Red Blood Cell Membrane-Coated Nanoparticles Enable Incompatible Blood Transfusions.

Blood transfusions save lives and improve health every day. Despite the matching of blood types being stricter than it ever has been, emergency transfusions among incompatible blood types are still inevitable in the clinic when there is a lack of acceptable blood types for recipients. Here to overcome this, a counter measure nanoplatform consisting of a polymeric core coated by a red blood cell (RBC) membrane is developed. With A-type or B-type RBC membrane camouflaging, the nanoplatform is capable of specifically capturing anti-A or anti-B IgM antibodies within B-type or A-type whole blood, thereby decreasing the corresponding IgM antibody levels and then allowing the incompatible blood transfusions. In addition to IgM, the anti-RBC IgG antibody in a passive immunization murine model can likewise be neutralized by this nanoplatform, leading to prolonged circulation time of incompatible donor RBCs. Noteworthily, nanoplatform made by expired RBCs (>42 days stored hypothermically) and then subjected to lyophilization does not impair their effect on antibody neutralization. Most importantly, antibody-captured RBC-NP do not exacerbate the risk of inflammation, complement activation, and coagulopathy in an acute hemorrhagic shock murine model. Overall, this biomimetic nanoplatform can safely neutralize the antibody to enable incompatible blood transfusion.

Vaginal Epithelial Cell Membrane-Based Phototherapeutic Decoy Confers a "Three-in-One" Strategy to Treat against Intravaginal Infection of Candida albicans.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

Doxorubicin Detoxification in Healthy Organs Improves Tolerability to High Drug Doses for Enhanced Antitumor Therapy.

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

Bacterial Toxin-Responsive Biomimetic Nanobubbles for Precision Photodynamic Therapy against Bacterial Infections.

With few options available for the effective treatment of multidrug-resistant bacteria, photodynamic therapy (PDT) has emerged as a promising therapeutic strategy that does not promote the development of antibiotic resistance. Unfortunately, the beneficial bactericidal effect of PDT is oftentimes accompanied by the uncontrollable production of reactive oxygen species. To overcome this issue, a pore-forming toxin (PFT)-responsive biomimetic nanobubble is designed, which is constructed by co-encapsulating a perfluorocarbon nanoemulsion and a photosensitizer within the red blood cell membrane. It is shown that PFTs derived from three pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), group A Streptococcus (GAS), and Listeria monocytogenes (LM), can be effectively absorbed by the nanobubble. Upon toxin absorption, the formation of pores on the nanobubble surface allows the accelerated release of oxygen dissolved inside the nanoemulsion along with the photosensitizer, thus resulting in enhanced PDT and bactericidal efficacy. In three skin infection models, treatment with the nanobubbles results in significantly decreased lesion formation and reduced inflammation. In addition to oxygen, the platform can be used to deliver nitric oxide in a bacterial toxin-dependent manner. Overall, biomimetic nanobubbles may work as a broad gas delivery system that is capable of responding to a variety of PFT-based stimuli for precision PDT.

Toxin-Enabled "On-Demand" Liposomes for Enhanced Phototherapy to Treat and Protect against Methicillin-Resistant Staphylococcus aureus Infection.

An effective therapeutic strategy against methicillin-resistant Staphylococcus aureus (MRSA) that does not promote further drug resistance is highly desirable. While phototherapies have demonstrated considerable promise, their application toward bacterial infections can be limited by negative off-target effects to healthy cells. Here, a smart targeted nanoformulation consisting of a liquid perfluorocarbon core stabilized by a lipid membrane coating is developed. Using vancomycin as a targeting agent, the platform is capable of specifically delivering an encapsulated photosensitizer along with oxygen to sites of MRSA infection, where high concentrations of pore-forming toxins trigger on-demand payload release. Upon subsequent near-infrared irradiation, local increases in temperature and reactive oxygen species effectively kill the bacteria. Additionally, the secreted toxins that are captured by the nanoformulation can be processed by resident immune cells to promote multiantigenic immunity that protects against secondary MRSA infections. Overall, the reported approach for the on-demand release of phototherapeutic agents into sites of infection could be applied against a wide range of high-priority pathogens.

