Crystalline Carriers: Designing pH- and Enzyme-Responsive Metal–Organic Frameworks for Albendazole Oral Delivery

Architectures of Porosity: Engineering the Molecular Logic of ABZ–MOF Systems

Metal–organic frameworks designed for oral drug delivery impose a structural logic on small-molecule pharmacology that fundamentally differs from traditional formulation strategies, because these hybrid crystalline lattices rely on periodic coordination networks that reorganize drug molecules within nanoscale cavities. In the case of albendazole encapsulation, the solvothermal co-crystallization pathway creates a synchronized assembly in which organic ligands and metal clusters generate an ordered pore grid that entraps drug molecules before the lattice fully consolidates. This dynamic crystallization environment transforms ABZ from its crystalline bulk state into a confined species whose mobility, reactivity, and dissolution behavior are dictated by pore geometry and host–guest interactions. The resulting morphological continuity between pre- and post-loading structures, especially in MOF-802 and UiO-66-NH₂, demonstrates that encapsulation occurs without compromising lattice topology, a feature that stabilizes encapsulated ABZ against premature decomposition. These structural features collectively form the physicochemical foundation for responsive release, positioning MOFs as architecturally programmable delivery matrices.

The crystalline fidelity observed after drug loading underscores the robustness of Zr- and Ti-based clusters, which maintain their coordination motifs even under chemical environments associated with ligand protonation and solvent exchange. Albendazole’s weak alkalinity enables partial ionization in acidic media, which subtly alters the electrostatic landscape within the MOF cavities and influences the Zeta potential shifts measured after encapsulation. This interplay between drug ionization and framework charge modifies pore microenvironments that later govern ABZ mobility during release, effectively encoding a chemical memory into the lattice. Furthermore, the transformation of nitrogen-containing ligands into stable bridging units establishes multiple potential binding vectors between ABZ and the internal surfaces, particularly through hydrogen bonding or coordination rearrangements. These interactions generate a microenvironment that protects ABZ from the solvolytic and thermal degradation typically observed in non-encapsulated drug forms.

The porosity measurements reveal that the micro- and mesoporous domains operate as cooperative compartments that regulate diffusion gradients upon hydration, allowing the framework to respond differently depending on local proton availability or enzyme influx. UiO-66-NH₂ and MIL-125-NH₂, with their higher internal surface areas and defect-susceptible coordination modes, create a multivalent interface capable of altering ABZ partitioning as the surrounding medium shifts from acidic to neutral pH. The constriction of available pore volume after drug loading further demonstrates that ABZ resides deeply within internal cavities rather than adhering to surfaces, thereby establishing controlled diffusional barriers. These barriers create a kinetic throttling mechanism where ABZ release begins only after pore fluid composition achieves specific thresholds. Such structural–functional coupling distinguishes MOF-based carriers from conventional solid dispersions, which lack these finely tunable internal architectures.

Because ABZ encapsulation reorganizes the lattice’s chemical microstructure without inducing crystallographic collapse, these frameworks maintain the fundamental rigidity needed to withstand gastric transit while still possessing the defect sensitivity that triggers release under intestinal conditions. This duality highlights how MOFs serve as molecularly encoded systems that sense local pH gradients and enzymatic flux, converting environmental cues into release behavior. As the next section details, these structural considerations determine how each ABZ–MOF variant enacts pH- and enzyme-responsive delivery, enabling distinct kinetic patterns across gastric and intestinal environments.

Responsive Release Behavior: Navigating pH, Enzyme Flux, and Framework Disassembly

The release dynamics of ABZ-loaded MOFs emerge from the interplay between pore wetting, framework dissolution, and the differential affinity of ABZ for microenvironments characterized by specific proton concentrations. Under strongly acidic pH, the rigid Zr- and Ti-based clusters remain structurally intact, limiting ABZ diffusion and effectively shielding the drug from premature release during gastric transit. As the medium transitions toward the weakly acidic or neutral range, alterations in proton distribution modulate both ligand coordination and hydrogen-bonding networks within the MOFs, enabling ABZ molecules to decouple from internal pore walls. These processes initiate a controlled diffusion pathway that respects the chemical thresholds encoded during synthesis, ensuring that release occurs only under conditions resembling the small intestine. The behavior of ABZ@UiO-66-NH₂ is particularly indicative of this mechanism, as its minimal release under gastric pH illustrates how amine-functionalized ligands stabilize ABZ more tightly at low proton concentrations.

