Predictors of cancer-specific survival and overall survival among patients aged ≥60 years with lung adenocarcinoma using the SEER database.

OBJECTIVE: We developed a simple, rapid predictive model to evaluate the prognosis of older patients with lung adenocarcinoma. METHODS: Demographic characteristics and clinical information of patients with lung adenocarcinoma aged ≥60 years were retrospectively analyzed using Surveillance, Epidemiology, and End Results (SEER) data. We built nomograms of overall survival and cancer-specific survival using Cox single-factor and multi-factor regression. We used the C-index, calibration curve, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to evaluate performance of the nomograms. RESULTS: We included 14,117 patients, divided into a training set and validation set. We used the chi-square test to compare baseline data between groups and found no significant differences. We used Cox regression analysis to screen out independent prognostic factors affecting survival time and used these factors to construct the nomogram. The ROC curve, calibration curve, C-index, and DCA curve were used to verify the model. The final results showed that our predictive model had good predictive ability, and showed better predictive ability compared with tumor-node-metastasis (TNM) staging. We also achieved good results using data of our center for external verification. CONCLUSION: The present nomogram could accurately predict prognosis in older patients with lung adenocarcinoma.

Determination of the pressure and composition of wet gas fluid inclusions: An in situ Raman spectroscopic approach.

Carbonaceous fluid within mineral-hosted inclusions provides important information for carbon cycle in deep Earth. In addition to CH4 and CO2, heavy hydrocarbons (e.g., C2H6 and C3H8) are frequently observed in carbonaceous fluid inclusions (i.e, wet gas inclusions with C1/∑Ci < 0.95). However, determination of the composition of such complex volatiles is difficult based on traditional microthermometric measurements. Here we carried out experimental calibrations on Raman spectroscopic measurements of the pressure (P) and composition of the CH4 ± C2H6 ± C3H8 ± H2S system at room temperature and 0.1-130 MPa. We confirmed that the C-H symmetric stretching vibration band of CH4 [ν1(CH4), ∼2917 cm-1] shifted to lower wavenumber with rising pressure, thus the P-ν1(CH4) relationship could be applied to calculate the pressure of wet gas. It should be noted that the presence of C2+ and/or H2S will shift the [ν1(CH4)] to lower wavenumber at constant pressure (with the order of C3H8 ≥ H2S > C2H6). Obviously, the P-ν1(CH4) relationship derived from pure CH4 system could not be simply applied to wet gas inclusion, otherwise the pressure would be overestimated. To avoid the overlap of the C-H vibrations of CH4, C2H6 and C3H8, the peak areas and peak heights of the overtone vibration of CH4 [2ν4(CH4), ∼2580 cm-1], C-C symmetric stretching vibrations of C2H6 [ν3(C2H6), ∼995 cm-1] and C3H8 [ν8(C3H8), ∼868 cm-1], and S-H symmetric stretching vibration of H2S [ν1(H2S), ∼2612 cm-1] were fitted using Gaussian + Lorentz functions. The obtained peak areas and peak heights were then used to calculate the Raman quantification factors (F factor and G factor, respectively) of C2H6, C3H8 and H2S relative to CH4, respectively. Both the F factor and G factor increased with rising pressure, whereas the FC2H6, FC3H8 and GH2S kept nearly constant at ∼5.69, 6.39 and 153.8, respectively in high pressure gas mixtures (e.g., >30 MPa). Therefore, for inclusions with higher internal pressure, the molar ratio of CH4, C2H6, C3H8 and H2S could be determined by the aforementioned F and G factors. This method was applied to the calcite-hosted single-phase gas inclusions in the Upper Permian Changxing Formation carbonate reservoir from the eastern Sichuan Basin (South China). Our results indicated that the trapping pressure would be obviously overestimated if the presence of heavy hydrocarbons was not taken into account.

Excessive SOX8 reprograms energy and iron metabolism to prime hepatocellular carcinoma for ferroptosis.