Targeted delivery of fat extract by platelet membrane-cloaked nanocarriers for the treatment of ischemic stroke.

BACKGROUND: Our previous studies suggest that human fat extract (FE) contains a variety of angiogenic factors and may provide an alternative treatment option for stroke. However, the therapeutic effect is largely limited due to its short half-life, and inaccurate targeting. RESULTS: Herein, we leverage the targeting abilities of platelets (PLTs) to the lesion area of stroke and Arg-Gly-Asp (RGD) peptides to the angiogenic blood vessels to develop a biomimetic nanocarrier that capable of delivering FE precisely to treat stroke. The biomimetic nanocarriers are comprised of FE-encapsulated PLGA (poly(lactic-co-glycolic acid)) core enclosed by RGD peptides decorated plasma membrane of PLTs, namely RGD-PLT@PLGA-FE. We found that RGD-PLT@PLGA-FE not only targeted damaged and inflamed blood vessels but also achieved rapid accumulation in the lesion area of ischemic brain. In addition, RGD-PLT@PLGA-FE kept a sustained release behavior of FE at the lesion site, effectively increased its half-life and promoted angiogenesis and neurogenesis with delivering neurotrophic factors including BDNF, GDNF and bFGF to the brain, that ultimately resulted in blood flow increase and neurobehavioral recovery. CONCLUSIONS: In conclusion, our study provides a new strategy to design a biomimetic system for FE delivery and it is a promising modality for stroke therapy.

A KPV-binding double-network hydrogel restores gut mucosal barrier in an inflamed colon.

Ulcerative colitis (UC) usually occurs in the superficial mucosa of the colorectum. Here, a double-network hydrogel (PMSP) was constructed from maleimided γ-polyglutamic acid and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. PMSP with a negative charge specifically adhered to the inflamed mucosa with positively charged proteins rather than to the healthy mucosa. PMSP exhibited good mechanical strength with storage modulus (G') of 17.6 Pa and a linear viscoelastic region (LVR) of 107.2% strain. Moreover, PMSP showed a stronger bio-adhesive force toward the inflamed tissue-mimicking substrate than toward its healthy counterpart. In vivo imaging confirmed that PMSP specifically adhered to the inflamed colonic mucosa of rats with TNBS-induced UC. KPV (Lys-Pro-Val) as a model drug was easily captured by PMSP through electrostatic interactions, thus retaining its bioactivity for a longer time under high temperature conditions. Moreover, the alleviating effect of KPV on rats with TNBS-induced colitis was significantly improved by PMSP after intracolonic administration. The epithelial barrier of the colon also effectively recovered following PMSP-KPV treatment. PMSP-KPV also modulated the gut flora, markedly augmenting the abundance of beneficial microorganisms in gut homeostasis. The mechanism by which PMSP-KPV induces a therapeutic effect may be associated with the inhibition of oxidative stress. Conclusively, the PMSP hydrogel seems to be a promising rectal delivery system for the therapy of UC. STATEMENT OF SIGNIFICANCE: Ulcerative colitis (UC) is a chronic and relapsing disease of the gastrointestinal tract. A key therapeutic approach to treat UC is to repair the mucosal barriers. Here, a double-network hydrogel (PMSP) was constructed from maleimided and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. The negatively charged PMSP specifically adhered to the inflamed colon rather than its healthy counterpart and was retained for a longer time. KPV as a model drug was easily captured by PMSP, which provided better stability to KPV when exposed to high temperature of 50 °C. The epithelial mucosal barrier of the colon was effectively recovered by the rectal administration of PMSP-KPV to rats with TNBS-induced UC. Moreover, PMSP-KPV modulated the gut flora of colitic rats, markedly augmenting the abundance of beneficial microorganisms. Conclusively, PMSP seems to be a promising rectal delivery system for UC therapy.

