Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis.

BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.

Flexocatalytic Reduction of Tumor Interstitial Fluid/Solid Pressure for Efficient Nanodrug Penetration.

The practical efficacy of nanomedicines for treating solid tumors is frequently low, predominantly due to the elevated interstitial pressure within such tumors that obstructs the penetration of nanomedicines. This increased interstitial pressure originates from both liquid and solid stresses related to an undeveloped vascular network and excessive fibroblast proliferation. To specifically resolve the penetration issues of nanomedicines for tumor treatment, this study introduces a holistic "dual-faceted" approach. A treatment platform predicated on the WS2/Pt Schottky heterojunction was adopted, and flexocatalysis technology was used to disintegrate tumor interstitial fluids, thus producing oxygen and reactive oxygen species and effectively mitigating the interstitial fluid pressure. The chemotherapeutic agent curcumin was incorporated to further suppress the activity of cancer-associated fibroblasts, minimize collagen deposition in the extracellular matrix, and alleviate solid stress. Nanomedicines achieve homologous targeting by enveloping the tumor cell membrane. It was found that this multidimensional strategy not only alleviated the high-pressure milieu of the tumor interstitium─which enhanced the efficiency of nanomedicine delivery─but also triggered tumor cell apoptosis via the generated reactive oxygen species and modulated the tumor microenvironment. This, in turn, amplified immune responses, substantially optimizing the therapeutic impacts of nanomedicines.

Piezoelectric Catalysis Induces Tumor Cell Senescence to Boost Chemo-Immunotherapy.

Cellular senescence, a vulnerable state of growth arrest, has been regarded as a potential strategy to weaken the resistance of tumor cells, leading to dramatic improvements in treatment efficacy. However, a selective and efficient strategy for inducing local tumor cellular senescence has not yet been reported. Herein, piezoelectric catalysis is utilized to reduce intracellular NAD+ to NADH for local tumor cell senescence for the first time. In detail, a biocompatible nanomedicine (BTO/Rh-D@M) is constructed by wrapping the piezoelectric BaTiO3 /(Cp* RhCl2 )2 (BTO/Rh) and doxorubicin (DOX) in the homologous cytomembrane with tumor target. After tumors are stimulated by ultrasound, negative and positive charges are generated on the BTO/Rh by piezoelectric catalysis, which reduce the intracellular NAD+ to NADH for cellular senescence and oxidize H2 O to reactive oxygen species (ROS) for mitochondrial damage. Thus, the therapeutic efficacy of tumor immunogenic cell death-induced chemo-immunotherapy is boosted by combining cellular senescence, DOX, and ROS. The results indicate that 23.9% of the piezoelectric catalysis-treated tumor cells senesced, and solid tumors in mice disappeared completely after therapy. Collectively, this study highlights a novel strategy to realize cellular senescence utilizing piezoelectric catalysis and the significance of inducing tumor cellular senescence to improve therapeutic efficacy.

Cascaded Antitumor Therapy Excited by Dual Nanozymes Based on Energy Restriction and Photocatalysis.

In nanocatalytic medicine, drugs can be transformed into toxic components through highly selective and highly specific catalytic reactions in the tumor microenvironment, avoiding toxic side effects on normal tissues. Due to the coexistence of Ce3+ and Ce4+, CeO2 is endowed with dual nanozyme activities. Herein, CeO2 nanoparticles served as templates to construct a biomimetic nanodrug delivery system (C/CeO2@M) by electrostatic adsorption of carbon quantum dots (CQDs) and coating a homologous tumor cytomembrane. After homologous targeting to tumors, the CQDs emitted 350-600 nm light under 660 nm laser irradiation by upconversion luminescence, which caused a CeO2-mediated photocatalytic reaction to generate reactive oxygen species. The catalase-like activity of CeO2-enabled converting excess H2O2 to O2, which not only alleviated tumor hypoxia and promoted intratumor drug delivery but also provided substrates for subsequent catalytic reactions. Meanwhile, the phosphatase activity of CeO2 could consume adenosine triphosphate (ATP) to block the energy supply for tumor cells, thus limiting cell proliferation and metastasis. The strategy of energy restriction and photocatalysis of dual nanozyme stimulation offers great potentials in enhancing drug penetration and eradicating solid tumors.

Vapor-Deposited Thin Films: Studying Crystallization and α-relaxation Dynamics of the Molecular Drug Celecoxib.

