Blood Circulation Time Research Articles

Abstract 17527: Plasma Proteomic Representations of Central Hemodynamics Over Time in Heart Failure

Introduction: Perturbation of central hemodynamic parameters are defining features in heart failure (HF) and strong prognostic factors, including increased filling pressures, reduced cardiac output (CI), extended blood circulation times and increased peripheral oxygen extraction (ΔAVO2). Invasive catheterization is used for precise assessment of central hemodynamics. Hypothesis: We postulated that plasma proteins may serve as non-invasive representations of central hemodynamics in HF patients. Methods: Affinity-based plasma proteomic profiling of 1305 proteins was applied to a cohort of patients with advanced HF undergoing invasive cardiac catheterization before and 6 months after heart transplantation. A total of 30 central hemodynamic parameters were measured and calculated. Protein profiles associated with central hemodynamics over time were identified from repeated-measures models. Results: We identified 1304 associations for 201 unique proteins meeting our Bonferroni-adjusted significance threshold (p<1x10-6) for at least one hemodynamic parameter. Most of the 201 proteins were associated with more than one parameter. Most proteins (70%) associated with parameters in more than one of five domains (filling pressures, left ventricular (LV) function, right ventricular (RV) function, systemic arterial function, pulmonary arterial function). No proteins were associated with 6 of the 30 hemodynamic parameters, which changed little after transplantation and related to arterial function or RV function. The largest number of protein associations were observed for RAP, cardiac power index, left ventricular stroke work index, and ΔAVO2 followed by systolic blood pressure, CI, and PAWP (>80). These include expected associations of natriuretic peptides, ST2 with LV function, filling pressures and of angiotensinogen with vascular function parameters. We further describe the discriminatory ability of identified proteins for clinically relevant differences in key hemodynamic parameters. Conclusions: We have identified circulating biomarkers to non-invasively monitor central hemodynamics in HF over time. Our findings may also inform understanding of pathways involved in HF pathophysiology and circulatory regulation.

High-precision detection and navigation surgery of colorectal cancer micrometastases

Surgical resection is an effective treatment for colorectal cancer (CRC) patients, whereas occult metastases hinder the curative effect. Currently, there is no effective method to achieve intraoperatively diagnosis of tumor-positive lymph nodes (LNs). Herein, we adopt a near-infrared-II (NIR-II) organic donor-pi-acceptor-pi-donor probe FE-2PEG, which exhibits bright fluorescence over 1100 nm, excellent photostability, blood circulation time, and biocompatibility, to achieve high-performance bioimaging with improved temporal and spatial resolution. Importantly, the FE-2PEG shows efficient passive enrichment in orthotopic CRC, metastatic mesenteric LNs, and peritoneal metastases by enhanced permeability and retention effect. Under NIR-II fluorescence-guided surgery (FGS), the peritoneal micrometastases were resected with a sensitivity of 94.51%, specificity of 86.59%, positive predictive value (PPV) of 96.57%, and negative predictive value of 79.78%. The PPV still achieves 96.07% even for micrometastases less than 3 mm. Pathological staining and NIR-II microscopy imaging proved that FE-2PEG could successfully delineate the boundary between the tumor and normal tissues. Dual-color NIR-II imaging strategy with FE-2PEG (1100 ~ 1300 nm) and PbS@CdS quantum dots (> 1500 nm) successfully protects both blood supply and normal tissues during surgery. The NIR-II-based FGS provides a promising prospect for precise intraoperative diagnosis and minimally invasive surgery of CRC.

