[Effect of Circulating Plasma Cells on the Prognosis of Patients with Multiple Myeloma].

OBJECTIVE: to analyze the effect of circulating plasma cells(CPC) on the prognosis of patients with multiple myeloma(MM) in the era of new drugs, and to explore the new definition standard of primary plasma cell leukemia(pPCL). METHODS: The clinical data of 321 patients with newly diagnosed MM and 21 patients with pPCL admitted to our hospital from January 2014 to May 2022 were retrospectively analyzed. According to the proportion of CPC in peripheral blood smears, all patients were divided into 4 groups: CPC 0% group(211 cases), CPC 1%-4% group(69 cases), CPC 5%-19% group(41 cases) and CPC≥20% group(21 cases). The clinical features of patients in each group were compared and the prognosis fators was analyzed. RESULTS: The median OS of the four groups were 44.5,21.3,24.6 and 12.8 months, respectively. Among them, 295 patients(86.3%) were treated with new drugs, and the median OS of the four groups were not reached, 26.7, 24.6 and 14.9 months, respectively. As the survival curves of CPC 5%-19% group and CPC≥20% group were similar, the patients were divided into CPC<5% group and CPC≥5% group, the median OS of CPC<5% group was better than that in CPC≥5% (43.5 vs 22.3 months, P<0.001). In addition, the median OS of patients in the CPC 1%-4% group was also significantly lower than that in the CPC 0% group and similar to that in the CPC≥5% group. Multivariate analysis showed that 1%-4% CPC was an independent risk factor for the OS of patients with CPC<5%. The patients with CPC<5% were stratified by R-ISS staging, and the OS of R-ISS stage Ⅰ or stage Ⅱ with 1%-4% CPC was similar to that of R-ISS stage Ⅲ. The newly defined pPCL patients showed increased tumor load and obvious invasive characteristics. Multivariate analysis showed no independent prognostic factors for pPCL, and high-risk cytogenetic abnormalities(HRCA) had no significant effect on the prognosis. CONCLUSION: The validity of IMWG's new pPCL definition standard was verified, and it was found that the survival of MM with 1%-4% CPC also is poor and the prognosis is very close to pPCL. In addition, the newly defined pPCL has unique clinical and biological characteristics.

[Correlation between D-Dimer/Fibrinogen Ratio and Bleeding in Patients with Newly Diagnosed Acute Promyelocytic Leukemia].

OBJECTIVE: To further explore the better indicators for predicting the degree of bleeding associated with newly diagnosed acute promyelocytic leukemia (APL). METHODS: A total of 131 patients with newly diagnosed APL were classified according to WHO bleeding scales before treatment and divided into two groups: scales 0, 1 and 2 were included in no severe bleeding group, scales 3 and 4 were included in severe bleeding group. The information of the patients were collected, including sex, age, hemoglobin (Hb), white blood cell (WBC) count and platelet (PLT) count, peripheral blood lymphocyte percentage (LYMPH%), peripheral blood monocyte percentage (MONO%), percentage of leukemic cells in pripheral blood and bone marrow, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, D-dimer (D-D), D-dimer/fibrinogen ratio (DFR). RESULTS: Among 131 patients, 110 were classified as no severe bleeding, and 21 were severe bleeding. The results of univariate analysis showed that patients with severe bleeding had significantly higher percentage of leukemic cells in pripheral blood, WBC, D-D, and DFR, as well as longer PT and lower LYMPH%, compared to those with no severe bleeding. Multivariate analysis revealed that DFR (OR =1.054, 95%CI : 1.024-1.084, P < 0.001) and percentage of peripheral blood leukemic cells (OR=1.026, 95%CI: 1.002-1.051, P =0.033) were independent risk factors for severe bleeding. The area under ROC curve (AUC) of peripheral blood leukemic cells, D-D and DFR were 0.748, 0.736 and 0.809, respectively. There was no statistical difference between the peripheral blood leukemic cells and D-D in diagnostic efficacy (P =0.8708). Compared with D-D, DFR had a higher predictive value (P =0.0302). The optimal cut-off value of DFR was 16.50, with a sensitivity of 90.5% and a specificity of 70.0%. CONCLUSION: DFR has a significant advantage in predicting the degree of bleeding associated with newly diagnosed APL. The greater the DFR value, the heavier the degree of bleeding. The risk of severe or fatal bleeding increases when DFR is greater than 16.50.

