pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

A pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2080–2095     

Rectal administration of nanosystems: from drug delivery to diagnostics

The rectal administration of drugs has been an enduring medical practice for either the management of local or systemic conditions. Although mostly regarded as an alternative to other delivery routes, the colorectal mucosa offers an effective pathway for enhanced systemic bioavailability of many active molecules. The fairly stable physicochemical and enzymatic environment of the mucosa and the possibility of partially avoiding the hepatic first-pass effect are some of the potential advantages of rectal drug delivery. At the same time, higher drug levels of drugs can be achieved at colorectal fluids and tissues, which can aid management of local conditions. However, problems with patient acceptability as well as poor and erratic drug absorption may impair efficient use of the rectal drug delivery route. The valuable features of nanotechnology-based systems for mucosal use are well recognized, and their potential as carriers for drug delivery has already been proven for different medical applications/delivery routes. Although still limited, the development of rectal nanomedicines with therapeutic, diagnostic, and prophylactic purposes is steadily emerging and may circumvent some of the problems associated with the more standard delivery approaches. This review discusses the rationale behind the use of nanotechnology-based strategies for rectal drug delivery and provides a critical overview on the various types of nanosystems proposed so far.     

Floxuridine Homomeric Oligonucleotides “Hitchhike” with Albumin In Situ for Cancer Chemotherapy

Automated attachment of chemotherapeutic drugs to oligonucleotides through phosphoramidite chemistry and DNA synthesis has emerged as a powerful technology in constructing structure‐defined and payload‐tunable oligonucleotide–drug conjugates. In practice, however, in vivo delivery of these oligonucleotides remains a challenge. Inspired by the systemic transport of hydrophobic payloads by serum albumin in nature, we report the development of a lipid‐conjugated floxuridine homomeric oligonucleotide (LFU20) that “hitchhikes” with endogenous serum albumin for cancer chemotherapy. Upon intravenous injection, LFU20 immediately inserts into the hydrophobic cave of albumin to form an LFU20/albumin complex, which accumulates in the tumor by the enhanced permeability and retention (EPR) effect and internalizes into the lysosomes of cancer cells. After degradation, cytotoxic floxuridine monophosphate is released to inhibit cell proliferation.     

Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14‐3‐3 Protein–Protein Interactions

The natural product family of fusicoccanes are stabilizers of 14‐3‐3 mediated protein–protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X‐ray crystallography confirmed the power of the MD‐based design approach, revealing the potential for an additional hydrogen bond with the 14‐3‐3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small‐molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization.     

A Mechanism‐Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases

Functional metagenomics has opened new opportunities for enzyme discovery. To exploit the full potential of this new tool, the design of selective screens is essential, especially when searching for rare enzymes. To identify novel glycosidases that employ cleavage strategies other than the conventional Koshland mechanisms, a suitable screen was needed. Focusing on the unsaturated glucuronidases (UGLs), it was found that use of simple aryl glycoside substrates did not allow sufficient discrimination against β‐glucuronidases, which are widespread in bacteria. While conventional glycosidases cannot generally hydrolyze thioglycosides efficiently, UGLs follow a distinct mechanism that allows them to do so. Thus, fluorogenic thioglycoside substrates featuring thiol‐based self‐immolative linkers were synthesized and assessed as selective substrates. The generality of the approach was validated with another family of unconventional glycosidases, the GH4 enzymes. Finally, the utility of these substrates was tested by screening a small metagenomic library.     

Conjugated Polymer Nanoparticles with Appended Photo‐Responsive Units for Controlled Drug Delivery,Release, and Imaging

Carriers that can afford tunable physical and structural changes are envisioned to address critical issues in controlled drug delivery applications. Herein, photo‐responsive conjugated polymer nanoparticles (CPNs) functionalized with donor–acceptor Stenhouse adduct (DASA) and folic acid units for controlled drug delivery and imaging are reported. Upon visible‐light (λ=550 nm) irradiation, CPNs simultaneously undergo structure, color, and polarity changes that release encapsulated drugs into the cells. The backbone of CPNs favors FRET to DASA units boosting their fluorescence. Notably, drug‐loaded CPNs exhibit excellent biocompatibility in the dark, indicating perfect control of the light trigger over drug release. Delivery of both hydrophilic and hydrophobic drugs with good loading efficiency was demonstrated. This strategy enables remotely controlled drug delivery with visible‐light irradiation, which sets an example for designing delivery vehicles for non‐invasive therapeutics.     

Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

Prolonged drug residence times may result in longer‐lasting drug efficacy, improved pharmacodynamic properties, and “kinetic selectivity” over off‐targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5‐iodotubercidin (5‐iTU) derivatives as a model for an archetypal active‐state (type I) kinase–inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen–aromatic π interactions in the haspin–inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding‐energy calculations.     

A Telomerase‐Responsive DNA Icosahedron for Precise Delivery of Platinum Nanodrugs to Cisplatin‐Resistant Cancer

A telomerase‐responsive DNA icosahedron was designed to precisely release caged platinum nanodrugs into cisplatin‐resistance tumor cells for effective therapy. This DNA icosahedron was constructed from two pyramidal DNA cages connected with telomerase primers and telomeric repeats, and platinum nanodrugs were then encapsulated into the DNA structure. In the presence of telomerase, the primers are extended, leading to inner‐chain substitution of the DNA icosahedron and subsequent release of the caged nanodrugs. This DNA icosahedron can precisely release caged nanodrugs in response to telomerase in tumor cells, giving enhanced anticancer efficacy in drug‐resistant carcinoma and with reduced toxicity to normal tissues. We speculate that this precisely designed, well controlled DNA cage could be generalized to diverse anticancer drugs.     

Selective,C-3 Friedel-Crafts acylation to generate functionally diverse,acetylated Imidazo[1,2-a]pyridine derivatives

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, CC bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance CC bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl₃. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.