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1. pH and redox triggered doxorubicin release from covalently linked carbon dots conjugates

   https://doi.org/10.1039/D0NR08381J  

   Hettiarachchi, Sajini D. ; Kirbas Cilingir, Emel ; Maklouf, Heidi ; Seven, Elif S. ; Paudyal, Suraj ; Vanni, Steven ; Graham, Regina M. ; Leblanc, Roger M. ( March 2021 , Nanoscale)

   null (Ed.)

   Tumor microenvironment responsive drug delivery systems are potential approaches to reduce the acute toxicity caused by high-dose cancer chemotherapy. Notwithstanding the conventional nano-drug delivery systems, the redox and pH stimuli drug delivery systems are currently gaining attention. Therefore, the current study was designed to compare three different covalent carbon dots (C-dots) systems based on doxorubicin (dox) release profiles and cancer cell viability efficacy under acidic and physiological conditions. The C-dots nanosystems that were examined in this study are directly conjugated (C-dots-dox), pH triggered (C-dots-HBA-dox), and the redox stimuli (C-dots-S–S-dox) conjugates. The drug loading content (DLC%) of the C-dots-S–S-dox, C-dots-HBA-dox, and C-dots-dox was 34.2 ± 0.4, 60.0 ± 0.3, and 70.0 ± 0.2%, respectively, that examined by UV-vis spectral analysis. The dox release paradigms were emphasized that all three conjugates were promisingly released the dox from C-dots faster in acidic pH than in physiological pH. The displayed highest dox released percentage in the acidic medium was 74.6 ± 0.8% obtained by the pH stimuli, C-dots-HBA-dox conjugate. When introducing the redox inducer, dithiothreitol (DTT), preferentially, the redox stimuli C-dot-S–S-dox conjugate demonstrated a faster dox release at acidic pH than in the pH 7.4. The SJGBM2 cell viability experiments revealed that the pH stimuli, C-dots-HBA-dox conjugate, displayed a significant cell viability drop in the artificially acidified pH 6.4 medium. However, in the physiological pH, the redox stimuli, C-dots-S–S-dox conjugate, was promising over the pH stimuli C-dots-HBA-dox, exhibiting cell viability of 60%, though its’ efficacy dropped slightly in the artificially acidified pH 6.4 medium. Moreover, the current study illustrates the stimuli conjugates’ remarkable efficacy on sustain drug release than direct amide linkage. 

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2. Doxorubicin‐Loaded Physalis Mottle Virus Particles Function as a pH‐Responsive Prodrug Enabling Cancer Therapy

   https://doi.org/10.1002/biot.202000077  

   Hu, He ; Steinmetz, Nicole F. ( October 2020 , Biotechnology Journal)

   The controlled release of drugs using nanoparticle‐based delivery vehicles is a promising strategy to improve the safety and efficacy of chemotherapy. A simple, scalable, and reproducible strategy is developed to synthesize a drug delivery system (DDS) by loading 6‐maleimidocaproyl‐hydrazone doxorubicin (DOX‐EMCH) into the empty core of virus‐like particles (VLPs) derived from Physalis mottle virus (PhMV) via a combination of chemical conjugation to cysteine residues and π–π stacking interactions with the anchored doxorubicin molecule. The DOX‐EMCH prodrug features an acid‐sensitive hydrazine linker that triggers the release of doxorubicin in the slightly acidic extracellular tumor microenvironment or acidic endosomal or lysosomal compartments following cellular uptake. The VLP external surface is coated with polyethylene glycol (PEG) to prevent non‐specific uptake and improve biocompatibility. The DOX‐PhMV‐PEG particles are stable in vitro and show greater efficacy in vivo compared to free doxorubicin in a breast tumor mouse model (using MDA‐MB‐231 cells and nude mice): 92% of the tumor‐bearing mice treated with DOX‐PhMV‐PEG are completely cured compared to 27% of those treated with free doxorubicin under the same conditions, representing a 3.4‐fold improvement. These results lay a foundation for the further development of this biological drug delivery system for a new generation of chemotherapy products.