PLGA nanoparticles enhanced cardio-protection of scutellarin and paeoniflorin against isoproterenol-induced myocardial ischemia in rats

This study aims to examine the impact of the microfluidic preparation process on the quality of poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) co-delivered with scutellarin (SCU) and paeoniflorin (PAE) in comparison to a conventional emulsification method and to evaluatethe potential cardio-protective effect of SCU-PAE PLGA NPs produced through emulsification method. As compared with microfluidics, the nanoparticles prepared by emulsification method exhibited a smaller size, higher encapsulation efficiency, higher drug loading and lower viscosity for injection. Subsequently, a rat myocardial ischemia (MI) was established using male Sprague-Dawley (SD) rats (250 ± 20 g) subcutaneously injected with 85 mg/kg isoproterenol (ISO) for two consecutive days. The pharmacokinetic findings demonstrated that our SCU-PAE PLGA NPs exhibited prolonged blood circulation time in MI rats, leading to increased levels of SCU and PAE in the heart. This resulted in significant improvements in electrocardiogram and cardiac index, as well as reduced serum levels of CK, LDH, AST. Histopathological analysis using H&E and TUNEL staining provided further evidence of improved cardiac function and decreased apoptosis. Additionally, experiments measuring SOD, MDA, GSH, NO, TNF-α and IL-6 levels indicated that SCU-PAE PLGA NPs may effectively treat MI through oxidative stress and inflammatory pathways, thereby establishing it as a promising therapeutic intervention.

An acid-engineered sericin nanoplatform enhances photothermal conversion and chemotherapy outcome for inducing immunogenic cell death

Inducing immunogenic cell death (ICD) by external-stimuli therapy holds great promise for cancer immunotherapy, however, hindered by widely-used photodynamic therapy (PDT) and sonodynamic therapy (SDT) due to oxygen depletion that compromises their therapeutic effect. Herein, we report a natural sericin nanoparticle (denoted as SDINPs) as ICD-inducer based on photothermal therapy (PTT) to alleviate immunosuppressive tumor microenvironment. The sericin-based ICD-inducer comprises chemically conjugated pH-responsive chemotherapeutic drugs, doxorubicin (DOX), and a physically loaded photosensitizers, indocyanine green (ICG), the therapeutic ability of which can be specifically activated by non-invasive laser radiation. Compared to free molecules, nanostructured SDINPs exhibit superior photothermal conversion efficiency, prolonged blood circulation time, and enhanced tumor accumulation, retention, and penetration capabilities. As a result of these advantages, they demonstrate potent therapeutic efficacy and PTT-mediated ICD burst induction for antitumor immunity. This study presents a pH/photo-activatable combination strategy that provides a novel perspective for clinical cancer treatment.

PH-Responsive NIR-II phototheranostic agents for in situ tumor vascular monitoring and combined anti-vascular/photothermal therapy

Developing nanoplatforms integrating superior fluorescence imaging ability in second near-infrared (NIR-II) window and tumor microenvironment responsive multi-modal therapy holds great potential for real-time feedback of therapeutic efficacy and optimizing tumor inhibition. Herein, we developed a pH-sensitive pyrrolopyrrole aza-BODIPY-based amphiphilic molecule (PTG), which has a balanced NIR-II fluorescence brightness and photothermal effect. PTG is further co-assembled with a vascular disrupting agent (known as DMXAA) to prepare PTDG nanoparticles for combined anti-vascular/photothermal therapy and real-time monitoring of the tumor vascular disruption. Each PTG molecule has an active PT-3 core which is linked to two PEG chains via pH-sensitive ester bonds. The cleavage of ester bonds in the acidic tumor environment would tricker releases of DMXAA for anti-vascular therapy and further assemble PT-3 cores into micrometer particles for long term monitoring of the tumor progression. Furthermore, benefiting from the high brightness in the NIR-II region (119.61 M−1 cm−1) and long blood circulation time (t1/2 = 235.6 min) of PTDG nanoparticles, the tumor vascular disrupting process can be in situ visualized in real time during treatment. Overall, this study demonstrates a self-assembly strategy to build a pH-responsive NIR-II nanoplatform for real-time monitoring of tumor vascular disruption, long-term tracking tumor progression and combined anti-vascular/photothermal therapy.