Exercise Inhibits NLRP3 Inflammasome Activation in Obese Mice via the Anti-Inflammatory Effect of Meteorin-like.

Obesity is associated with chronic low-grade inflammation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether exercise can regulate NLRP3 inflammasome activation in obese adipose tissue remains unknown. Meteorin-like (METRNL), a recently discovered myokine, has been implicated in mediating the effect of exercise on metabolism. Herein, we examined the effect of exercise and METRNL on NLRP3 inflammasome activation. High-fat diet (HFD)-induced obese mice were subjected to treadmill exercise for 8 weeks. A subgroup of HFD mice was switched to normal chow with the exercise intervention. Exercise and diet attenuated weight gain, fat accumulation, and insulin resistance in obese mice. In addition, exercise downregulated gene and protein levels of inflammasome markers, including NLRP3 and caspase-1, in adipose tissue. In isolated bone marrow-derived macrophages, activation of NLRP3 inflammasome was suppressed in the exercise group, as confirmed by the downregulation of IL-1ß and IL-18. Exercise significantly enhanced the expression of METRNL in various muscle depots, and further in vitro analysis revealed that recombinant METRNL treatment inhibited IL-1ß secretion in macrophages. In conclusion, exercise exerts its anti-inflammatory action by suppressing adipose tissue NLRP3 inflammasome, and this is, in part, associated with METRNL induction in muscle and its anti-inflammatory effects in macrophages.

Ganoderma Lucidum Polysaccharides Enhance the Abscopal Effect of Photothermal Therapy in Hepatoma-Bearing Mice Through Immunomodulatory, Anti-Proliferative, Pro-Apoptotic and Anti-Angiogenic.

Hepatocellular carcinoma is a malignant tumor with high morbidity and mortality, a highly effective treatment with low side effects and tolerance is needed. Photothermal immunotherapy is a promising treatment combining photothermal therapy (PTT) and immunotherapy. PTT induces the release of tumor-associated antigens by ablating tumor and Ganoderma lucidum polysaccharides (GLP) enhance the antitumor immunity. Results showed that Indocyanine Green (ICG) was successfully encapsulated into SF-Gel. ICG could convert light to heat and SF-Gel accelerates the photothermal effect in vitro and in vivo. PTT based on ICG/ICG-SF-Gel inhibited the growth of primary and distal tumors, GLP enhanced the inhibitory efficacy. ICG/ICG-SF-Gel-based PTT and GLP immunotherapy improved the survival time. ICG/ICG-SF-Gel-based PTT induces tumor necrosis and GLP enhanced the photothermal efficacy. ICG/ICG-SF-Gel-based PTT inhibited cell proliferation and angiogenesis, induced cell apoptosis, enhanced cellular immunity, and GLP enhanced these effects. In conclusion, GLP could enhance the abscopal effect of PTT in Hepatoma-bearing mice.

Glucose-responsive hydrogel enhances the preventive effect of insulin and liraglutide on diabetic nephropathy of rats.

Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus. The combination of insulin (Ins) with liraglutide (Lir) has a greater potential for preventing DN than monotherapy. However, the renal protective effect of the combined Ins/Lir therapy is largely compromised due to their short half-lives after subcutaneous injection. Herein, a glucose-responsive hydrogel was designed in situ forming the dynamic boronic esters bonds between phenylboronic acid-grafted γ-Polyglutamic acid (PBA-PGA) and konjac glucomannan (KGM). It was hypothesized that the KGM/PBA-PGA hydrogel as the delivery vehicle of Ins/Lir would enhance the combinational effect of the latter on preventing the DN progress. Scan electronic microscopy and rheological studies showed that KGM/PBA-PGA hydrogel displayed good glucose-responsive property. Besides, the glucose-sensitive release profile of either Ins or Lir from KGM/PBA-PGA hydrogel was uniformly displayed at hyperglycemic level. Furthermore, the preventive efficacy of KGM/PBA-PGA hydrogel incorporating insulin and liraglutide (Ins/Lir-H) on DN progress was evaluated on streptozotocin-induced rats with diabetic mellitus (DM). At 6 weeks after subcutaneous injection of Ins/Lir-H, not only the morphology of kidneys was obviously recovered as shown by ultrasonography, but also the renal hemodynamics was significantly improved. Meanwhile, the 24-h urinary protein and albumin/creatinine ratio were well modulated. Inflammation and fibrosis were also largely inhibited. Besides, the glomerular NPHS-2 was obviously elevated after treatment with Ins/Lir-H. The therapeutic mechanism of Ins/Lir-H was highly associated with the alleviation of oxidative stress and activation of autophagy. Conclusively, the better preventive effect of the combined Ins/Lir via KGM/PBA-PGA hydrogel on DN progress was demonstrated as compared with their mixed solution, suggesting KGM/PBA-PGA hydrogel might be a potential vehicle of Ins/Lir to combat the progression of DN.

Fibroblast growth factor 2 exacerbates inflammation in adipocytes through NLRP3 inflammasome activation.

Chronic inflammation in adipose tissue is the hallmark of obesity and a major risk factor for the development of obesity-induced insulin resistance. NLRP3 inflammasome regulates the maturation and secretion of pro-inflammatory cytokines, such as IL-1ß and IL-18, and was recently discovered to be involved in obesity-related metabolic diseases. Fibroblast growth factors (FGFs) such as FGF1, FGF10, and FGF21 are adipokines that regulate adipocyte development and metabolism, but reports on the effect of other FGFs on adipocytes are lacking. In the present study, the novel role of FGF2 in NLRP3 inflammasome activation was elucidated. Our results showed that FGF2 levels were increased during adipocyte differentiation and in the adipose tissue of high-fat diet (HFD)-induced obese mice. Recombinant FGF2 treatment upregulated inflammasome markers such as NLRP3, which was further exaggerated by TNF-ɑ treatment. Interestingly, ß-Klotho, a co-receptor of FGF21, was significantly decreased by FGF2 treatment. Results from mice confirmed the positive correlation between FGF2 and NLRP3 expression in epididymal and subcutaneous adipose tissue, while exercise training effectively reversed HFD-induced NLRP3 expression as well as FGF2 levels in both adipose depots. Our results suggest that FGF2 is an adipokine that may exacerbate the inflammatory response in adipocytes through NLRP3 inflammasome activation.

Injected laquinimod D-α-tocopheryl polyethylene glycol-1000 succinate polymeric micelles for the treatment of inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) are chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Laquinimod (LAQ), a poorly water-soluble compound, was proved to be effective for colitis remission at low dose of 0.5 mg/kg in patients with Crohn's disease. Due to its extremely low solubility in water, it was difficult to develop an injectable liquid dosage form. Herein, D-α-Tocopheryl polyethylene glycol-1000 succinate (TPGS) polymeric micelles were developed as a delivery vehicle of LAQ for the management of inflammatory bowel disease. Using the LAQ/TPGS ratio of 1:100, LAQ-loaded micelles were successfully prepared by thin-film dispersion method. The solubility of LAQ in water was significantly increased from 10.5 µg/mL in pure water to 500 µg/mL in TPGS micelles. LAQ-loaded micelles of TPGS exhibited the fine particle size of 34.6 nm and Zeta potential of -0.67 mV. Moreover, the good stability of LAQ-loaded micelles in physiology-mimicking medium was confirmed by detecting their particle size, zeta potential and leakage of the loading drug. Therapeutic effect of LAQ-loaded micelles on DSS-induced mice was proved by detecting DAI score, colon length and loss of body weight. Moreover, the morphology and colonic mucosal barrier of the injured colon of DSS-induced mice was largely recovered after treatment with LAQ-loaded micelles. Meanwhile, the inflammation of colitis colon was also obviously alleviated by LAQ-loaded micelles. Conclusively, polymeric micelles of TPGS may be a promising delivery vehicle of LAQ for the management of inflammatory bowel disease.