Lipid peroxidation and redox imbalance are hallmarks of ferroptosis, an iron-dependent form of cell death. Growing evidence suggests that dysregulation in glycolipid metabolism and iron homeostasis substantially contribute to the development of hepatocellular carcinoma (HCC). However, there is still a lack of comprehensive understanding regarding the specific transcription factors that are capable of coordinating glycolipid and redox homeostasis to initiate the onset of ferroptosis. We discovered that overexpression of SOX8 leads to impaired mitochondria integrate, increased oxidative stress, and enhanced lipid peroxidation. These effects can be attributed to the inhibitory impact of SOX8 on de novo lipogenesis, glycolysis, the tricarboxylic acid cycle (TCA), and the pentose phosphate pathway (PPP). Additionally, upregulation of SOX8 results in reduced synthesis of NADPH, disturbance of redox homeostasis, disruption of mitochondrial structure, and impairment of the electron transport chain. Furthermore, the overexpression of SOX8 enhances the process of ferroptosis by upregulating the expression of genes associated with ferroptosis and elevating intracellular levels of ferrous ion. Importantly, the overexpressing of SOX8 has been observed to inhibit the proliferation of HCC in immunodeficient animal models. In conclusion, the findings suggest that SOX8 has the ability to alter glycolipid and iron metabolism of HCC cells, hence triggering the process of ferroptosis. The results of our study present a novel strategy for targeting ferroptosis in the therapy of HCC.

Near-infrared light-triggered prodrug photolysis by one-step energy transfer.

Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm2, 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy.

Case report of severe pneumothorax due to lung cancer treated with anlotinib.

Anlotinib is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor for the treatment of lung cancer. Pneumothorax is a rare complication of anlotinib treatment. Here, the case of a male patient in his early seventies, with lung cancer combined with emphysema, who developed a pneumothorax during treatment with anlotinib, is described. The patient was admitted to hospital mainly for dyspnoea and was diagnosed with pneumothorax after digital radiography of the chest. The patient's symptoms improved significantly after closed chest drainage, and a repeat chest digital radiography showed a more resolved pneumothorax. The patient had no previous history of pneumothorax. After discontinuation of anlotinib, the latest follow-up chest computed tomography assessment in August 2023 showed no recurrence of pneumothorax, thus, the pneumothorax is presumed to have been associated with anlotinib in this patient. In addition, the authors speculate that emphysema may be a cause of pneumothorax in patients with lung cancer receiving anlotinib treatment. Therefore, clinicians should be alert to the risk of pneumothorax occurrence in patients with emphysema combined with lung cancer who are treated with anlotinib.

Treatment of a case of primary alveolar soft part sarcoma of the lung: Case report and literature review.

Alveolar soft part sarcoma (ASPS) is an extremely rare type of soft tissue sarcoma. The primary sites of ASPS are mostly located in the extremities and trunk. Primary pulmonary ASPS is extremely rare. A search of the PubMed® database identified only five cases of primary pulmonary ASPS. This current case report describes the sixth case of ASPS in a 15-year-old male that presented with recurrent headaches. Head computed tomography showed space-occupying lesions in the left parietal lobe. Positron emission tomography-computed tomography confirmed the space-occupying lesions in the left parietal lobe and showed multiple nodules and masses in the two lungs and pleura, which were considered to be low-grade malignant mesenchymal tumours. The case report presents the clinical characteristics, diagnosis and treatment process. Programmed cell death protein 1 monoclonal antibody (sintilimab) combined with a tyrosine kinase inhibitor (anlotinib hydrochloride) achieved a good therapeutic effect, indicating that this combination therapy is worth exploring further. Large-scale prospective studies are needed to explore and develop standardized treatments for ASPS.

Differentiation Kinetics of Hematopoietic Stem and Progenitor Cells In Vivo Are Not Affected by ß-Glucan Treatment in Trained Immunity.

Agonists of trained immunity induce epigenetic changes in hematopoietic stem and progenitor cells (HSPCs) to generate long-lasting immune protection. Although trained HSPCs generate myeloid cells with increased responsiveness to secondary challenges, whether their differentiation kinetics is affected by prior exposure to inducers of trained immunity remains elusive. Here, we used lineage tracing to examine the cell fates of endothelial protein C receptor-positive hematopoietic stem cells (EPCR+ HSCs) and fms-like tyrosine kinase 3-positive multipotent progenitor cells (Flt3+ MPPs) in ß-glucan-induced trained immunity. We found that although ß-glucan triggered the expected expansion of myeloid progenitors, the differentiation behaviors of EPCR+ HSCs and Flt3+ MPPs in multiple cycles of hematopoietic regeneration were hardly affected. Thus, our results rule out changed kinetics in cell differentiation by EPCR+ HSC and Flt3+ MPP as the cause of enhanced myelopoiesis upon secondary immune challenges.