Ginsenoside Rg3 endows liposomes with prolonged blood circulation and reduced accelerated blood clearance

PEGylated cholesterol-containing liposomes (Chol-PEG-lipo) have been widely used as a drug carrier for their good stealth property in blood circulation where cholesterol maintains the stability of the liposomal lipid bilayer and PEGylation endows liposomes with long circulation capability. However, cholesterol-related disadvantages and the accelerated blood clearance (ABC) phenomenon caused by PEGylation greatly limit the application of conventional stealth liposomes in clinic. Herein, ginsenoside Rg3 was selected to substitute cholesterol and PEG for liposomes preparation (Rg3-lipo). Rg3 was proved with similar liposomal membrane regulation ability to cholesterol and comparable long circulation effect to PEG. In addition, repeated administrations of Chol-PEG-lipo and Rg3-lipo were performed. The circulation time of the second dose of Chol-PEG-lipo was substantially reduced accompanied by a greatly increased accumulation in the liver due to the induction of anti-PEG IgM and the subsequent activated complement system. In contrast, no significantly increased level of relative plasma cells, IgM secretion and the complement activation in blood circulation was observed after the second injection of Rg3-lipo. As a result, Rg3-lipo showed great stealth property without ABC phenomenon. Therefore, developing liposomes utilizing Rg3 instead of PEG and cholesterol presents a promising strategy to prolong the blood circulation time of liposomes without triggering the ABC phenomenon and activated immune responses.

Ultra-Bright Heptamethine Dye Clusters Based on a Self-Adaptive Co-Assembly Strategy for NIR-IIb Biomedical Imaging.

Despite the wide range of applications of bright NIR-II polymethine scaffolds in biomedical imaging, their solvatochromism and aggregation-caused quenching (ACQ) effects in aqueous solutions limit their inherent brightness using traditional encapsulation methods, and effective hydrophilization strategies are still scarce. Here, a new set of Flav dyes is synthesized and PEGylated, followed by manufacturing DSPE@FlavP2000 nanoparticles using a self-adaptive co-assembly strategy to overcome these limitations. FlavP2000 can autonomously adjust its conformation when co-assembled with DSPE-PEG2000 , resulting in high-efficiency luminescence (≈44.9% fluorescence of Flav in DMSO). DSPE@FlavP2000 enables NIR-IIb (>1500nm) angiography with high signal-to-noise ratios. Notably, this co-assembly can occur in situ between FlavP2000 with proteins in the living body based on a novel mechanism of brightness activation induced by disassembly (BAD), achieving consistent brightness as DSPE@FlavP2000 in blood or serum. The self-adaptive co-assembly strategy can be enhanced by incorporating an IPA moiety, which dynamically binds to albumin to prolong the dye's blood circulation time. Thus, the "enhanced" BAD is successfully applied to long-term vascular imaging and sciatic nerve imaging. Both the self-adaptive co-assembly strategy and BAD phenomenon improve the selectivity and availability of the hydrophilization methods, paving the way for efficient biological applications of polymethine dyes.

Cancer Cell Membrane-Based Materials for Biomedical Applications.

The nanodelivery system provides a novel direction for disease diagnosis and treatment; however, its delivery effectiveness is restricted by the short biological half-life and inadequate tumor targeting. The immune evasion properties and homologous targeting capabilities of natural cell membranes, particularly those of cancer cell membranes (CCM), have gained significant interest. The integration of CCM and nanoparticles has resulted in the emergence of CCM-based nanoplatforms (CCM-NPs), which have gained significant attention due to their unique properties. CCM-NPs not only prolong the blood circulation time of core nanoparticles, but also direct them for homologous tumor targeting. Herein, the history and development of CCM-NPs as well as how these platforms have been used for biomedical applications are discussed. The application of CCM-NPs for cancer therapy will be described in detail. Translational efforts are currently under way and further research to address key areas of need will ultimately be required to facilitate the successful clinical adoption of CCM-NPs.

Hydrophobicity-Adaptive Polymers Trigger Fission of Tumor-Cell-Derived Microparticles for Enhanced Anticancer Drug Delivery.