    

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3. Biocompatible FePO4 Nanoparticles: Drug Delivery, RNA Stabilization, and Functional Activity

   https://doi.org/10.1186/s11671-021-03626-8  

   Rayamajhi, Sagar ; Wilson, Sarah ; Aryal, Santosh ; DeLong, Robert ( November 2021 , Nanoscale Research Letters)

   FePO₄NPs are of special interest in food fortification and biomedical imaging because of their biocompatibility, high bioavailability, magnetic property, and superior sensory performance that do not cause adverse organoleptic effects. These characteristics are desirable in drug delivery as well. Here, we explored the FePO₄nanoparticles as a delivery vehicle for the anticancer drug, doxorubicin, with an optimum drug loading of 26.81% ± 1.0%. This loading further enforces the formation of Fe³⁺doxorubicin complex resulting in the formation of FePO₄-DOX nanoparticles. FePO₄-DOX nanoparticles showed a good size homogeneity and concentration-dependent biocompatibility, with over 70% biocompatibility up to 80 µg/mL concentration. Importantly, cytotoxicity analysis showed that Fe³⁺complexation with DOX in FePO₄-DOX NPs enhanced the cytotoxicity by around 10 times than free DOX and improved the selectivity toward cancer cells. Furthermore, FePO₄NPs temperature-stabilize RNA and support mRNA translation activity showing promises for RNA stabilizing agents. The results show the biocompatibility of iron-based inorganic nanoparticles, their drug and RNA loading, stabilization, and delivery activity with potential ramifications for food fortification and drug/RNA delivery.

    

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4. Supramolecular Loading of DNA Hydrogels with Dye–Drug Conjugates for Real‐Time Photoacoustic Monitoring of Chemotherapy

   https://doi.org/10.1002/advs.202204330  

   Borum, Raina M. ; Moore, Colman ; Mantri, Yash ; Xu, Ming ; Jokerst, Jesse V. ( November 2022 , Advanced Science)

   A longstanding problem with conventional cancer therapy is the nonspecific distribution of chemotherapeutics. Monitoring drug release in vivo via noninvasive bioimaging can thus have value, but it is difficult to distinguish loaded from released drug in live tissue. Here, this work describes an injectable supramolecular hydrogel that allows slow and trackable release of doxorubicin (Dox) via photoacoustic (PA) tomography. Dox is covalently linked with photoacoustic methylene blue (MB) to monitor Dox before, during, and after release from the hydrogel carrier. The conjugate (MB‐Dox) possesses an IC50 of 161.4 × 10⁻⁹ magainst human ovarian carcinoma (SKOV3) cells and loads into a DNA‐clad hydrogel with 91.3% loading efficiency due to MB‐Dox's inherent intramolecular affinity to DNA. The hydrogel is biodegradable by nuclease digestion, which causes gradual release of MB‐Dox. This release rate is tunable based on the wt% of the hydrogel. This hydrogel maintains distinct PA contrast on the order of days when injected in vivo and demonstrates activatable PA spectral shifts   during hydrogel degradation. The released and loaded payload can be imaged relative to live tissue via PA and ultrasound signal being overlaid in real‐time. The hydrogel slowed the rate of the murine intraperitoneal tumor growth 72.2% more than free Dox.

    

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5. Developing New Peptides and Peptide–Drug Conjugates for Targeting the FGFR2 Receptor-Expressing Tumor Cells and 3D Spheroids

   https://doi.org/10.3390/biomimetics9090515  

   Biggs, Mary A ; Das, Amrita ; Goncalves, Beatriz G ; Murray, Molly E ; Frantzeskos, Sophia A ; Hunt, Hannah L ; Phan, Chau_Ahn N ; Banerjee, Ipsita A ( August 2024 , Biomimetics)

   In this work, we utilized a biomimetic approach for targeting KATO (III) tumor cells and 3D tumoroids. Specifically, the binding interactions of the bioactive short peptide sequences ACSAG (A-pep) and LPHVLTPEAGAT (L-pep) with the fibroblast growth factor receptor (FGFR2) kinase domain was investigated for the first time. Both peptides have been shown to be derived from natural resources previously. We then created a new fusion trimer peptide ACSAG-LPHVLTPEAGAT-GASCA (Trimer-pep) and investigated its binding interactions with the FGFR2 kinase domain in order to target the fibroblast growth factor receptor 2 (FGFR2), which is many overexpressed in tumor cells. Molecular docking and molecular dynamics simulation studies revealed critical interactions with the activation loop, hinge and glycine-rich loop regions of the FGFR2 kinase domain. To develop these peptides for drug delivery, DOX (Doxorubicin) conjugates of the peptides were created. Furthermore, the binding of the peptides with the kinase domain was further confirmed through surface plasmon resonance studies. Cell studies with gastric cancer cells (KATO III) revealed that the conjugates and the peptides induced higher cytotoxicity in the tumor cells compared to normal cells. Following confirmation of cytotoxicity against tumor cells, the ability of the conjugates and the peptides to penetrate 3D spheroids was investigated by evaluating their permeation in co-cultured spheroids grown with KATO (III) and colon tumor-associated fibroblasts (CAFs). Results demonstrated that Trimer-pep conjugated with DOX showed the highest permeation, while the ACSAG conjugate also demonstrated reasonable permeation of the drug. These results indicate that these peptides may be further explored and potentially utilized to create drug conjugates for targeting tumor cells expressing FGFR2 for developing therapeutics.

    

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