Site-Specific Construction of Long-Term Drug Depot for Suppression of Tumor Recurrence.

Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long-term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide-based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long-term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.

Endogenous Reactive Oxygen Species-Triggered Morphology Transformation for Enhanced Cooperative Interaction with Mitochondria.

The morphology controlled molecular assemblies play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)-triggered morphology transformation of polymer-peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of (i) a ß-sheet-forming peptide KLVFF conjugated with poly(ethylene glycol) through ROS-cleavable thioketal, (ii) a mitochondria-targeting cytotoxic peptide KLAK, and (iii) a poly(vinyl alcohol) backbone. The self-assembled PPCs nanoparticles can enter cells and target mitochondria. Because of overgenerated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROS-triggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.

Autocatalytic Morphology Transformation Platform for Targeted Drug Accumulation.

The precise and highly efficient drug delivery of nanomedicines into lesions remains a critical challenge in clinical translational research. Here, an autocatalytic morphology transformation platform is presented for improving the tumor-specific accumulation of drugs by kinetic control. The in situ reorganization of prodrug from nanoparticle to ß-sheet fibrous structures for targeted accumulation is based on nucleation-based growth kinetics. During multiple administrations, the autocatalytic morphology transformation can be realized for skipping slow nucleating process and constructing the bulky nanoassembly instantaneously, which has been demonstrated to induce the cumulative effect of prodrug. Furthermore, the sustained drug release from fibrous prodrug depot in the tumor site inhibits the tumor growth efficiently. The autocatalytic morphology transformation strategy in vivo offers a novel perspective for targeted delivery strategy by introducing chemical kinetics and shows great potential in disease theranostics.

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(ß-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.

[Relationship between Iron Metabolism and Platelet Parameters in Patients with Iron Deficiency Anemia].

OBJECTIVE: To investigate the relationship between iron metabolism and thrombocytosis. METHODS: iron metabolism indexes , erythrocyte and platelet parameters of iron deficiency anemia patients with thrombocytosis were collected, the correlation of platelet parameters with iron metabolism indexes and erythrocyte parameters was analysed; the difference in erythrocyte，platelet and iron parameters between severe anemia group (hemoglobin<60 g / L) and mild and moderate anemia group (hemoglobin≥60 g / L) were compared; the changes of platelet count before and after treatment were observed. RESULTS: There was a significant negative correlation between serum iron and platelet count (r=-0.404,P<0.01).Serum iron negatively correlated with platelet crit(r=-0.288,P<0.05). Transferrin saturation negatively correlated with platelet count and platelet crit(r=-0.353,P<0.01;r=-0.271, P<0.05).Serum ferritin and total iron binding capacity revealed no significant relation with any platelet parameters.Hemoglobin level , hematocrit and mean corpuscular hemoglobin concentration negatively correlated with platelet count(r=-0.239,P<0.05;r=-0.250,P<0.05;r=-0.339,P<0.01).There were differences in iron metabolism indexes and platelet parameters between mild to moderate anemia group and severe anemia group. After treatment, the platelet count decreased or was normal. CONCLUSION: The important iron metabolism indexes affecting platelet count are serum iron and transferrin saturation,that is,the severer iron deficiency, the higher platelet count.Patients with more severe and hypochronic anemia has higher platelet count.

Self-Assembled Fluorescent Organic Nanomaterials for Biomedical Imaging.

Fluorescent nanomaterials, self-assembled from building blocks through multiple intermolecular interactions show diversified structures and functionalities, and are potential fluorescence contrast agents/probes for high-performance biomedical imaging. Self-assembled nanomaterials exhibit high stability, long circulation time, and targeted biological distribution. This review summarizes recent advances of self-assembled nanomaterials as fluorescence contrast agents/probes for biomedical imaging. The self-assembled nanomaterials are classified into two groups, i.e., ex situ and in situ construction of self-assembled nanomaterials. The advantages of ex situ as well as in situ constructed nanomaterials for biomedical applications are discussed thoroughly. The directions of future developments for self-assembled nanomaterials are provided.

Self-Assembled Peptide-Based Nanomaterials for Biomedical Imaging and Therapy.