Tumor-cell-derived microparticles (MPs) can function as anticancer drug-delivery carriers. However, short blood circulation time, large-size-induced insufficient tumor accumulation and penetration into tumor parenchyma, as well as limited cellular internalization by tumor cells and cancer stem cells (CSCs), and difficult intracellular drug release restrict the anticancer activity of tumor-cell-derived MP-based drug-delivery systems. In this work, hydrophobicity-adaptive polymers based on poly(N-isopropylacrylamide) are anchored to tumor-cell-derived MPs for enhanced delivery of the anticancer drug doxorubicin (DOX). The polymers are hydrophilic in blood to prolong the circulation time of DOX-loaded MPs (DOX@MPs), while rapidly switching to hydrophobic at the tumor acidic microenvironment. The hydrophobicity of polymers drives the fission of tumor-cell-derived MPs to form small vesicles, facilitating tumor accumulation, deep tumor penetration, and efficient internalization of DOX@MPs into tumor cells and CSCs. Subsequently, the hydrophobicity of polymers in acidic lysosomes further promotes DOX release to nuclei for strong cytotoxicity against tumor cells and CSCs. The work provides a facile and simple strategy for improved anticancer drug delivery of tumor-cell-derived MPs.

Self‐Assembled Amphiphilic Camptothecin Nanoparticles with Glutathione‐Responsive and Tumor‐Targeting Ability for Enhanced Colorectal Cancer Therapy

AbstractCamptothecin (CPT) is impeded by low solubility, non‐tumor‐targeting ability, and fast blood clearance. Self‐assembly of hydrophobic drugs into nanostructures, especially nanoparticles (NPs), can improve their anti‐cancer effects. In this study, arginine‐glycine‐aspartic acid (RGD), a hydrophilic and tumor‐targeting peptide, is conjugated with CPT through a glutathione‐cleavable disulfide bond. The synthesized amphiphilic molecule CPT‐ss‐RGD self‐assembled into stable NPs in an aqueous solution with diameters of ≈86nm. They exhibited low critical aggregation concentrations, good stability, and glutathione responsiveness. They can be specifically taken up by CRC cells through RGD integrin‐mediated uptake, and exhibit high toxicity to CRC cells and multicellular tumor spheroids. As expected, CPT‐ss‐RGD NPs prolonged the blood circulation time and enhanced the tumor accumulation of CPT, exhibiting excellent anti‐tumor growth ability and few side effects. Thus, CPT‐ss‐RGD NPs have great clinical translational potential for CRC therapy. The successful self‐assembly of the CPT‐ss‐RGD NPs provides a new method for the self‐delivery of hydrophobic therapeutics in vivo.

Long cruising aptamer-albumin nanobots intelligently capture and restrain circulating tumor cells

Circulating tumor cells (CTC) are the root cause of life-threatening cancer metastases. The rare CTC cannot be specifically killed by anti-cancer agents without producing any side effects, nor be targeted-and-eradicated by antibody or aptamer complexes because of the complexes’ limited circulating half-life in the blood owing to metabolism and immune clearance. Here, we build the biosafe and biostable aptamer-albumin nanobots that can cruise in the blood much long together with the CTC, resulting in the increased capture efficiency and specificity of the nanobots targeting CTC. The intelligent-recognizing unit of the novel nanobots is composed of three EpCAM-targeting aptamers (AP) that can specifically target breast CTC, and their sticky ends are completely closed to form the biostable circular trivalent aptamers (CTA). The binding energy, specificity and stability of the circular three arms CTA are significantly superior to their linear AP. After conjugating CTA to human serum albumin (CTA-HSA) by amination reaction, the blood circulation time of CTA-HSA in mice was significantly prolonged by 3 folds, resulting in the enhanced collision probability and increased capture efficiency of CTA-HSA to CTC. CTA-HSA can escape the immune clearance and inhibit adhesion/invasion and cell cycle of CTC, resulting in CTC apoptosis. This proof-of-concept study provides a promising nanobiomaterial for CTC-induced cancer metastases.

Mesoporous Nano-Badminton with Asymmetric Mass Distribution: How Nanoscale Architecture Affects the Blood Flow Dynamics.