Cross-linked nanoparticles of silk fibroin with proanthocyanidins as a promising vehicle of indocyanine green for photo-thermal therapy of glioma.

Instability of silk fibroin nanoparticles (SFNPs) in physiologic condition hinders its application as drug delivery vehicle. Herein, indocyanine green (ICG) loaded silk fibroin nanoparticles (ICG-SFNPs) was firstly prepared and then crosslinked by proanthocyanidins to obtain the stable ICG-CSFNPs for killing the residual tumour niche under near infra-red irradiation (NIR) after surgery. The particle size and zeta potentials of ICG-CSFNPs was 120.1 nm and -40.4 mV, respectively. Moreover, ICG-CSFNPs exhibited good stability of particle size in the physiological medium. Meanwhile, the stable photothermal properties of ICG-CSFNPs were not compromised even after several cycles of NIR. Few of the ICG-CSFNPs were phagocytized by RAW264.7 macrophage in vitro, while they were easily internalized by C6 glioma cells, resulting in their significant toxicity on tumour cells after NIR. The pharmacokinetic study showed that ICG-CSFNPs had a longer blood circulation time than ICG-SFNPs, making them more distribution in glioma after intravenous administration in vivo. Meanwhile, the pharmacological study showed the more effective inhibition of tumour growth was exhibited by ICG-CSFNPs in C6 glioma-bearing mice after NIR. Overall, the cross-linked nanoparticles of silk fibroin may be a promising vehicle of ICG for photothermal therapy of glioma after surgical resection.

Ulcerative colitis-specific delivery of keratinocyte growth factor by neutrophils-simulated liposomes facilitates the morphologic and functional recovery of the damaged colon through alleviating the inflammation.

Keratinocyte growth factor (KGF) was effective to treat ulcerative colitis. However, its poor stability and unspecific distribution toward inflamed bowel were two important obstacles hindering its consistent efficacy. Herein, KGF was firstly encapsulated into the liposomes (KGF-Lips) to improve its stability. Thereafter, the neutrophil membrane vesicle (NEM) was extracted from the activated neutrophil which was isolated from the healthy mice and then activated by lipopolysaccharide. Subsequently, NEM was inlaid in KGF-Lips to construct a neutrophil-like liposome (KGF-Neus). KGF was easily encapsulated into KGF-Neus with a high encapsulation efficiency of 95.3 ±â€¯0.72%. Controlling NEM/lipid ratio at 1:50, KGF-Neus displayed the spherical morphology with Dh of 154.8 ±â€¯2.7 nm, PDI of 0.18, and zeta potential of -2.37 ±â€¯0.14 mV. Moreover, KGF-Neus exhibited good stability of Dh and significantly improved the chemical stability of KGF. Owing to NEM-associated proteins, KGF-Neus were specifically internalized by the inflammatory HUVECs. Moreover, KGF-Neus were specifically homed to the inflamed bowel in dextran sulfate sodium-induced mice after intravenous injection, resulting in the effective recovery of the morphology and function of the bowel. The therapeutic mechanisms of KGF-Neus were highly associated with alleviation of inflammation in colitis. Overall, the neutrophil-like liposome may be an excellent carrier for the colitis-targeted delivery of KGF.

Novel multi-drug delivery hydrogel using scar-homing liposomes improves spinal cord injury repair.