Enzyme-responsive behavior adds an additional layer of regulation by exploiting the intrinsic susceptibility of coordination bonds to nucleophilic and proteolytic environments. Pancreatic protease, lipase, and α-amylase each interact with the MOF surface in distinct ways that accelerate pore destabilization, with lipase exerting the strongest influence on ABZ mobility. These enzymes impose localized perturbations on the lattice through mechanisms such as hydrolytic attack on metal–ligand bonds or steric intrusion into defect sites, thereby facilitating structural relaxation. As frameworks loosen, ABZ diffuses outward following concentration gradients that evolve as pore channels hydrate. This enzymatic modulation aligns release timing with digestive activity, ensuring a synchrony between intestinal physiology and molecular escape from the carrier. For ABZ@UiO-66-NH₂, this synergy between pH responsiveness and enzyme sensitivity marks it as the most efficient release vehicle among the three formulations.

The collapse of the PXRD signatures for MOF-802 and UiO-66-NH₂ after release studies demonstrates that framework degradation is mechanistically tied to ABZ liberation, making disassembly an intentional component of the drug-delivery strategy rather than a failure of structural robustness. Phosphate ions in PBS act as competitive ligands that disrupt metal–carboxylate coordination, accelerating lattice dissolution and facilitating ABZ exposure to the bulk medium. Meanwhile, MIL-125-NH₂ preserves its crystallinity even after 24 hours of release, indicating slower degradation kinetics that correlate with the more restrained release profile. By maintaining structural integrity, MIL-125-NH₂ prioritizes sustained retention over rapid diffusional discharge, revealing how framework composition dictates release architecture. Such contrasts underscore that each MOF variant embodies a different pharmacokinetic philosophy encoded at the nanoscale.

These collective observations point toward a design paradigm in which the MOF acts not merely as a passive reservoir but as a chemically intelligent system that synchronizes dissolution behavior with physiological transitions. The selective sensitivity to pH and enzymatic triggers creates structured checkpoints that ABZ must pass before reaching systemic circulation, replacing the erratic dissolution typical of poorly soluble drugs. As the next section expands, these dissolution-triggered events establish the preconditions necessary for effective transmembrane transport across intestinal epithelial layers, where particle size, charge, and structural flexibility determine cellular interaction patterns.

Transmembrane Transport: Cellular Interfaces and Mechanisms of ABZ–MOF Permeation

The transmembrane journey of ABZ-loaded MOFs across Caco-2 monolayers illustrates how nanoscale engineering transforms oral drug delivery into a sequence of physicochemically choreographed events. The positively shifted Zeta potentials of ABZ@UiO-66-NH₂ after loading enhance electrostatic attraction to negatively charged intestinal epithelial membranes, facilitating initial cell–particle engagement. This interaction becomes the first gating step in the absorption process, where the nanoscale rigidity and polyhedral morphology of the carriers determine how they align and settle on the apical membrane. The nanoscale dimensions of UiO-66-NH₂, residing near 228 nm, allow efficient internalization or paracellular routing compared to the larger MIL-125-NH₂ particles, which encounter steric hindrance. These size-dependent efficiencies explain the higher transmembrane flux observed for ABZ@UiO-66-NH₂ across both apical-to-basolateral and basolateral-to-apical directions.

Temperature-dependent transport measurements reveal that ABZ@UiO-66-NH₂ engages in a hybrid mechanism combining passive diffusion with active, energy-dependent processes. At reduced temperatures, decreased Papp values indicate diminished endocytic or transporter-mediated contributions, confirming that cellular machinery participates in translocation. Meanwhile, efflux ratios near unity for several concentration ranges show that these carriers avoid substantial recognition by efflux pumps that commonly limit the absorption of hydrophobic drugs. This evasion likely arises because MOF encapsulation masks ABZ’s inherent hydrophobicity and prevents premature membrane recognition that would otherwise induce efflux. MIL-125-NH₂, meanwhile, exhibits primarily passive diffusion behavior, consistent with its larger particle size and lower surface reactivity.

