Molecular Engineering‐Based Aptamer–Drug Conjugates with Accurate Tunability of Drug Ratios for Drug Combination Targeted Cancer Therapy

Polytherapy (or drug combination cancer therapy (DCCT)), targeting multiple mechanisms associated with tumor proliferation, can efficiently maximize therapeutic efficacy, decrease drug dosage, and reduce drug resistance. However, most DCCT strategies cannot coordinate the specific delivery of a drug combination in an accurately tuned ratio into cancer cells. To address these limitations, the present work reports the engineering of circular bivalent aptamer–drug conjugates (cb‐ApDCs). The cb‐ApDCs exhibit high stability, specific recognition, excellent cellular uptake, and esterase‐triggered release. Furthermore, the drug ratios in cb‐ApDCs can be tuned for an enhanced synergistic effect without the need for complex chemistry. Therefore, cb‐ApDCs provide a promising platform for the development of DCCT strategies for different drug combinations and ratios.     

Orthogonal Cysteine Protection Enables Homogeneous Multi‐Drug Antibody–Drug Conjugates

A strategy for the preparation of homogeneous antibody–drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site‐specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug‐linkers that have differing physiochemical properties and exert complementary anti‐cancer activities. Dual‐auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual‐drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site‐specific protein modification.     

Enhanced Drug Delivery by Dissolution of Amorphous Drug Encapsulated in a Water Unstable Metal–Organic Framework (MOF)

Encapsulating a drug molecule into a water‐reactive metal–organic framework (MOF) leads to amorphous drug confined within the nanoscale pores. Rapid release of drug occurs upon hydrolytic decomposition of MOF in dissolution media. Application to improve dissolution and solubility for the hydrophobic small drug molecules curcumin, sulindac, and triamterene is demonstrated. The drug@MOF composites exhibit significantly enhanced dissolution and achieves high supersaturation in simulated gastric and/or phosphate buffer saline media. This combination strategy where MOF inhibits crystallization of the amorphous phase and then releases drug upon MOF irreversible structural collapse represents a novel and generalizable approach for drug delivery of poorly soluble compounds while overcoming the traditional weakness of amorphous drug delivery: physical instability of the amorphous form.     

A Biomimetic Coordination Nanoplatform for Controlled Encapsulation and Delivery of Drug–Gene Combinations

Inspired by natural biomineralization processes, a simple and universal strategy is introduced to construct a biomimetic nanoplatform for systemic codelivery of a nucleic acid therapeutic (G3139) and a chemotherapeutic drug doxorubicin (DOX). This codelivery system was synthesized through one‐pot supramolecular self‐assembly of G3139, DOX, and Fe^II ions through multiple coordination interactions, followed by an adapted surface mineralization with metal–organic frameworks. The resulting core–shell nanoparticles have uniform size, well‐defined nanosphere structure, robust colloidal stability, ultrahigh drug loading efficiency and capacity, and precisely adjustable ratios of two therapeutic agents. The system can efficiently accumulate in the tumor, allowing for sensitive MRI detection and synergistical inhibition of tumor growth without apparent systemic toxicity.     

Programmed Release of Dihydroartemisinin for Synergistic Cancer Therapy Using a CaCO3 Mineralized Metal–Organic Framework

Dihydroartemisinin (DHA) has attracted increasing attention as an anticancer agent. However, using DHA to treat cancer usually depends on the synergistic effects of exogenous components, and the loss of DHA during delivery reduces its effectiveness in cancer therapy. Reported herein is a programmed release nanoplatform of DHA to synergistically treat cancer with a Fe‐TCPP [(4,4,4,4‐(porphine‐5,10,15,20‐tetrayl) tetrakis(benzoic acid)] NMOF (nanoscale MOF) having a CaCO₃ mineralized coating, which prevents DHA leakage during transport in the bloodstream. When the nanoplatform arrives at the tumor site, the weakly acidic microenvironment and high concentration of glutathione (GSH) trigger DHA release and TCPP activation, enabling the synergistic Fe²⁺‐DHA‐mediated chemodynamic therapy, Ca²⁺‐DHA‐mediated oncosis therapy, and TCPP‐mediated photodynamic therapy. In vivo experiments demonstrated that the nanoplatform showed enhanced anticancer efficiency and negligible toxicity.     

