three different types of glycols in SC: dipropylene glycol (diPG), propylene glycol (PG), and butylene glycol (BG). The aim is to understand how these molecules influence the molecular mobility and structure of the SC components, and to relate the molecular effects to the efficiency of these molecules as permeation enhancers. We used complementary experimental techniques, including natural abundance 13C NMR spectroscopy and wide-angle X-ray diffraction to characterize the molecular consequences of these compounds at different doses in SC at 97% RH humidity and 32 °C. In addition, we study the permeation enhancing effects of the same glycols in comparable conditions using Raman spectroscopy. Based on the results from NMR, we conclude that all three glycols cause increased mobility in SC lipids, and that the addition of glycols has an effect on the keratin filaments in similar manner as Natural Moisturizing Factor (NMF). The highest mobility of both lipids and amino acids can be reached with BG, which is followed by PG. It is also shown that one reaches an apparent saturation level for all three chemicals in SC, after which increased addition of the compound does not lead to further increase in the mobility of SC lipids or protein components. The examination with Raman mapping show that BG and PG give a significant permeation enhancement as compared to SC without any added glycol at corresponding conditions. Finally, we observe a non-monotonic response in permeation enhancement with respect to the concentration of glycols, where the highest concentration does not give the highest permeation. This is explained by the dehydration effects at highest glycol concentrations. In summary, we find a good correlation between the molecular effects of glycols on the SC lipid and protein mobility, and macroscopic permeation enhances of the same molecules.
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| 10. |
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| 11. |
- Leitao, Charles Dahlsson, 1992-, et al.
(author)
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Conditionally activated affibody-based prodrug targeting EGFR demonstrates improved tumour selectivity
- 2023
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 357, s. 185-195
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Journal article (peer-reviewed)abstract
- Safety and efficacy of cancer-targeting treatments can be improved by conditional activation enabled by the distinct milieu of the tumour microenvironment. Proteases are intricately involved in tumourigenesis and commonly dysregulated with elevated expression and activity. Design of prodrug molecules with protease -dependent activation has the potential to increase tumour-selective targeting while decreasing exposure to healthy tissues, thus improving the safety profile for patients. Higher selectivity could also allow for adminis-tration of higher doses or use of more aggressive treatment options, leading to higher therapeutic efficacy. We have previously developed an affibody-based prodrug with conditional targeting of EGFR conferred by an anti-idiotypic affibody masking domain (ZB05). We could show that binding to endogenous EGFR on cancer cells in vitro was restored following proteolytic removal of ZB05. In this study we evaluate a novel affibody-based pro -drug design, which incorporates a protease substrate sequence recognized by cancer-associated proteases and demonstrate the potential of this approach for selective tumour-targeting and shielded uptake in healthy tissues in vivo using tumour-bearing mice. This may widen the therapeutic index of cytotoxic EGFR-targeted thera-peutics by decreasing side effects, improving selectivity of drug delivery, and enabling the use of more potent cytotoxic drugs.
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| 12. |
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| 13. |
- Mehta, Meenu, et al.
(author)
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Recent trends of NFkB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases
- 2021
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In: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 337, s. 629-644
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Research review (peer-reviewed)abstract
- Nuclear factor Kappa B (NFicB) is a unique protein complex that plays a major role in lung inflammation and respi-ratory dysfunction. The NFicB signaling pathway, therefore becomes an avenue for the development of potential pharmacological interventions, especially in situations where chronic inflammation is often constitutively active and plays a key role in the pathogenesis and progression of the disease. NFicB decoy oligodeoxynucleotides (ODNs) are double-stranded and carry NFicB binding sequences. They prevent the formation of NFicB-mediated inflammatory cytokines and thus have been employed in the treatment of a variety of chronic inflammatory diseases. However, the systemic administration of naked decoy ODNs restricts their therapeutic effectiveness because of their poor pharmacokinetic profile, instability, degradation by cellular enzymes and their low cellular uptake. Both structural modification and nanotechnology have shown promising results in enhancing the pharmacokinetic profiles of potent therapeutic substances and have also shown great potential in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. In this review, we examine the contribution of NFicB activation in respiratory diseases and recent advancements in the thera-peutic use of decoy ODNs. In addition, we also highlight the limitations and challenges in use of decoy ODNs as therapeutic molecules, cellular uptake of decoy ODNs, and the current need for novel delivery systems to provide efficient delivery of decoy ODNs. Furthermore, this review provides a common platform for discussion on the existence of decoy ODNs, as well as outlining perspectives on the latest generation of delivery systems that encapsulate decoy ODNs and target NFxB in respiratory diseases.
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| 14. |
- Pinto, Soraia, et al.
(author)
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Nanoparticles targeting the intestinal Fc receptor enhance intestinal cellular trafficking of semaglutide
- 2024
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 366, s. 621-636
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Journal article (peer-reviewed)abstract
- Semaglutide is the first oral glucagon-like peptide-1 (GLP-1) analog commercially available for the treatment of type 2 diabetes. In this work, semaglutide was incorporated into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NPs) to improve its delivery across the intestinal barrier. The nanocarriers were surface-decorated with either a peptide or an affibody that target the human neonatal Fc receptor (hFcRn), located on the luminal cell surface of the enterocytes. Both ligands were successfully conjugated with the PLGA-PEG via maleimide-thiol chemistry and thereafter, the functionalized polymers were used to produce semaglutide-loaded NPs. Monodisperse NPs with an average size of 170 nm, neutral surface charge and 3% of semaglutide loading were obtained. Both FcRn-targeted NPs exhibited improved interaction and association with Caco-2 cells (cells that endogenously express the hFcRn), compared to non-targeted NPs. Additionally, the uptake of FcRn-targeted NPs was also observed to occur in human intestinal organoids (HIOs) expressing hFcRn through microinjection into the lumen of HIOs, resulting in potential increase of semaglutide permeability for both ligand-functionalized nanocarriers. Herein, our study demonstrates valuable data and insights that the FcRn-targeted NPs has the capacity to promote intestinal absorption of therapeutic peptides.
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| 15. |
- Yin, Wen, 1993-, et al.
(author)
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Comparison of HER2-targeted affibody conjugates loaded with auristatin-and maytansine-derived drugs
- 2023
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In: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 355, s. 515-527
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Journal article (peer-reviewed)abstract
- Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. ZHER2-ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAFbased conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-overexpressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of ZHER2-ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting ZTaq-ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of ZHER2-ABDmcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects.
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| 16. |
- Zhang, Jie, et al.
(author)
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Half-life extension via ABD-fusion leads to higher tumor uptake of an affibody-drug conjugate compared to PAS- and XTENylation.
- 2024
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 370, s. 468-478
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Journal article (peer-reviewed)abstract
- A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney filtration, and in vivo half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD.
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