Proper selection and effective delivery of combination drugs targeting multiple pathophysiological pathways key to spinal cord injury (SCI) hold promise to address the thus far scarce clinical therapeutics for improving recovery after SCI. In this study, we aim to develop a clinically feasible way for targeted delivery of multiple drugs with different physiochemical properties to the SCI site, detail the underlying mechanism of neural recovery, and detect any synergistic effect related to combination therapy. Methods: Liposomes (LIP) modified with a scar-targeted tetrapeptide (cysteine-alanine-glutamine-lysine, CAQK) were first constructed to simultaneously encapsulate docetaxel (DTX) and brain-derived neurotrophic factor (BDNF) and then were further added into a thermosensitive heparin-modified poloxamer hydrogel (HP) with affinity-bound acidic fibroblast growth factor (aFGF-HP) for local administration into the SCI site (CAQK-LIP-GFs/DTX@HP) in a rat model. In vivo fluorescence imaging was used to examine the specificity of CAQK-LIP-GFs/DTX binding to the injured site. Multiple comprehensive evaluations including biotin dextran amine anterograde tracing and magnetic resonance imaging were used to detect any synergistic effects and the underlying mechanisms of CAQK-LIP-GFs/DTX@HP both in vivo (rat SCI model) and in vitro (primary neuron). Results: The multiple drugs were effectively delivered to the injured site. The combined application of GFs and DTX supported neuro-regeneration by improving neuronal survival and plasticity, rendering a more permissive extracellular matrix environment with improved regeneration potential. In addition, our combination therapy promoted axonal regeneration via moderation of microtubule function and mitochondrial transport along the regenerating axon. Conclusion: This novel multifunctional therapeutic strategy with a scar-homing delivery system may offer promising translational prospects for the clinical treatment of SCI.

Efficient treatment of Parkinson's disease using ultrasonography-guided rhFGF20 proteoliposomes.

Fibroblast growth factor-20 (FGF20) is a paracrine member of the FGF family that is preferentially expressed in the substantia nigra pars compacta (SNpc). Previous studies have demonstrated that FGF20 enhances the survival of dopaminergic neurons suggesting the potential use of FGF20 to treat Parkinson's disease (PD). However, the reduced solubility of the bacterial recombinant human FGF20 (rhFGF20) and the absence of efficient strategies to transport rhFGF20 across the blood-brain barrier (BBB) have halted its clinical application. In the present study, we have examined the efficiency of fuzing a small ubiquitin-related modifier (SUMO) to rhFGF20 to enhance its soluble expression and further investigated the efficacy of FUS-guided, rhFGF20-liposome transport across the BBB. We also examined the bioavailability and behavioral improvement in a 6-hydroxydopamine-lesioned rat model of PD following 2 weeks' FUS-liposomal combinatorial treatment. Our results showed that, in contrast with rhFGF20 or LIP-FGF20, the FUS-LIP-rhFGF20 treatment could significantly improve the apomorphine-induced rotations by protecting against the loss of dopaminergic neurons in the SNpc. Our Results suggest that our combinatorial method would help overcome key challenges that hinder the currently available methods for the use of rhFGF20 in PD treatment.

Ratiometric delivery of two therapeutic candidates with inherently dissimilar physicochemical property through pH-sensitive core-shell nanoparticles targeting the heterogeneous tumor cells of glioma.

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core-shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8 nm and a zeta-potential of -30.5 mV, while its core-shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.

Intrarenal delivery of bFGF-loaded liposome under guiding of ultrasound-targeted microbubble destruction prevent diabetic nephropathy through inhibition of inflammation.