While the nanobio interaction is crucial in determining nanoparticles' in vivo fate, a previous work on investigating nanoparticles' interaction with biological barriers is mainly carried out in a static state. Nanoparticles' fluid dynamics that share non-negligible impacts on their frequency of encountering biological hosts, however, is seldom given attention. Herein, inspired by badmintons' unique aerodynamics, badminton architecture Fe3O4&mPDA (Fe3O4 = magnetite nanoparticle and mPDA = mesoporous polydopamine) Janus nanoparticles have successfully been synthesized based on a steric-induced anisotropic assembly strategy. Due to the "head" Fe3O4 having much larger density than the mPDA "cone", it shows an asymmetric mass distribution, analogous to real badminton. Computational simulations show that nanobadmintons have a stable fluid posture of mPDA cone facing forward, which is opposite to that for the real badminton. The force analysis demonstrates that the badminton-like morphology and mass distribution endow the nanoparticles with a balanced motion around this posture, making its movement in fluid stable. Compared to conventional spherical Fe3O4@mPDA nanoparticles, the Janus nanoparticles with an asymmetric mass distribution have straighter blood flow trails and ∼50% reduced blood vessel wall encountering frequency, thus providing doubled blood half-life and ∼15% lower organ uptakes. This work provides novel methodology for the fabrication of unique nanomaterials, and the correlations between nanoparticle architectures, biofluid dynamics, organ uptake, and blood circulation time are successfully established, providing essential guidance for designing future nanocarriers.

In Situ Bioconjugation of a Maleimide-Functionalized Ruthenium-Based Photosensitizer to Albumin for Photodynamic Therapy.

Maleimide-containing prodrugs can quickly and selectively react with circulating serum albumin following their injection in the bloodstream. The drug-albumin complex then benefits from longer blood circulation times and better tumor accumulation. Herein, we have applied this strategy to a previously reported highly phototoxic Ru polypyridyl complex-based photosensitizer to increase its accumulation at the tumor, reduce off-target cytotoxicity, and therefore improve its pharmacological profile. Specifically, two complexes were synthesized bearing a maleimide group: one complex with the maleimide directly incorporated into the bipyridyl ligand, and the other has a hydrophilic linker between the ligand and the maleimide group. Their interaction with albumin was studied in-depth, revealing their ability to efficiently bind both covalently and noncovalently to the plasma protein. A crucial finding is that the maleimide-functionalized complexes exhibited significantly lower cytotoxicity in noncancerous cells under dark conditions compared to the nonfunctionalized complex, which is a highly desirable property for a photosensitizer. The binding to albumin also led to a decrease in the phototoxicity of the Ru bioconjugates in comparison to the nonfunctionalized complex, probably due to a decreased cellular uptake. Unfortunately, this decrease in phototoxicity was not compensated by a dramatic increase in tumor accumulation, as was demonstrated in a tumor-bearing mouse model using inductively coupled plasma mass spectrometry (ICP-MS) studies. Consequently, this study provides valuable insight into the future design of in situ albumin-binding complexes for photodynamic therapy in order to maximize their effectiveness and realize their full potential.

Dynamically assembled nanomedicine based on host-guest molecular recognition for NIR laser-excited chemotherapy and phototheranostics.