Peptide-based materials are one of the most important biomaterials, with diverse structures and functionalities. Over the past few decades, a self-assembly strategy is introduced to construct peptide-based nanomaterials, which can form well-controlled superstructures with high stability and multivalent effect. More recently, peptide-based functional biomaterials are widely utilized in clinical applications. However, there is no comprehensive review article that summarizes this growing area, from fundamental research to clinic translation. In this review, the recent progress of peptide-based materials, from molecular building block peptides and self-assembly driving forces, to biomedical and clinical applications is systematically summarized. Ex situ and in situ constructed nanomaterials based on functional peptides are presented. The advantages of intelligent in situ construction of peptide-based nanomaterials in vivo are emphasized, including construction strategy, nanostructure modulation, and biomedical effects. This review highlights the importance of self-assembled peptide nanostructures for nanomedicine and can facilitate further knowledge and understanding of these nanosystems toward clinical translation.

Reconfigurable Peptide Nanotherapeutics at Tumor Microenvironmental pH.

Peptide nanomaterials have recently attracted considerable interest in the biomedical field. However, their poor bioavailability and less powerful therapeutic efficacy hamper their further applications. Herein, we discovered reconfigurable and activated nanotherapeutics in the tumor microenvironment. Two peptides, that is, a pH-responsive peptide HLAH and a matrix metalloprotease-2 (MMP2)-sensitive peptide with a poly(ethylene glycol) (PEG) terminal were conjugated onto the hydrophobic poly(ß-thioester)s backbones to gain the copolymer P-S-H. The therapeutic activity of the HLAH peptide could be activated in tumors owing to its reconfiguration under microenvironmental pH. The resultant copolymers self-assembled into nanoparticles under physiological condition, with HLAH in cores protected by PEG shells. The moderate size (∼100 nm) and negative potential enabled the stable circulation of P-S-H in the bloodstream. Once arrived at the tumor site, the P-S-H nanoparticles were stimulated by overexpressed MMP2 and acidic pH, and subsequently the shedding of the PEG shell and protonation of the HLAH peptide induced the reassembly of nanoparticles, resulting in the formation of nanoparticles with activated cytotoxic peptides on the surface. In vivo experiments demonstrated that the reorganized nanoassembly contained three merits: (1) effective accumulation in the tumor site, (2) enhanced antitumor capacity, and (3) no obvious toxic effect at the treatment dose. This on-site reorganization strategy provides an avenue for developing high-performance peptide nanomaterials in cancer treatment.

Photothermal Ring Integrated Intraocular Lens for High-Efficient Eye Disease Treatment.

Posterior capsule opacification (PCO) is the most common complication after cataract surgery. So far, the only method for PCO treatment is the precisely focused laser surgery. However, it causes severe complications such as physical damages and neuron impairments. Here, a nanostructured photothermal ring integrated intraocular lens (Nano-IOLs) is reported, in which the rim of commercially available IOLs (C-IOLs) is decorated with silica coated Au nanorods (Au@SiO2 ), for high-efficient prevention of PCO after cataract surgery. The Nano-IOLs is capable of eliminating the residual lens epithelial cells (LECs) around Nano-IOLs under mild laser treatment and block the formation of disordered LECs fibrosis, which eventually leads to the loss of vision. The Nano-IOLs shows good biocompatibility as well as extraordinary region-confined photothermal effect. In vivo studies reveal that PCO occurrence in rabbit models is about 30%-40% by using Nano-IOLs, which is significantly lower than the control group that treated with C-IOLs (100% PCO occurrence) 30 d postsurgery. To the best of our knowledge, it is the first example to integrate nanotechnology with intraocular implants aiming to clinically relevant PCO. Our findings indicate that spatial controllability of photothermal effect from nanomaterials may provide a unique way to intervene the PCO-induced loss of vision.

Transformable Nanomaterials as an Artificial Extracellular Matrix for Inhibiting Tumor Invasion and Metastasis.