Microenvironment‐Induced In Situ Self‐Assembly of Polymer–Peptide Conjugates That Attack Solid Tumors Deeply

In cancer treatment, the unsatisfactory solid‐tumor penetration of nanomaterials limits their therapeutic efficacy. We employed an in vivo self‐assembly strategy and designed polymer–peptide conjugates (PPCs) that underwent an acid‐induced hydrophobicity increase with a narrow pH‐response range (from 7.4 to 6.5). In situ self‐assembly in the tumor microenvironment at appropriate molecular concentrations (around the IC₅₀ values of PPCs) enabled drug delivery deeper into the tumor. A cytotoxic peptide KLAK, decorated with the pH‐sensitive moiety cis‐aconitic anhydride (CAA), and a cell‐penetrating peptide TAT were conjugated onto poly(β‐thioester) backbones to produce PT‐K‐CAA, which can penetrate deeply into solid tumors owing to its small size as a single chain. During penetration in vivo, CAA responds to the weak acid, leading to the self‐assembly of PPCs and the recovery of therapeutic activity. Therefore, a deep‐penetration ability for enhanced cancer therapy is provided by this in vivo assembly strategy.     

Flexible,Luminescent Metal–Organic Frameworks Showing Synergistic Solid‐Solution Effects on Porosity and Sensitivity

Mixing molecular building blocks in the solid solution manner is a valuable strategy to obtain structures and properties in between the isostructural parent metal–organic frameworks (MOFs). We report nonlinear/synergistic solid‐solution effects using highly related yet non‐isostructural, phosphorescent Cu^I triazolate frameworks as parent phases. Near the phase boundaries associated with conformational diversity and ligand heterogeneity, the porosity (+150 %) and optical O₂ sensitivity (410 times, limit of detection 0.07 ppm) can be drastically improved from the best‐performing parent MOFs and even exceeds the records hold by precious‐metal complexes (3 ppm) and C₇₀ (0.2 ppm).     

Palladium Catalysis for Aerobic Oxidation Systems Using Robust Metal–Organic Framework

Described here is a new and viable approach to achieve Pd catalysis for aerobic oxidation systems (AOSs) by circumventing problems associated with both the oxidation and the catalysis through an all‐in‐one strategy, employing a robust metal–organic framework (MOF). The rational assembly of a Pd^II catalyst, phenanthroline ligand, and Cu^II species (electron‐transfer mediator) into a MOF facilitates the fast regeneration of the Pd^II active species, through an enhanced electron transfer from in situ generated Pd⁰ to Cu^II, and then Cu^I to O₂, trapped in the framework, thus leading to a 10 times higher turnover number than that of the homogeneous counterpart for Pd‐catalyzed desulfitative oxidative coupling reactions. Moreover, the MOF catalyst can be reused five times without losing activity. This work provides the first exploration of using a MOF as a promising platform for the development of Pd catalysis for AOSs with high efficiency, low catalyst loading, and reusability.     

Reversible Optical Writing and Data Storage in an Anthracene‐Loaded Metal–Organic Framework

Metal–organic frameworks (MOFs) enable the design of host–guest systems with specific properties. In this work, we show how the confinement of anthracene in a well‐chosen MOF host leads to reversible yellow‐to‐purple photoswitching of the fluorescence emission. This behavior has not been observed before for anthracene, either in pure form or adsorbed in other porous hosts. The photoresponse of the host–guest system is caused by the photodimerization of anthracene, which is greatly facilitated by the pore geometry, connectivity, and volume as well as the structural flexibility of the MOF host. The photoswitching behavior was used to fabricate photopatternable and erasable surfaces that, in combination with data encryption and decryption, hold promise in product authentication and secure communication applications.     

Rapid and Efficient Generation of Stable Antibody–Drug Conjugates via an Encoded Cyclopropene and an Inverse‐Electron‐Demand Diels–Alder Reaction

Homogeneous antibody–drug conjugates (ADCs), generated by site‐specific toxin linkage, show improved therapeutic indices with respect to traditional ADCs. However, current methods to produce site‐specific conjugates suffer from low protein expression, slow reaction kinetics, and low yields, or are limited to particular conjugation sites. Here we describe high yielding expression systems that efficiently incorporate a cyclopropene derivative of lysine (CypK) into antibodies through genetic‐code expansion. We express trastuzumab bearing CypK and conjugate tetrazine derivatives to the antibody. We show that the dihydropyridazine linkage resulting from the conjugation reaction is stable in serum, and generate an ADC bearing monomethyl auristatin E that selectively kills cells expressing a high level of HER2. Our results demonstrate that CypK is a minimal bioorthogonal handle for the rapid production of stable therapeutic protein conjugates.     