Biochemical, transcriptomic and metabolomic responses to total dissolved gas supersaturation and their underlying molecular mechanisms in Yangtze sturgeon (Acipenser dabryanus).

With the rapid development of hydropower facility construction, the total dissolved gas (TDG) generated by dam discharge is seriously threatening the survival of fish and has become an ecological environmental issue of global concern. However, how TDG affects fish physiology and the underlying molecular mechanism remain poorly known. In this study, Acipenser dabryanus, an ancient living fossil that is a flagship species of the Yangtze River, was exposed to water supersaturated with TDG at a level of 116% for 48 h. A comprehensive analysis was performed to study the effect of TDG supersaturation stress on A. dabryanus, including histopathological, biochemical, transcriptomic and metabolomic analyses. The histopathological results showed that mucosal-associated lymphoid tissues were seriously damaged after TDG supersaturation stress. Plasma catalase levels increased significantly under TDG supersaturation stress, while superoxide dismutase levels decreased significantly. Transcriptomic analysis revealed 289 upregulated genes and 162 downregulated genes in gill tissue and 535 upregulated and 104 downregulated genes in liver tissue. Metabolomic analysis revealed 63 and 164 differentially abundant metabolites between the control group and TDG group in gill and liver, respectively. The majority of heat shock proteins and genes related to ubiquitin and various immune-related pathways were significantly upregulated by TDG supersaturation stress. Integrated transcriptomic and metabolomic analyses revealed the upregulation of amino acid metabolism and glycometabolism pathways under TDG supersaturation stress. Glycerophospholipid metabolism was increased which might be associated with maintaining cell membrane integrity. This is the first study revealing the underlying molecular mechanisms of effects of TDG supersaturation on fish. Our results suggested that acute TDG supersaturation stress could enhance immune and antioxidative functions and activate energy metabolic pathways as an adaptive mechanism in A. dabryanus.

Inhibitory effects of oat peptides on lipolysis: A physicochemical perspective.

Studies on the control of lipid digestion by food-derived active substances have prioritized the direct inhibition of lipase, ignoring the influence of these substances on the stability of bile salt (BS)-stabilized oil emulsions, which are essential for the hydrolysis of triglycerides by lipase. This study aimed to demonstrate the inhibitory potential of oat peptides (OPs) on lipolysis due to lipase inhibition, in particular, the physicochemical destruction of BS-stabilized emulsions. OPs were characterized by an enterostatin-like X-Pro-Y-Pro-Arg terminal sequence, competitively and/or noncompetitively inhibited lipase, and even caused lipase conformational changes. Interestingly, OPs destabilized BS-stabilized emulsions by weakening the rheological cross-linking structure of the emulsions through competitive hydrophobic binding to BS. Further analysis revealed that the H-bond binding of OP to BS significantly destroyed the hydrophilic and lipophilic balance of BS by increasing the surface hydrophobicity. These findings provided novel insights into the action mechanism of bioactive peptides on lipid digestion.

Controllable synthesis of BiPr composite oxide nanowires electrocatalyst for sensitive L-cysteine sensing properties.

BiPr composite oxide nanowires with rhombodedral Bi1.35Pr0.65O3, monoclinic Bi2O3and monoclinic Pr5O9phases were synthesized via a facile sodium dodecyl sulfate (SDS) assisted hydrothermal route. The obtained nanowires were characterized by x-ray diffraction, electron microscopy, x-ray photoelectron spectroscopy and electrochemical measurements. The BiPr composite oxide nanowires possess poly-crystalline structure, semi-circular tips, diameter and length of 20-100 nm and several micrometers, respectively. SDS is essential for the formation of the BiPr composite oxide nanowires which can be explained by a SDS assisted hydrothermal growth process. Electrochemical impedance spectroscopy shows that the electrons are easier to transfer by the surface of the BiPr composite oxide nanowires modified glassy carbon electrode (GCE) than bare GCE. The BiPr composite oxide nanowires modified GCE possesses good electro-catalytic activity for L-cysteine detection with a pair of quasi-reversible cyclic voltammetry peaks at +0.04 V and -0.72 V for the oxidation and reduction of L-cysteine, respectively. The roles of the scan rate, electrolyte species and L-cysteine concentration on the electrochemical responses of L-cysteine at the nanowires modified GCE were systematically analyzed. The BiPr composite oxide nanowires modified GCE presents a linear response range from 0.001 to 2 mM and detection limit of 0.27µM, good reproducibility and stability.

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy.