Crystallization is one of the major challenges in using glassy solids for technological applications. Considering pharmaceutical drugs, maintaining a stable amorphous form is highly desirable for improved solubility. Glasses prepared by the physical vapor deposition technique got attention because they possess very high stability, taking thousands of years for an ordinary glass to achieve. In this work, we have investigated the effect of reducing film thickness on the α-relaxation dynamics and crystallization tendency of vapor-deposited films of celecoxib (CXB), a pharmaceutical substance. We have scrutinized its crystallization behavior above and below the glass-transition temperature (Tg). Even though vapor deposition of CXB cannot inhibit crystallization completely, we found a significant decrease in the crystallization rate with decreasing film thickness. Finally, we have observed striking differences in relaxation dynamics of vapor-deposited thin films above the Tg compared to spin-coated counterparts of the same thickness.

Pressure Dependence of the Crystallization Rate for the S-Enantiomer and a Racemic Mixture of Ibuprofen.

This paper examines the pressure effect on the crystallization rate of the pharmaceutically active enantiomerically pure S-enantiomer and the racemic mixture of the well-known drug ibuprofen. Performed experimental studies revealed that at ambient pressure S-ibuprofen crystallizes faster than the racemic mixture. When the pressure increases, the crystallization rate slows down for both systems, but interestingly it is more apparent in the case of the S-enantiomer. It is found that this experimentally observed trend can be understood based on the predictions of the classical nucleation theory. We suggest that the solid-liquid interfacial free energy is the main reason for the observed variations in S- and RS-ibuprofen's stability behaviors. Employing a special method of computational studies, i.e., the capillary fluctuation method, we show that the increase in pressure affects the solid-liquid interfacial free energy for S- and RS-ibuprofen in an entirely different way. Importantly, the detected differences correspond to the experimentally observed variations in the overall crystallization rates.

On the Segmental Dynamics and the Glass Transition Behavior of Poly(2-vinylpyridine) in One- and Two-Dimensional Nanometric Confinement.

Geometric nanoconfinement, in one and two dimensions, has a fundamental influence on the segmental dynamics of polymer glass-formers and can be markedly different from that observed in the bulk state. In this work, with the use of dielectric spectroscopy, we have investigated the glass transition behavior of poly(2-vinylpyridine) (P2VP) confined within alumina nanopores and prepared as a thin film supported on a silicon substrate. P2VP is known to exhibit strong, attractive interactions with confining surfaces due to the ability to form hydrogen bonds. Obtained results show no changes in the temperature evolution of the α-relaxation time in nanopores down to 20 nm size and 24 nm thin film. There is also no evidence of an out-of-equilibrium behavior observed for other glass-forming systems confined at the nanoscale. Nevertheless, in both cases, the confinement effect is seen as a substantial broadening of the α-relaxation time distribution. We discussed the results in terms of the importance of the interfacial energy between the polymer and various substrates, the sensitivity of the glass-transition temperature to density fluctuations, and the density scaling concept.

Experimental evidence of co-existence of equilibrium and nonequilibrium in two-glass-transition miscible mixtures.

Two glass-transitions have been observed in some miscible molecular mixtures with notable differences in geometry or chemistry of constituents. The explanation of the phenomena has been puzzling with diverse structural models. Here, we present detailed studies on two glass-transition mixtures composed of tripropyl phosphate (TPP) and polystyrene (PS) by using calorimetric and dielectric measurements. We found that ageing between the two transitions always generates endothermic peaks at temperatures ∼4 K higher than the ageing temperatures and, subsequent thermal cycles around the peaks can remove the ageing effect and restore the systems, confirming the co-existence of nonequilibrium and equilibrium states in the regions. We also found that the broad glass transition thermogram is associated with highly stretched relaxation dynamics. The results allow us to draw a conclusion of continuous mobility gradient spanning the two TPP-PS glass-transitions, rather than complete phase separation.

Effect of Surface Chemistry on the Glass-Transition Dynamics of Poly(phenyl methyl siloxane) Confined in Alumina Nanopores.

Broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC) are combined to study the effect of changes in the surface chemistry on the segmental dynamics of glass-forming polymer, poly(methylphenylsiloxane) (PMPS), confined in anodized aluminum oxide (AAO) nanopores. Measurements were carried for native and silanized nanopores of the same pore sizes. Nanopore surfaces are modified with the use of two silanizing agents, chlorotrimethylsilane (ClTMS) and (3-aminopropyl)trimethoxysilane (APTMOS), of much different properties. The results of the dielectric studies have demonstrated that for the studied polymer located in 55 nm pores, changes in the surface chemistry and thermal treatment allows the confinement effect seen in temperature evolution of the segmental relaxation time, τα(T) to be removed. The bulk-like evolution of the segmental relaxation time can also be restored upon long-time annealing. Interestingly, the time scale of such equilibration process was found to be independent of the surface conditions. The calorimetric measurements reveal the presence of two glass-transition events in DSC thermograms of all considered systems, implying that the changes in the interfacial interactions introduced by silanization are not strong enough to inhibit the formation of the interfacial layer. Although DSC traces confirmed the two-glass-transition scenario, there is no clear evidence that vitrification of the interfacial layer affects τα(T) for nanopore-confined polymer.