Nanomedicines combining multimodal therapeutic modalities supply opportunities to eliminate tumors in a safe and efficient manner. However, the rigid encapsulation and covalent conjugation of different therapeutic reagents suffer from the complicated preparation process, premature drug leakage and severe adverse events. Herein, we report a self-enhanced supramolecular nanomedicine (SND) based on the host-guest molecular recognition between β-cyclodextrin (β-CD) and camptothecin (CPT) for trimodal synergistic chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT) using a single 670 nm near-infrared (NIR) laser. Thioketal bond and polyethylene glycol (PEG) segment are introduced into the structure of CPT-tk-PEG prodrug, thus the premature release of CPT is efficiently inhibited and the specific drug release is realized at tumor site where singlet oxygen (1O2)-generated PDT is performed. A boron dipyrromethene (BODIPY) theranostic agent is anchored onto β-CD, endowing SND with capabilities of fluorescence imaging, PDT and PTT. Benefiting from the supramolecular assembly, not only the solubility of CPT is improved by 40 times, but also the blood circulation time and tumor accumulation of SND are greatly promoted. In vivo, SND can effectively induce the immunogenic cell death (ICD) of tumor cells, thus performing prominent inhibition against both primary and distal tumors, and even anti-metastasis effect against liver without causing obvious systemic toxicity. STATEMENT OF SIGNIFICANCE: Although nanomedicines supply opportunities to eliminate tumors in an efficient manner, they usually suffer from premature drug leakage, complicated preparation process and severe side effects owing to the rigid encapsulation or covalent conjugation. Based on the host-guest molecular recognition, we developed a self-enhanced SND for synergistic chemotherapy, photodynamic therapy and photothermal therapy. Introduction of thioketal bond in CPT prodrug avoided the premature drug release, and the specific drug release was realized in the tumor cells. Profiting from the facile supramolecular assembly strategy, SND not only displayed a primary anticancer efficacy with a low systemic toxicity, but also efficiently inhibited the growth of distal tumors, contributing a vaccine-like function to eradicate the recurrent and metastatic tumors.

Surface-modified cationic liposomes with a matrix metalloproteinase-degradable polyethylene glycol derivative improved doxorubicin delivery in murine colon cancer

PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake.

Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery.

Dendrimers are a family of polymers with highly branched structure, well-defined composition, and extensive functional groups, which have attracted great attention in biomedical applications. Micelles formed by dendrimers are ideal nanocarriers for delivering anticancer agents due to the explicit study of their characteristics of particle size, charge, and biological properties such as toxicity, blood circulation time, biodistribution, and cellular internalization. Here, the classification, preparation, and structure of dendrimer micelles are reviewed, and the specific functional groups modified on the surface of dendrimers for tumor active targeting, stimuli-responsive drug release, reduced toxicity, and prolonged blood circulation time are discussed. In addition, their applications are summarized as various platforms for biomedical applications related to cancer therapy including drug delivery, gene transfection, nano-contrast for imaging, and combined therapy. Other applications such as tissue engineering and biosensor are also involved. Finally, the possible challenges and perspectives of dendrimer micelles for their further applications are discussed.

Superparamagnetic Nanocrystals Clustered Using Poly(ethylene glycol)-Crosslinked Amphiphilic Copolymers for the Diagnosis of Liver Cancer.

Superparamagnetic iron oxide (SPIO) nanocrystals have been extensively studied as theranostic nanoparticles to increase transverse (T2) relaxivity and enhance contrast in magnetic resonance imaging (MRI). To improve the blood circulation time and enhance the diagnostic sensitivity of MRI contrast agents, we developed an amphiphilic copolymer, PCPZL, to effectively encapsulate SPIO nanocrystals. PCPZL was synthesized by crosslinking a polyethylene glycol (PEG)-based homobifunctional linker with a hydrophobic star-like poly(ε-benzyloxycarbonyl-L-lysine) segment. Consequently, it could self-assemble into shell-crosslinked micelles with enhanced colloidal stability in bloodstream circulation. Notably, PCPZL could effectively load SPIO nanocrystals with a high loading capacity of 66.0 ± 0.9%, forming SPIO nanoclusters with a diameter of approximately 100 nm, a high cluster density, and an impressive T2 relaxivity value 5.5 times higher than that of Resovist®. In vivo MRI measurements highlighted the rapid accumulation and contrast effects of SPIO-loaded PCPZL micelles in the livers of both healthy mice and nude mice with an orthotopic hepatocellular carcinoma tumor model. Moreover, the magnetic micelles remarkably enhanced the relative MRI signal difference between the tumor and normal liver tissues. Overall, our findings demonstrate that PCPZL significantly improves the stability and magnetic properties of SPIO nanocrystals, making SPIO-loaded PCPZL micelles promising MRI contrast agents for diagnosing liver diseases and cancers.