Basic fibroblast growth factor (bFGF) has shown great therapeutic effects for diabetic nephropathy (DN). However, its clinical applications are limited due to its short half-life, low stability and poor penetration. Herein, a bFGF-loaded liposome (bFGF-lip) was constructed and combined with ultrasound-targeted microbubble destruction (UTMD) to overcome these drawbacks. bFGF-lip exhibited spherical morphology with a diameter of 171.1 ± 14.2 nm and a negative zeta potential of -5.15 ± 2.08 mV, exhibiting a sustained-release profile of bFGF. DN rat models were successfully induced by streptozotocin. After treatment with bFGF-lip + UTMD, the concentration of bFGF in kidney of DN rats was significantly enhanced in comparison with free bFGF treatment. Additionally, the morphology and the function of the kidneys were obviously recovered after bFGF-lip + UTMD treatment as shown by ultrasonography and histological analyse. The molecular mechanism was associated with the inhibition of renal inflammation. After treatment with bFGF-lip + UTMD, the activation of NF-κB was obviously reduced in the renal tissues, and downstream inflammatory mediators including TGF-ß1, MCP-1, IL-6 and IL-1ß were also down regulated. In addition, inflammation-induced cellular apoptosis of renal tubular cells was also significantly inhibited by detecting Bax, caspase-3 and Bcl-2. Therefore, bFGF-lip in combination with UTMD might be a potential strategy to reverse the progression of early DN.

CoQ10-loaded liposomes combined with UTMD prevented early nephropathy of diabetic rats.

Nephropathy is one of the most severe complications of diabetic patients. The therapeutic strategies for diabetic patients should not only focus on the control of blood glucose but also pay attention to the occurrence of diabetic nephropathy (DN). Coenzyme Q10 (CoQ10) has great therapeutic potential for DN. However, the clinical application of CoQ10 has been limited because of its low water-solubility and non-specific distribution. Liposomes were supposed to be an effective way for delivering CoQ10 to kidney. CoQ10 was effectively encapsulated into the liposome (CoQ10-LIP) with a high entrapment efficiency of 86.15 %. The CoQ10-LIP exhibited a small hydrodynamic diameter (180 ± 2.1 nm) and negative zeta potential (-18.20 mV). Moreover, CoQ10-LIP was combined with ultrasound-mediated microbubble destruction (UTMD) to enhance specific distribution of CoQ10 in kidney. In early stage of diabetic mellitus (DM), rats were administrated with CoQ10-LIP followed by UTMD (CoQ10-LIP+UTMD) to prevent occurrence of DN. Results revealed that CoQ10-LIP+UTMD effectively prevented the renal morphology and function of diabetics rats from damage. The protective mechanism of CoQ10-LIP was highly associated with protecting podocyte, promoting vascular repair and inhibiting cell apoptosis. Conclusively, CoQ10-LIP in combination with UTMD might be a potential strategy to prevent occurrence of DN.

Glioma-Targeted Delivery of a Theranostic Liposome Integrated with Quantum Dots, Superparamagnetic Iron Oxide, and Cilengitide for Dual-Imaging Guiding Cancer Surgery.

Herein, a theranostic liposome (QSC-Lip) integrated with superparamagnetic iron oxide nanoparticles (SPIONs) and quantum dots (QDs) and cilengitide (CGT) into one platform is constructed to target glioma under magnetic targeting (MT) for guiding surgical resection of glioma. Transmission electron microscopy and X-ray photoelectron spectroscopy confirm the complete coencapsulation of SPIONs and QDs in liposome. Besides, CGT is also effectively encapsulated into the liposome with an encapsulation efficiency of ∼88.9%. QSC-Lip exhibits a diameter of 100 ± 1.24 nm, zeta potential of -17.10 ± 0.11 mV, and good stability in several mediums. Moreover, each cargo shows a biphasic release pattern from QSC-Lip, a rapid initial release within initial 10 h followed by a sustained release. Cellular uptake of QSC-Lip is significantly enhanced by C6 cells under MT. In vivo dual-imaging studies show that QSC-Lip not only produces an obvious negative-contrast enhancement effect on glioma by magnetic resonance imaging but also makes tumor emitting fluorescence under MT. The dual-imaging of QSC-Lip guides the accurate resection of glioma by surgery. Besides, CGT is also specifically distributed to glioma after administration of QSC-Lip under MT, resulting in an effective inhibition of tumors. The integrated liposome may be a potential carrier for theranostics of tumor.