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1. Self-assembly of a 5-fluorouracil and camptothecin dual drug dipeptide conjugate

   https://doi.org/10.1039/d2ob00762b  

   Sun, Yuan; Fry, Cathleen M.; Shieh, Aileen; Cai, Xiangchen; Reardon, Thomas J.; Parquette, Jon R. (July 2022, Organic & Biomolecular Chemistry)

   Nano-formulated, combinatory therapeutics that control the spatiotemporal aspects of drug release have potential to overcome many of the challenges faced in cancer therapy. Herein, we describe a peptide nanotube functionalized with two anticancer drugs, 5-fluoruracil (5-FU) and camptothecin (CPT). The nanotube was formed via peptide self-assembly, which positioned 5-FU on the surface at the aqueous interface; whereas, CPT was sequestered within the hydrophobic walls. Thus, two different release profiles were observed: rapid release of 5-FU, followed by slower, sustained production of CPT. This profile emerged from the rapid hydrolytic cleavage of 5-FU at the aqueous/nanotube interface, which produced a smaller nanotube comprised of the peptide fragment. 

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2. Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide–Drug Conjugates

   https://doi.org/10.1021/acs.biomac.4c00519  

   Sis, Matthew J; Liu, Dongping; Allen, Isabella; Webber, Matthew J (July 2024, Biomacromolecules)

   Supramolecular peptide-drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and site-specific delivery of therapeutic agents using a discrete single-component molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impact of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug-produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug/alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels, as well as their drug release profiles, showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design, with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials. 

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3. Macrophage-targeted anti-CCL2 immunotherapy enhances tumor sensitivity to 5-fluorouracil in a Balb/c-CT26 murine colon carcinoma model measured using diffuse reflectance spectroscopy

   https://doi.org/10.1186/s12865-022-00493-5  

   Bess, Shelby N.; Greening, Gage J.; Rajaram, Narasimhan; Muldoon, Timothy J. (December 2022, BMC Immunology)

   Abstract Background Immunotherapy in colorectal cancer (CRC) regulates specific immune checkpoints and, when used in combination with chemotherapy, can improve patient prognosis. One specific immune checkpoint is the recruitment of circulating monocytes that differentiate into tumor-associated macrophages (TAMs) and promote tumor angiogenesis. Changes in vascularization can be non-invasively assessed via diffuse reflectance spectroscopy using hemoglobin concentrations and oxygenation in a localized tumor volume. In this study, we examine whether blockade of monocyte recruitment via CCL2 (macrophage chemoattractant protein-1) leads to enhanced sensitivity of 5-fluorouracil (5-FU) in a CT26-Balb/c mouse model of CRC. It was hypothesized that the blockade of TAMs will alter tumor perfusion, increasing chemotherapy response. A subcutaneous tumor model using Balb/c mice injected with CT26 colon carcinoma cells received either a saline or isotype control, anti-CCL2, 5-FU, or a combination of anti-CCL2 and 5-FU. Results Findings show that 12 days post-treatment, monocyte recruitment was significantly reduced by approximately 61% in the combination group. This shows that the addition of anti-CCL2 to 5-FU slowed the fold-change (change from the original measurement to the final measurement) in tumor volume from Day 0 to Day 12 (~ 5 fold). Modest improvements in oxygen saturation (~ 30%) were observed in the combination group. Conclusion The findings in this work suggest that the blockade of CCL2 is sufficient in the reduction of TAMs that are recruited into the tumor microenvironment and has the ability to modestly alter tumor perfusion during early-tumor response to treatment even though the overall benefit is relatively modest. 

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4. Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform

   https://doi.org/10.1101/2024.05.21.595134  

   Pogostin, Brett H; Wu, Samuel X; Swierczynski, Michael J; Pennington, Christopher; Li, Si-Yang; Vohidova, Dilrasbonu; Seeley, Erin H; Agrawal, Anushka; Tang, Chaoyang; Cabler, Jacob; et al (May 2024, bioRxiv)

   Abstract Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventingMycobacterium tuberculosisgrowth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation. 

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5. Clues from cocrystals: a ternary solid, polymorphism, and rare supramolecular isomerism involving resveratrol and 5-fluorouracil

   https://doi.org/10.1039/D0CC08388G  

   Ortiz-de León, Celymar; MacGillivray, Leonard R. (April 2021, Chemical Communications)

   null (Ed.)

   We describe a supramolecular synthesis of a ternary cocrystal involving resveratrol and 5-fluorouracil ( 5-fu ) with trans -bis(4-pyridyl)ethylene ( bpe ). We also have discovered a polymorph of a binary cocrystal involving 5- fu and bpe that originates from rare supramolecular isomerism. 

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