BACKGROUND: Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as "cell-free" therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency. RESULTS: In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells. CONCLUSIONS: In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy.

Improving emulsifying properties of carboxylated microcrystalline cellulose by calcium bridging to hydrophobic peptides.

This study aimed to improve the emulsifying properties of microcrystalline cellulose by carboxylating (CC) and bridging to hydrophobic oat globule peptides (HP) via Ca2+ (CC-Ca-HP). FTIR and XRD spectra analysis proved the successful attachment of HP to CC through a salt bridge. The Ca2+-bridging significantly changed the particle characteristics of CC-Ca-HP, including particle size, ζ-potential, and wettability. The Ca2+-bridged composite CC-Ca-HP demonstrated remarkable emulsifying stability compared with the nonbridged blend (CC-HP). Further analysis of the steady flow characteristics and dynamic viscoelastic properties revealed a network structure formed in the CC-Ca-HP emulsion. Moreover, the CC-Ca-HP emulsion showed a marked release of free fatty acids, increased bioaccessibility of zeaxanthin in the simulated gastrointestinal digestion, and less oil oxidation under the accelerated oxidation condition, indicating that the stable structure of CC-Ca-HP imparted by Ca2+-bridging prevented the aggregation of oil droplets as collision occurred under the harsh gastric conditions.

Rational Design of Near-Infrared-Absorbing Pt(II)-Chelated Azadipyrromethene Dyes as a New Generation of Photosensitizers for Synergistic Phototherapy.

Pt(II) photosensitizers are emerging as novel Pt anticancer agents for cancer photodynamic therapy (PDT) to avoid uncontrollable toxicity of cisplatin. However, the application of Pt(II) photosensitizers is limited by tumor hypoxia and the poor penetration depth of excitation light. To overcome these drawbacks, exploiting the next generation of Pt anticancer agents is of urgent need. According to theoretical calculations, novel near-infrared (NIR)-absorbing Pt(II)-chelated azadipyrromethene dyes (PtDP-X, where X = N, C, and S) were designed. Importantly, spin-orbit coupling of the Pt atom could promote the intersystem crossing of a singlet-to-triplet transition for converting oxygen to singlet oxygen (1O2), and the azadipyrromethene skeleton could provide a strong photothermal effect. As expected, PtDP-X exhibited intense NIR absorption and synergistic PDT and photothermal effects with low dark cytotoxicity. Furthermore, water-soluble and biocompatible PtDP-N nanoparticles (PtDP-N NPs) were prepared that achieved effective tumor cell elimination with low side effects under 730 nm light irradiation in vitro and in vivo. This pioneering work could push the exploitation of NIR-absorbing metal-chelated azadipyrromethene dyes, so as to promote the positive evolution of phototherapy agents.

Rational design of type I photosensitizers based on Ru(ii) complexes for effective photodynamic therapy under hypoxia.

Photodynamic therapy (PDT) has been widely used in conjunction with molecular oxygen to cause cancer cell death. Hypoxia, the inherent property in solid tumors, is the obstacle during the process of PDT. It is urgent to develop PDT photosensitizers independent of the oxygen concentration. Herein, triphenylamine-modified Ru(ii) complexes have been used as photosensitizers to produce superoxide anions (O2-˙) and hydroxyl radicals (˙OH) through a type I photochemical process. Ru(ii) complexes with triphenylamine can provide a possibility to drive the reactive oxygen species production through low oxidation potential and good light-harvesting abilities. The investigation on light-mediated radical production showed that Ru4 could produce abundant ˙OH and O2-˙ compared to Ru1-Ru3 under hypoxic environments owing to the strong absorption. These radicals exhibit potent toxicity, which can damage the neighbouring biomolecules and cause the apoptosis of cancer cells. The PDT effect was evaluated in vitro under hypoxia, suggesting that Ru4 could maintain excellent performance in inducing a sharp decrease in the activity of cancer cells.

Rational design of near-infrared platinum(II)-acetylide conjugated polymers for photoacoustic imaging-guided synergistic phototherapy under 808 nm irradiation.