Multitarget, multiagent PLGA nanoparticles for simultaneous tumor eradication and TME remodeling in a melanoma mouse model

Despite the fact that chemoimmunotherapy has emerged as a key component in the era of cancer immunotherapy, it is challenged by the complex tumor microenvironment (TME) that is jam-packed with cellular and non-cellular immunosuppressive components. The aim of this study was to design a nanoparticulate system capable of sufficiently accumulating in the tumor and spleen to mediate local and systemic immune responses, respectively. The study also aimed to remodel the immunosuppressive TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered to simultaneously eradicate the cancer cells, silence the tumor-associated fibroblasts (TAFs), and re-educate the tumor-associated macrophages (TAMs) using doxorubicin, losartan, and metformin, respectively. These agents were also selected for their ability to tip the balance of the splenic immune cells towards immunostimulatory phenotypes. To establish TAM and TAF cultures, normal macrophages and fibroblasts were incubated with B16F10 melanoma cell (Mel)-derived secretome. Drug-loaded PLGA NPs were prepared, characterized, and tested in the target cell types. Organ distribution of fluorescein-loaded PLGA NPs was evaluated in a mouse model of melanoma. Finally, the local and systemic effects of different combination therapy programs were portrayed. The in vitro studies showed that the drug-loaded PLGA NPs could significantly ablate the immunosuppressive nature of Mel and skew TAMs and TAFs towards more favorable phenotypes. While in vivo, PLGA NPs were proven to exhibit long blood circulation time and to localize preferentially in the tumor and the spleen. The combination of either metformin or losartan with doxorubicin was superior to the monotherapy, both locally and systemically. However, the three-agent combo produced detrimental effects in the form of compromised well-being, immune depletion, and metastasis. These findings indicate the potential of TME remodeling as means to prime the tumors for successful chemoimmunotherapy. In addition, they shed light on the importance of the careful use of combination therapies and the necessity of employing dose-reduction strategies.Graphical D-NPs doxorubicin-loaded NPs, M-NPs metformin-loaded NPs, L-NPs losartan-loaded NPs, TAMs tumor-associated macrophages, TAFs tumor-associated fibroblasts, PD-L1 programmed death ligand 1, TNF-α tumor necrosis factor alpha, TGF-β transforming growth factor beta, CD206/40/86 cluster of differentiation 206/40/86, α-SMA alpha-smooth muscle actin, MMPs matrix metalloproteases

Lipid based drug delivery systems for oral, transdermal and parenteral delivery: Recent strategies for targeted delivery consistent with different clinical application

Lipid-based drug delivery systems (LBDDS) are valuable and biocompatible nano-carriers for the vehiculation and potential delivery of various hydrophilic, hydrophobic, or amphiphilic compounds. LBDDS have the advantage of targeted drug delivery, as free drugs may have poor targeting, higher systemic toxicity, and possibilities of drug resistance. There is various type of lipid carrier systems for drug delivery based on the properties of drugs and clinical applications; nanoemulsion, microemulsion, lipid vesicles, and lipid nanoparticles. The era of targeted drug delivery is advancing from the superficial convention vesicles to the second generation of LBDDS by modulating the surface chemistry through modifying/surface functionalizing the lipid layer composition. The surfaces of lipid vehicles have been modified with small molecules, antibodies, peptides, and enzymes for targeted drug delivery and reduced toxicity. In this regard, polyethylene glycosylation (PEGylation) on the lipid surface was the first novel approach that improves blood circulation time and curtails opsonin resistance and clearance. However, multi-drug and multi-receptor strategies in the targeted-liposomal approach may be an innovative pathway to overcoming drug resistance while treating certain tumors. Several second-generation conventional drug delivery systems among liposomal formulations are at various stages of clinical trials. This review recapitulates the types of lipid formulations, characterization, and their applications in clinical aspects. Additionally, discuss the strategies for enhancement of disease targeting by surface functionalization with various entities to improve the drug delivery system.

Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway

Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO2). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn2+ to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.