Selective Catalytic Chemistry at Rhodium(II) Nodes in Bimetallic Metal–Organic Frameworks

We report the first study of a gas‐phase reaction catalyzed by highly dispersed sites at the metal nodes of a crystalline metal–organic framework (MOF). Specifically, CuRhBTC (BTC^3?=benzenetricarboxylate) exhibited hydrogenation activity, while other isostructural monometallic and bimetallic MOFs did not. Our multi‐technique characterization identifies the oxidation state of Rh in CuRhBTC as +2, which is a Rh oxidation state that has not previously been observed for crystalline MOF metal nodes. These Rh²⁺ sites are active for the catalytic hydrogenation of propylene to propane at room temperature, and the MOF structure stabilizes the Rh²⁺ oxidation state under reaction conditions. Density functional theory calculations suggest a mechanism in which hydrogen dissociation and propylene adsorption occur at the Rh²⁺ sites. The ability to tailor the geometry and ensemble size of the metal nodes in MOFs allows for unprecedented control of the active sites and could lead to significant advances in rational catalyst design.     

A Titanium(IV)‐Based Metal–Organic Framework Featuring Defect‐Rich Ti‐O Sheets as an Oxidative Desulfurization Catalyst

While titanium‐based metal–organic frameworks (MOFs) have been widely studied for their (photo)catalytic potential, only a few Ti^IV MOFs have been reported owing to the high reactivity of the employed titanium precursors. The synthesis of COK‐47 is now presented, the first Ti carboxylate MOF based on sheets of Ti^IVO₆ octahedra, which can be synthesized with a range of different linkers. COK‐47 can be synthesized as an inherently defective nanoparticulate material, rendering it a highly efficient catalyst for the oxidation of thiophenes. Its structure was determined by continuous rotation electron diffraction and studied in depth by X‐ray total scattering, EXAFS, and solid‐state NMR. Furthermore, its photoactivity was investigated by electron paramagnetic resonance and demonstrated by catalytic photodegradation of rhodamine 6G.     

Lock‐and‐Key and Shape‐Memory Effects in an Unconventional Synthetic Path to Magnesium Metal–Organic Frameworks

We report a new magnesium metal–organic framework (MOF) (CPM‐107) with a special interaction with CO₂. CPM‐107 contains Mg₂‐acetate chains crosslinked into a 3D net by terephthalate. It has an anionic framework encapsulating ordered extra‐framework cations and solvent molecules. The desolvated form is closed and unresponsive to common gasses, such as N₂, H₂, and CH₄. Yet, with CO₂ at 195 K, it abruptly opens and turns into a rigid porous form that is irreversible via desorption. Once opened by CO₂, CPM‐107 remains in the stable porous state accessible to additional gas types over multiple cycles or CO₂ itself at different temperatures. The porous phase can be re‐locked to return to the initial closed phase via re‐solvation and desolvation. Such peculiar properties of CPM‐107 are apparently linked to a convergence of factors related to both framework and extra‐framework features. The unusual CO₂ effect is currently the only available path to porous CPM‐107 which shows efficient C₂H₂/CO₂ separation.     

Step‐Growth Copolymerization Between an Immobilized Monomer and a Mobile Monomer in Metal–Organic Frameworks

The A–A/B–B step‐growth copolymerization between a monomer immobilized in the crystalline state and a monomer mobile in the solution state is demonstrated. One of the two monomers was immobilized as organic ligands of the metal–organic framework (MOF) and polymerized with the mobile guest monomer, resulting in the formation of linear polymers. The polymerization behavior was completely different from that of the solution polymerizations. In particular, the degrees of polymerization (DP) converged to a specific value depending on the MOF structures. The inevitable termination is caused not by imperfectness of the polymerization reaction, but by the selection of the two polymerization partners among the several adjacent immobilized monomers. This is fully supported by the Monte Carlo simulation on the basis of the polymerization mechanism. Precise immobilization of monomers in the supramolecular assemblies is a promising way for the controlled A–A/B–B step‐growth polymerization.