Glass Transition Dynamics and Physical Stability of Amorphous Griseofulvin in Binary Mixtures with Low-Tg Excipients.

Amorphization of drug formulations containing active pharmaceutical ingredients (APIs) and excipients has been proven to be an effective strategy to improve their poor aqueous solubility. The excipients can also impact the physical stability of the prepared amorphous forms. Generally, researchers are more apt to select excipients that have high values of glass transition temperature (Tg) because of the antiplasticization effect of the additives on APIs. In this article, we studied the glass transition dynamics as well as crystallization behavior in binary blends composed of griseofulvin (GSF) and two low-Tg additives, octaacetylmaltose (acMAL) and polyvinyl acetate (PVAc), with a particular focus on the plasticization effect. Effectively suppressed crystallization of GSF is observed in both systems when higher excipient contents are used. Our finding aims to encourage the use of specifically developed protocols in which suitable plasticizers are used as excipients for stabilizing the amorphous state of a drug.

Co-Stabilization of Amorphous Pharmaceuticals-The Case of Nifedipine and Nimodipine.

Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate recrystallization and to develop effective methods for stabilizing amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1,4-dihydropyridine derivatives (nifedipine, nisoldipine, and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T = 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when as little as 10 MPa of pressure is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing coamorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite the fact that the nimodipine acts as a plasticizer.

Direct Evidence of Relaxation Anisotropy Resolved by High Pressure in a Rigid and Planar Glass Former.

Rigid molecular glass-formers with no internal degrees of freedom nonetheless have a single secondary ß-relaxation. For a rigid and planar molecule, 1-methylindole (1MID), although a secondary relaxation is resolved at ambient pressure, its properties do not conform to the rules established for rigid molecules reported in early studies. By applying pressure to the dielectric spectra of 1MID, we find the single secondary relaxation splits into two. The slower one is pressure sensitive showing connections to the α-relaxation as observed in other rigid molecules, while the faster one is almost pressure insensitive and dominate the loss at ambient pressure. The two secondary relaxations, identified to associate with the out-of-plane and in-plane rotations of the rigid and planar 1MID, are resolved and observed for the first time by increasing density via elevating pressure.

Glass formability in medium-sized molecular systems/pharmaceuticals. I. Thermodynamics vs. kinetics.

Scrutinizing critical thermodynamic and kinetic factors for glass formation and the glass stability of materials would benefit the screening of the glass formers for the industry of glassy materials. The present work aims at elucidating the factors that contribute to the glass formation by investigating medium-sized molecules of pharmaceuticals. Glass transition related thermodynamics and kinetics are performed on the pharmaceuticals using calorimetric, dielectric, and viscosity measurements. The characteristic thermodynamic and kinetic parameters of glass transition are found to reproduce the relations established for small-molecule glass formers. The systematic comparison of the thermodynamic and kinetic contributions to glass formation reveals that the melting-point viscosity is the crucial quantity for the glass formation. Of more interest is the finding of a rough correlation between the melting-point viscosity and the entropy of fusion normalized by the number of beads of the pharmaceuticals, suggesting the thermodynamics can partly manifest its contribution to glass formation via kinetics.

Revisiting the glass transition and dynamics of supercooled benzene by calorimetric studies.

The glass transition and dynamics of benzene are studied in binary mixtures of benzene with five glass forming liquids, which can be divided into three groups: (a) o-terphenyl and m-xylene, (b) N-butyl methacrylate, and (c) N,N-dimethylpropionamide and N,N-diethylformamide to represent the weak, moderate, and strong interactions with benzene. The enthalpies of mixing, ΔH(mix), for the benzene mixtures are measured to show positive or negative signs, with which the validity of the extrapolations of the glass transition temperature T(g) to the benzene-rich regions is examined. The extrapolations for the T(g) data in the mixtures are found to converge around the point of 142 K, producing T(g) of pure benzene. The fragility m of benzene is also evaluated by extrapolating the results of the mixtures, and a fragility m ∼ 80 is yielded. The obtained T(g) and m values for benzene allow for the construction of the activation plot in the deeply supercooled region. The poor glass formability of benzene is found to result from the high melting point, which in turn leads to low viscosity in the supercooled liquid.