Tumor metastasis is one of the big challenges in cancer treatment and is often associated with high patient mortality. Until now, there is an agreement that tumor invasion and metastasis are related to degradation of extracellular matrix (ECM) by enzymes. Inspired by the formation of natural ECM and the in situ self-assembly strategy developed in our group, herein, we in situ constructed an artificial extracellular matrix (AECM) based on transformable Laminin (LN)-mimic peptide 1 (BP-KLVFFK-GGDGR-YIGSR) for inhibition of tumor invasion and metastasis. The peptide 1 was composed of three modules including (i) the hydrophobic bis-pyrene (BP) unit for forming and tracing nanoparticles; (ii) the KLVFF peptide motif that was inclined to form and stabilize fibrous structures through intermolecular hydrogen bonds; and (iii) the Y-type RGD-YIGSR motif, derived from LN conserved sequence, served as ligands to bind cancer cell surfaces. The peptide 1 formed nanoparticles (1-NPs) by the rapid precipitation method, owing to strong hydrophobic interactions of BP. Upon intravenous injection, 1-NPs effectively accumulated in the tumor site due to the enhanced permeability and retention (EPR) effect and/or targeting capability of RGD-YIGSR. The accumulated 1-NPs simultaneously transformed into nanofibers (1-NFs) around the solid tumor and further entwined to form AECM upon binding to receptors on the tumor cell surfaces. The AECM stably existed in the primary tumor site over 72 h, which consequently resulted in efficiently inhibiting the lung metastasis in breast and melanoma tumor models. The inhibition rates in two tumor models were 82.3% and 50.0%, respectively. This in vivo self-assembly strategy could be widely utilized to design effective drug-free biomaterials for inhibiting the tumor invasion and metastasis.

Host Materials Transformable in Tumor Microenvironment for Homing Theranostics.

A pathology-adaptive nanosystem, in which nest-like hosts are built based on nanofibers that are transformed from i.v. injected nanoparticles under the acidic tumor microenvironment. The solid tumor is artificially modified by nest-like hosts readily and firmly, resulting in highly efficient accumulation and stabilization of guest theranostics. This strategy shows great potential for the theranostics delivery to tumors.

Bio-inspired metal ions regulate the structure evolution of self-assembled peptide-based nanoparticles.

We report an assembly and transformation process of a supramolecular module, BP-KLVFF-RGD (BKR) in solution and on specific living cell surfaces for imaging and treatment. The BKR self-assembled into nanoparticles, which further transformed into nanofibers in situ induced by coordination with Ca(2+) ions.

pH-Sensitive polymer assisted self-aggregation of bis(pyrene) in living cells in situ with turn-on fluorescence.

Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self-aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future.

pH-Sensitive Polymeric Nanoparticles with Gold(I) Compound Payloads Synergistically Induce Cancer Cell Death through Modulation of Autophagy.

Various nanomaterials have been demonstrated as autophagy inducers owing to their endocytosis cell uptake pathway and impairment of lysosomes. pH-dependent nanomaterials as drug delivery systems that are capable of dissociating in weakly acidic lysosomal environment (pH 4-5) and consequently releasing the payloads into the cytoplasm have been paid extensive attention, but their autophagy-modulating effects are less reported so far. In this study, we report pH-sensitive micelle-like nanoparticles (NPs) that self-assembled from poly(ß-amino ester)s to induce cell autophagy. By encapsulation of gold(I) compounds (Au(I)) into hydrophobic domains of NPs, the resultant Au(I)-loaded NPs (Au(I)⊂NPs) shows synergistic cancer cell killing performance. The Au(I)⊂NPs enter cells through endocytosis pathway and accumulate into acidic lysosomes. Subsequently, the protonation of tertiary amines of poly(ß-amino ester)s triggers the dissociation of micelles, damages the lysosomes, and blocks formation of autolysosomes from fusion of lysosomes with autophagosomes. In addition, Au(I) preferentially inhibits thioredoxin reductase (TrxR) in MCF-7 human breast cancer cells that directly links to up-regulate reactive oxygen species (ROS) and consequently induce autophagy and apoptosis. The blockade of autophagy leads to excessive depletion of cellular organelles and essential proteins and ultimately results in cell death. Therefore, pH-sensitive polymeric nanoparticles with gold(I) compound payloads can synergistically induce cancer cell death through regulation of autophagy. Identification of the pH-sensitive nanomaterials for synergistically inducing cell death through regulation autophagy may open a new avenue for cancer therapy.

A pH-responsive natural cyclopeptide RA-V drug formulation for improved breast cancer therapy.