These permeation characteristics highlight how MOFs function as kinetic equalizers that mitigate the physicochemical disadvantages of ABZ, enabling drug molecules to access intracellular or paracellular spaces at rates otherwise unattainable for free ABZ. Encapsulation alters ABZ’s apparent diffusional identity by imposing a nanoparticle-like transport profile that harmonizes with the structural and electrochemical constraints of intestinal epithelia. The controlled internal release of ABZ from within the MOF during or after membrane traversal further ensures that drug molecules encounter reduced enzymatic degradation during transit. This spatial–temporal coupling of transport and release introduces a mechanistic sophistication not achievable with conventional formulations.

Because these MOF–drug complexes modulate how ABZ interfaces with cellular surfaces, their transcellular behavior establishes the necessary platform for improved systemic pharmacokinetics. The next section explores how these transmembrane transport advantages culminate in enhanced in vivo absorption, prolonged plasma residence, and extended therapeutic exposure following oral administration.

Pharmacokinetic Enhancement: Systemic Exposure and In Vivo Disposition

The pharmacokinetic behavior of ABZ delivered through MOF carriers reveals how nanoscale structural engineering reshapes systemic drug exposure. When administered intragastrically, ABZ@UiO-66-NH₂ maintains elevated plasma concentrations over extended periods relative to free ABZ, reflecting both enhanced dissolution in intestinal fluids and improved transmembrane transport. The prolonged mean residence time demonstrates that release kinetics within the intestinal lumen align with absorption rates, preventing premature clearance and ensuring steady influx into systemic circulation. ABZ@MIL-125-NH₂ also elevates systemic exposure but exhibits faster post-absorption clearance, consistent with a release pattern that liberates ABZ more slowly within the intestinal environment and more rapidly after systemic entry. These distinctions highlight how internal lattice behavior governs pharmacokinetic trajectories.

The increased area under the concentration–time curve observed for both MOF formulations reflects successful circumvention of ABZ’s inherent solubility limitations, showcasing how porous crystalline carriers can convert poorly soluble drugs into orally viable agents. The microenvironment created within MOF pores stabilizes ABZ long enough to survive gastric transit and dissolve efficiently only once reaching the enzymatically active intestinal milieu. This sequencing prevents the erratic dissolution that ordinarily undermines ABZ bioavailability. The capacity of UiO-66-NH₂ to sustain release and optimize uptake exemplifies how amine-functionalized frameworks strike a balance between stability and controlled disassembly, positioning this carrier as the most efficient oral delivery matrix among the evaluated systems.

The interplay between dissolution dynamics, epithelial transport, and systemic pharmacokinetics illustrates that MOFs operate not as static containers but as programmed machines whose structural disassembly is synchronized with biological gradients. Their coordination networks function as chemical timers that regulate ABZ exposure from ingestion through absorption, thereby compressing formulation design and physiological responsiveness into a unified system. This mechanistic coherence explains the dramatic improvement in systemic drug exposure achieved without altering ABZ’s chemical structure. Through these behaviors, MOFs redefine the boundaries of oral delivery for hydrophobic antiparasitic agents, translating structural materials science into pharmacological performance.

Taken together, these findings point to a future in which rationally designed crystalline carriers can be tuned to match the dissolution landscapes and epithelial barriers of specific therapeutic contexts. The ability to encode responsiveness to pH, enzymes, and biological interfaces directly into framework architecture expands the design space for oral delivery systems beyond what traditional formulations can offer. Such engineered responsiveness positions MOFs as promising platforms for next-generation oral antiparasitic therapies and potentially for broader classes of poorly soluble therapeutics.

Study DOI: https://doi.org/10.3390/ph18060819

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CompE

Editor-in-Chief, PharmaFEATURES