The preferable photoconversion tunability of conjugated polymers (CPs) is of great interest in cancer phototherapy. However, very few molecular design strategies have been developed for achieving CPs with highly efficient photoconversion performance. Herein, a rational design of near-infrared (NIR) Pt-acetylide conjugated polymer CP3 with highly efficient photoconversion behaviors for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) was demonstrated. CP3 containing boron dipyrromethene (BDP) units displayed intense absorption peaks in the NIR region, which were red-shifted approximately 60 nm compared to the corresponding small-molecule precursor of BDP. Compared with control polymers CP1 and CP2, after the introduction of Pt into CP3, the triplet state, which benefits the generation of reactive oxygen species for photodynamic therapy, was identified clearly in both CP3 and the prepared CP3 nanoparticles (CP3-NPs) by ultrafast femtosecond transient absorption (fs-TA) spectroscopy. Notably, different from the traditional nonradiative decay channel with lifetime of 1.1 ps in CP3, CP3-NPs possess an additional nonradiative decay channel with lifetime of 10 ps, both of which contribute to the superior photothermal conversion effect upon 808 nm irrradiation. All these photoconversion performances lead to excellent tumor ablation. This study elucidates the excited-state dynamics in Pt-acetylide CPs, which provide an insightful understanding and valuable guidelines for the future design of high-performance theranostic agents based on CPs for synergistic cancer phototherapy.

Stable and Well-Organized Near-Infrared Platinum(II)-Acetylide-Based Metallacycles-Mediated Cancer Phototherapy.

The development of metallacycles with high stability and intense near-infrared (NIR) absorption is important for biomedical applications. However, very few molecular design strategies have been developed on such metallacycles. Herein, we report a new series of stable and well-defined NIR-absorbing metallacycles (M1-M3) through the Pt-acetylide coordination with highly efficient photoconversion performance for cancer phototherapy. The metallacycles showed high stability and strong NIR absorption, and the absorption peaks were red shifted approximately 30 nm in comparison with their corresponding precursors. The introduction of Pt into metallacycles promotes significant photoconversions, including the singlet-to-triplet and nonradiative transitions. Moreover, the fabricated M3 nanoparticles (M3-NPs) showed favorable photoconversions into both thermal effect and singlet oxygen generation upon NIR irradiation, achieving tumor ablation. This novel design of Pt-acetylide metallacycles possesses not only complex topological architectures but also a valuable paradigm for precise cancer phototherapy, which is important for grafting stimuli-responsive functional groups into metallacycles for the development of high-performance biomedical supramolecular materials.

Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer.

Engineered exosomes have become popular drug delivery carriers for cancer treatment. This is partially due to the interesting property, i.e. exosome organotropism, which plays an important role in organ distribution post systemic administration. Here, we demonstrated that breast cancer (MDA-MB-231) cell-derived exosomes (231-Exo) could be specifically internalized by non-small cell lung cancer cells via a specific interaction between overexpressed integrin ß4 (on exosomes) and surfactant protein C (SPC) on the cancer cells. We showed that 231-Exo was capable of recognizing A549 cells in blood and effectively escaping from the immune surveillance system in vitro. Once loaded with microRNA molecules in the exosome carriers, the resulting, miRNA-126 loaded 231-Exo (miRNA-231-Exo) strongly suppressed A549 lung cancer cell proliferation and migration through the interruption of the PTEN/PI3K/AKT signaling pathway. Intravenous administration of the miRNA-126 laden exosomes led to an effective lung homing effect in mice. When tested in a lung metastasis model, miRNA-231-Exo resulted in an efficacious effect in inhibiting the formulation of lung metastasis in vivo. Collectively, our data demonstrated the possibility of using the organotropism feature of exosomes in exosome carrier design, generating a potent anti-metastasis effect in a mouse model.

Redox/NIR dual-responsive MoS2 for synergetic chemo-photothermal therapy of cancer.

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.

Rational Design of Efficient Organic Phototherapeutic Agents via Perturbation Theory for Enhancing Anticancer Therapeutics.

The development of efficient phototherapeutic agents (PTA) through rational and specific principles exhibits great potential to the biomedical field. In this study, a facile and rational strategy was used to design PTA through perturbation theory. According to the theory, both the intersystem crossing rate for singlet oxygen generation and nonradiative transition for photothermal conversion efficiency can be simultaneously enhanced by the rational optimization of donor-acceptor groups, heavy atom number, and their functional positions, which can effectively decrease the energy gap between the singlet and triplet states and increase the spin-orbit coupling constant. Finally, efficient PTA were obtained that showed excellent performance in multimode-imaging-guided synergetic photodynamic/photothermal therapy. This study therefore expands the intrinsic mechanism of organic PTA and should help guide the rational design of future organic PTA via perturbation theory.

Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes.

The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox.