Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

Hole-Transporting Materials based on Oligo(hetero)aryls with a Naphthodithiophene Core - Succinct Synthesis by Twofold Direct C-H Olefination.

This work demonstrated the first synthetic application of direct C-H olefinations in the step-saving preparation of various hole-transporting materials (HTM) for efficient perovskite solar cells (PSC). Cross-dehydrogenative couplings of naphthodithiophene (NDT) with vinyl arenes under palladium-catalysis facilely generated various new oligo(hetero)aryls with internal alkenes. Reaction conditions were optimized, which gave the product isolated yields of up to 71 % with high (E)-stereoselectivity. These readily accessible NDT core-based small molecules involving olefin as π-spacers displayed immediate power conversion efficiencies of up to 17.2 % without a device oxidation process that is required for the commercially available spiro-OMeTAD and most other existing HTMs while fabricated in corresponding PSC devices.

New Molecular Design, Step-Saving Synthesis, and Applications of Indolocarbazole Core-Based Oligo(hetero)arenes.

In this work, we have successfully synthesized 15 new examples (LLA01-06; LinLi01-10) of small-molecule hole-transporting materials (HTM) using the less explored indolocarbazole (ICbz) as core moiety. Different from previously reported ICbz HTMs, LinLi01-10 exhibit new molecular designs in which 3,4-ethylenedioxythiophene (EDOT) units are inserted as crucial π-spacers and fluorine atoms are introdcued into end-group molecules. These substantially improve the materials solubility and device power conversion efficiencies (PCEs) while fabricated in perovskite solar cells (PSC). More importantly, LinLi01-10 are generated by a sustainable synthetic approach involving the use of straightforward C-H/C-Br couplings as key transformations, thus avoiding additional synthetic transformations including halogenation and borylation reactions called substrate prefunctionalizations usually required in Suzuki reactions. Most HTM molecules can be purified simply by reprecipitations instead of conducting column chromatography. In contrast to LLA01-06 without additional EDOT moieties, PSC devices using LinLi01-10 as hole-transport layers display promising PCEs of up to 17.5 %. Interestingly, PSC devices employing seven of the LinLi01-10 as hole-transport molecules, respectively, are all able to show an immediate >10 % PCE (t=0) without any device oxidation/aging process that is necessary for the commercial spiro-OMeTAD based PSCs.

Tailored Supersaturable Immediate Release Behaviors of Hypotensive Supersaturating Drug-Delivery Systems Combined with Hot-Melt Extrusion Technique and Self-Micellizing Polymer.

The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended "spring-parachute" process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy.

Effects of Osteocyte Shape on Fluid Flow and Fluid Shear Stress of the Loaded Bone.

This study was conducted to better understand the specific behavior of the intraosseous fluid flow. We calculated the number and distribution of bone canaliculi around the osteocytes based on the varying shapes of osteocytes. We then used these calculated parameters and other bone microstructure data to estimate the anisotropy permeability of the lacunar-canalicular network. Poroelastic finite element models of the osteon were established, and the influence of the osteocyte shape on the fluid flow properties of osteons under an axial displacement load was analyzed. Two types of boundary conditions (BC) that might occur in physiological environments were considered on the cement line of the osteon. BC1 allows free fluid passage from the outer elastic restraint boundary, and BC2 is impermeable and allows no free fluid passage from outer displacement constrained boundary. They both have the same inner boundary conditions that allow fluid to pass through. Changes in the osteocyte shape altered the maximum value of pressure gradient (PG), pore pressure (PP), fluid velocity (FV), and fluid shear stress (FSS) relative to the reference model (spherical osteocytes). The maximum PG, PP, FV, and FSS in BC2 were nearly 100% larger than those in BC1, respectively. It is found that the BC1 was closer to the real physiological environment. The fluid flow along different directions in the elongated osteocyte model was more evident than that in other models, which may have been due to the large difference in permeability along different directions. Changes in osteocyte shape significantly affect the degrees of anisotropy of fluid flow and porous media of the osteon. The model presented in this study can accurately quantify fluid flow in the lacunar-canalicular network.

Study on the biomechanical responses of the loaded bone in macroscale and mesoscale by multiscale poroelastic FE analysis.

BACKGROUND: Bone is a hierarchically structured composite material, and different hierarchical levels exhibit diverse material properties and functions. The stress and strain distribution and fluid flow in bone play an important role in the realization of mechanotransduction and bone remodeling. METHODS: To investigate the mechanotransduction and fluid behaviors in loaded bone, a multiscale method was developed. Based on poroelastic theory, we established the theoretical and FE model of a segment bone to provide basis for researching more complex bone model. The COMSOL Multiphysics software was used to establish different scales of bone models, and the properties of mechanical and fluid behaviors in each scale were investigated. RESULTS: FE results correlated very well with analytical in macroscopic scale, and the results for the mesoscopic models were about less than 2% different compared to that in the macro-mesoscale models, verifying the correctness of the modeling. In macro-mesoscale, results demonstrated that variations in fluid pressure (FP), fluid velocity (FV), von Mises stress (VMS), and maximum principal strain (MPS) in the position of endosteum, periosteum, osteon, and interstitial bone and these variations can be considerable (up to 10, 8, 4 and 3.5 times difference in maximum FP, FV, VMS, and MPS between the highest and the lowest regions, respectively). With the changing of Young's modulus (E) in each osteon lamella, the strain and stress concentration occurred in different positions and given rise to microscale spatial variations in the fluid pressure field. The heterogeneous distribution of lacunar-canalicular permeability (klcp) in each osteon lamella had various influence on the FP and FV, but had little effect on VMS and MPS. CONCLUSION: Based on the idealized model presented in this article, the presence of endosteum and periosteum has an important influence on the fluid flow in bone. With the hypothetical parameter values in osteon lamellae, the bone material parameters have effect on the propagation of stress and fluid flow in bone. The model can also incorporate alternative material parameters obtained from different individuals. The suggested method is expected to provide dependable biological information for better understanding the bone mechanotransduction and signal transduction.