The natural plant cyclopeptide RA-V, which was isolated from the roots of Rubia yunnanensis, was discovered to be a novel anti-cancer candidate. However, the cyclic hexapeptide exhibited poor solubility in physiological conditions, limiting its application for cancer therapy in vivo. To solve this problem, pH-sensitive polymers were developed for targeted RA-V delivery into tumor sites and for acid-triggered drug release. The poly(ß-amino ester)s (PAE) copolymers self-assembled into micelle-like nanoparticles in an aqueous solution at pH 7.4, and the solubility of RA-V was enhanced by loading the drug into the hydrophobic cores of micelles. The near-infrared (NIR) fluorescent probe squaraine (SQ) dye, as an imaging probe, could also be encapsulated into polymer micelles simultaneously. The diameters of the RA-V/SQ loaded micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), which proved that the micelles with sizes of 35-60 nm were suitable as anti-cancer drug nano-vehicles. The drug-loading capacity and drug release profiles of RA-V-loaded micelles were calculated and monitored by high performance liquid chromatography (HPLC) measurements. The RA-V/SQ loaded micelles were stable at a neutral pH, and drug release could be greatly accelerated by the acid-triggered ionization of copolymer chains. Similarly, with free RA-V cyclopeptide, the RA-V/SQ loaded micelles exhibited high anti-cancer efficiency toward MCF-7 cells and Hela cells, while the intact polymer micelles and SQ-loaded micelles are non-toxic. Moreover, the endocytosis pathway and mitochondria-regulated apoptosis of RA-V/SQ loaded micelles were proved by lysosome colocalization and JC-1 assay, respectively. Finally, biodistribution and tumor growth inhibition were evaluated in MCF-7 cell-xenografted nude mice, demonstrating that RA-V/SQ loaded micelles could realize tumor imaging and effectively and simultaneously inhibit tumor growth. Therefore, the RA-V/SQ loaded micelles may find use as potential nano-scaled cancer therapeutics and imaging agents.

Synthesis and molecular recognition studies on small-molecule inhibitors for thioredoxin reductase.

Thioredoxin reductase (TrxR), which is overexpressed in many aggressive cancers, plays a crucial role in redox balance and antioxidant function, including defense of oxidative stress, control of cell proliferation, and regulation of cell apoptosis. Deactivation of TrxR can destroy the homeostasis of the cancer cells, inducing elevation of reactive oxygen species (ROS) levels and the oxidation of enzymatic substrates. Here, we synthesized and identified a new gold(I) small molecule (D9) that possesses two strong electron-donating moieties, i.e., 4-methylphenyl alkynyl and thionyldiphenyl phosphine, exhibiting an enhanced p-π conjunction effect. The resulting compound shows the increased soft Lewis acids and the stability of gold(I). And we demonstrated that D9 could efficiently and specifically inhibit the activity of TrxR in vitro and in vivo, and it could effectively avoid the ligand exchange with albumin that was one of the most abundant proteins in blood. We believe that these comprehensive studies on the relationship between the structure and performance will provide inspiring information on the precise synthesis and design of new compounds for targeting TrxR.

A photoacoustic approach for monitoring the drug release of pH-sensitive poly(ß-amino ester)s.

Drug delivery systems are capable of delivering medications to target sites and controlled releasing payloads to circumvent common problems associated with traditional drugs such as low bioavailability and undesired side-effects. Real-time and spatio-temporal monitoring of the drug release kinetics is crucial for evaluating treatment efficacy. The photoacoustic tomography (PAT) imaging technique has become an emerging tool for non-invasively studying the drug release behaviour of drug-loaded nanocarriers under physiological conditions. In this work, we prepared PEG modified poly(ß-amino ester) graft copolymers with pH-sensitive properties, which were proved by pyrene fluorescence and pH titration measurements. The copolymers could form micelle-like nanoparticles with hydrophobic cores at pH 7.4 and dissociated into single chains in mildly acidic media. The anticancer drug doxorubicin (DOX) and the near-infrared fluorescence squaraine (SQ) dye as a built-in PAT reporter molecule were loaded into the hydrophobic core of micelles simultaneously, and their release profiles were investigated by using UV/Vis, fluorescence spectrometers and the PAT technique. The polymer micelles were stable at pH 7.4 and released the loaded molecules quickly under mildly acidic conditions, accompanied by the change of photoacoustic signals. The drug-loaded micelles entered into human breast cancer MCF-7 cells by endocytosis and accumulated in the lysosomes that provide an acidic environment to promote the release of DOX, which were monitored by PAT imaging. The time-dependent photoacoustic signals in tissue-mimic phantoms containing micelle-like nanoparticle treated cells reflected the drug release process in lysosomes, which was further validated by using a cell-based confocal fluorescence microscope.