Anomaly in dielectric relaxation dispersion of glass-forming alkoxy alcohols.

The dielectric relaxations in six primary and secondary alkoxy alcohols with varying molecular size and different separation between -O- and hydroxyl group are studied at temperatures around glass transition. The analyses of the apparent full width at half maximum of the main relaxations of the alkoxy alcohols reveal minima in the temperature dependence of the relaxation dispersions. The stretching exponents for the main relaxations of the alkoxy alcohols are also found not to follow the empirical correlations with other dynamic quantities established for generic liquids. A comparison of the relaxation dispersions in the alkoxy alcohols with those in Debye and non-Debye (generic) liquids is presented. The impacts of the ß-relaxations on the apparent main relaxation widths are reviewed for molecular glass formers.

Unveiling the dependence of glass transitions on mixing thermodynamics in miscible systems.

The dependence of the glass transition in mixtures on mixing thermodynamics is examined by focusing on enthalpy of mixing, ΔHmix with the change in sign (positive vs. negative) and magnitude (small vs. large). The effects of positive and negative ΔHmix are demonstrated based on two isomeric systems of o- vs. m-methoxymethylbenzene (MMB) and o- vs. m-dibromobenzene (DBB) with comparably small absolute ΔHmix. Two opposite composition dependences of the glass transition temperature, Tg, are observed with the MMB mixtures showing a distinct negative deviation from the ideal mixing rule and the DBB mixtures having a marginally positive deviation. The system of 1, 2- propanediamine (12PDA) vs. propylene glycol (PG) with large and negative ΔHmix is compared with the systems of small ΔHmix, and a considerably positive Tg shift is seen. Models involving the properties of pure components such as Tg, glass transition heat capacity increment, ΔCp, and density, ρ, do not interpret the observed Tg shifts in the systems. In contrast, a linear correlation is revealed between ΔHmix and maximum Tg shifts.

Comparative study of dynamics in glass forming mixtures of Debye-type N-ethylacetamide with water, alcohol, and amine.

The glass transition and relaxation dynamics in the binary mixtures of a Debye liquid, N-ethylacetamide, with water, monoalcohol, and amine are studied by calorimetric and dielectric measurements in the highly viscous regimes near the glass transition. Calorimetric measurements show the glass transition temperature in the N-ethylacetamide-water mixtures is remarkably enhanced as water is added as high as 70 mol. % before crystallization is detected. A similar increase is also observed in the N-ethylacetamide-rich mixtures with the non-Debye 1,2-propanediamine. However, the dielectric measurements show that the main relaxation in the N-ethylacetamide-water mixtures with water fraction up to 60 mol. % reproduces the dynamic characters of the mixtures constituted by two Debye liquids, N-ethylacetamide and 2-ethyl-1-butanol. The comparison of the calorimetric and dielectric features for the three mixing systems suggests that the Debye relaxation persists in the N-ethylacetamide-water mixtures within the experimentally studied compositions.

Glass transition and mixing thermodynamics of a binary eutectic system.

A quantitative evaluation of the contribution of mixing thermodynamics to glass transition is performed for a binary eutectic benzil and m-nitroaniline system. The microcalorimetric measurements of the enthalpy of mixing give small and positive values, typically ~200 J mol(-1) for the equimolar mixture. The composition dependence of the glass transition temperature, T(g), is found to show a large and negative deviation from the ideal mixing rule. The Gordon-Taylor and Couchman-Karasz models are subsequently applied to interpret the T(g) behavior, however, only a small fraction of the deviation is explained. The analyses of the experimental results manifest quantitatively the importance of the mixing thermodynamics in the glass transition in miscible systems.

Dielectric relaxation of long-chain glass-forming monohydroxy alcohols.

The dielectric relaxation of two long-chain glass forming monohydroxy alcohols, 2-butyl-1-octanol and 2-hexyl-1-decanol, is studied at low temperature. Remarkable broadening from the pure Debye relaxation is identified for the slowest dynamics, differing from the dielectric spectra of short-chain alcohols. The broadening of the Debye-like relaxation in the two liquids develops as temperature increases, and the approaching of the Debye-like and structural relaxation widths is shown. Similar results are observed in the dielectric spectra of dilute 2-ethyl-1-hexanol in either 2-hexyl-1-decanol or squalane. The results of the liquids and mixtures reveal a correlation between the broadening and the Debye-like relaxation strength. Molecular associations in monohydroxy alcohols are discussed with the modification of the Debye relaxation.