[Effect of artery pulse on the osteonal interstitial fluid flow behavior].

There are two main types of fluid in bone tissue: blood and interstitial fluid. The metabolism of cells mainly relies on the microenvironment of the interstitial fluid. Researches of osteonal fluid seepage behavior based on the microstructure of bone tissue have become a hot point. The aim of the present research work is to assess the effect of blood pressure oscillation on the osteonal interstitial fluid seepage behavior. We established finite element osteon models for a hollow and that considering blood pressure oscillation, respectively, with COMSOL Multiphysics software in order to compare their fluid flow behavior under the axial loading. The results predicted that the interstitial fluid pressure field was enlarged considering the blood pressure oscillation, while the velocity filed changed little. Specifically, the increase of blood pressure oscillatory amplitude could result in the increase of osteonal interstitial fluid pressure, while the blood pressure oscillatory frequency had limited effects on the osteonal pore fluid pressure. Moreover, the blood pressure oscillatory amplitude and frequency had no effect on the osteonal interstitial fluid velocity. The finite element model can be used for the study of the poroelastic behaviors of the osteon under non-axisymmetric loads and microcracks, and can also be a new way to study the mechanism of bone mechanotransduction and electromechanotransduction.

Effects of the microcrack shape, size and direction on the poroelastic behaviors of a single osteon: a finite element study.

PURPOSE: In this work, a finite element study is proposed by using the Comsol Multiphysics software to evaluate the effects of microcrack shape, size and direction on the poroelastic behaviors of a single osteon. METHODS: This finite element model is established by using the Comsol Multiphysics software, and we just focus on the comparison of the influences of those microcrack geometric parameters on the osteonal fluid pressure and velocity. RESULTS: The results show that: (1) microcracks in the osteon wall can induce a release of the fluid pressure, but enlarge the velocity in this region; (2) equal-area microcrack with ellipsoid-like shape produced a larger fluid pressure and velocity fields in the osteon than that of rectangular shape; (3) in the elliptic microcracks, the longer of the length (major semi-axis) induces a smaller fluid pressure and velocity amplitudes, whereas the width (minor axis) has little effect; (4) the direction of the microcracks (major axial direction) has an limited influence area around about 1/15 of the osteon cross-sectional area. CONCLUSIONS: This model permits the linking of the external loads and microcracks to the osteonal fluid pressure and velocity, which can be used for other purpose associate microcracks with the mechanotransduction and bone remodeling.

Mathematically modeling fluid flow and fluid shear stress in the canaliculi of a loaded osteon.

BACKGROUND: Mechanical load-induced intraosseous pressure gradients may result in some fluid stimuli effects, such as fluid flow and fluid shear stress (FSS), which may enable bone cells to detect external mechanical signals. Interstitial bone fluid flow is known to occur in lacunar-canalicular porosity (PLC). METHODS: In order to characterize lacunar-canalicular fluid flow behavior, a hierarchical osteon system is developed. The osteon is modeled as a poroelastic annular cylinder with two types of impermeable boundary cases considered on its outer wall: one is elastic restrained (Case I), whereas the other is displacement confined (Case II). Analytical solutions such as canalicular fluid velocity, pressure, fluid flow rate (FFR), and shear stress are obtained. RESULTS: Results show that the amplitudes of FFR and FSS are proportional to strain amplitude and frequency. However, the key loading factor governing canalicular fluid flow behavior is the strain rate. The larger canalicular radius is, the larger amplitudes of FFR and FSS generalized, especially, the FSS amplitude is proportional to canalicular radius. In addition, both FFR and FSS amplitudes produced in case II are larger than those of case I. CONCLUSION: Strain rate can be acted as a representative loading parameter governing the canalicular fluid flow behavior under a physiological state. This model can facilitate better understanding the load induced the fluid permeation in the PLC. The approach can also be used to analyze the structure of the proteoglycan matrix in the fluid space surrounding the osteocytic process in the canaliculus.

Spirohexenolide A targets human macrophage migration inhibitory factor (hMIF).

Spirohexenolides A and B comprise a unique family of spirotetronate natural products. We report on the identification of their binding to and modulation of human macrophage migration inhibitor factor (hMIF). Using an immunoaffinity-fluorescent labeling method, the properties of this interaction are detailed and evidence is provided that hMIF plays a key role in the cytostatic activity of the spirohexenolides.