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Granzyme B (GrB)-based immunotherapy is of interest for cancer treatment. However, insufficient cellular uptake and a lack of targeting remain challenges to make use of GrB for solid tumour therapy. As GrB induced cell death requires the help of perforin (PFN), we designed a system (nGPM) for the co-delivery of GrB and PFN. Therefore, GrB and PFN were loaded in a porous polymeric nanocapsule rich in acetylcholine analogues and matrix metalloproteinase-2 (MMP-2) responsive peptides. The neutrally charged nGPM nanocapsules showed as long circulating time and accumulated at the tumour sites. Once in the tumour the outside shell of nanocapsules became degraded by overexpressed MMP-2 proteases, resulting in the release of GrB and PFN. We found that the PFN complex formed small pores on the surface of tumour cells which allow GrB to enter the cytoplasm of tumour cells inducing cell apoptosis and tumour suppression significantly. [Display omitted] [ABSTRACT FROM AUTHOR]

To develop a PEGylated and CD44-targeted liposomes, enabled by surface coating with hyaluronic acid (HA) via amide bond to improve the efficacy of imatinib mesylate (IM), for tumor-targeted cytoplasmic drug delivery. HA was covalently grafted on DSPE-PEG2000-NH2 polymer. HA-modified or unmodified PEGylated liposomes were prepared with ethanol injection method, and the stability, drug release, and cytotoxicity of these liposomes were studied. Meanwhile, intracellular drug delivery efficiency, antitumor efficacy, and pharmacokinetics were also investigated. Ex vivo fluorescence biodistribution was also detected by small animal imaging. In addition, endocytosis mechanism was also explored HA-coated PEGylated liposomes (137.5 nm ± 10.24) had a negative zeta potential (−29.3 mV ± 5.44) and high drug loading (27.8%, w/w). The liposomes were stable with cumulative drug leakage (<60%) under physiological conditions. Blank liposomes were nontoxic to Gist882 cells, and IM-loaded liposomes had higher cytotoxicity to Gist882 cells. HA-modified PEGylated liposomes were internalized more effectively than non-HA coating via CD44-mediated endocytosis. Besides, the cellular uptake of HA-modified liposomes also partly depends on caveolin-medicated endocytosis and micropinocytosis. In rats, both liposomes produced a prolonged half-life of IM (HA/Lp/IM: 14.97h; Lp/IM: 11.15h) by 3- to 4.5-folds compared with the IM solution (3.61h). HA-decorated PEGylated liposomes encapsulated IM exhibited strong inhibitory effect on tumor growth in Gist882 cell-bearing nude mice and formation of 2D/3D tumor spheroids. The Ki67 immunohistochemistry result was consistent with the above results. IM-loaded PEGylated liposomes modified with HA exerted the excellent anti-tumor effect on tumor-bearing mice and more drugs accumulated into the tumor site. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • ginsenoside Rg3 can substitute cholesterol and PEG for liposomes preparation. • Rg3 liposomes exhibits long circulation comparable to PEGylated liposomes. • Rg3 liposomes show stealth property without accelerated blood clearance phenomenon. [ABSTRACT FROM AUTHOR]

Liposomes are the predominant drug delivery system widely used in the pharmaceutical industry, but rapid clearance and endosome degradation are the main barriers to improve the delivery efficiency of liposomes, especially for protein or genes. Simulating viral membrane fusion peptides, four asymmetrically dihydrophobic chain polyethylene glycol (PEG) lipids with long circulating and membrane fusion properties have been designed and synthesized with a high yield. The structure of synthetic PEG lipids is characterized by 1H NMR and mass spectrometry. The critical micelle concentrations of PEG lipids are lower by one or two orders of magnitude compared with traditional surfactants such as SDBS or SDS, which show excellent self‐assembly performance of lipids. The size and morphology of liposomes constituted with neutral lipid DOPC and PEG lipid are characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In the conditions of 50% ethanol and 5–25 mmol L−1 Ca2+, the PEG neutral lipid complexes encapsulated pEGFP are almost neutral with a diameter below 300 nm. [ABSTRACT FROM AUTHOR]

Successful hepatocellular carcinoma (HCC) therapy in vivo remains a significant challenge due to the down-regulated expression of the receptors on the surface of tumor cells for compromised active targeting efficiency and cellular uptake of nanoparticles (NPs)-based drug delivery systems (DDSs) and "accelerated blood clearance" and premature unpackaging of NPs in vivo induced by the poly(ethylene glycol)ylation (PEGylation). Inspired by the repeatedly highlighted prolonged blood circulation property of RBCm-camouflaged NPs, we hypothesis that the prolonged blood circulation property resulting from RBCm coating outperforms the active targeting mechanisms of various targeting ligands for enhanced HCC therapy in vivo. Clarification of this hypothesis is therefore of great significance and urgency to break the afore mentioned bottlenecks that hamper the efficient HCC treatment in vivo. For this purpose, we reported in this study the first identification of a determining factor of nanocarriers for enhanced HCC therapy in vivo by the use of the previously fabricated pectin-doxorubicin nanoparticles (PDC-NPs) as a typical example, i.e., the natural RBCm was used as a stealth coating of PDC-NPs for the fabrication of biomimetic DDSs, PDC@RBC-NPs via hypotonic dialysis and mechanical co-extrusion methods. Comprehensive in vitro and in vivo evaluation and comparison of the properties and performance of PDC@RBC-NPs and PDC-NPs were performed in terms of colloidal stability, biosafety, drug release profiles, macrophage escape, anti-HCC effect. The resulting PDC@RBC-NPs outperformed PDC-NPs for HCC therapy in vitro and in vivo. Notably, PDC@RBC-NPs-treated BALB/c nude mice showed a significantly smaller final average tumor volume of 613 mm3 after 16 days than the PDC-NPs-treated group with an average value of 957 mm3. Therefore, the PDC@RBC-NPs developed herein showed great potential for clinical transformations due to the facile preparation and superior therapeutic efficiency against HCC. Most importantly, prolonged blood circulation was identified as a determining factor of nanocarriers instead of active targeting for enhanced HCC therapy in vivo, which could be used to direct the future design and development of advanced DDSs with greater therapeutic efficiency for HCC. [Display omitted] • Biomimetic PDC@RBC-NPs were fabricated by using RBCm as a stealth coating of PDC-NPs. • PDC@RBC-NPs outperformed PDC-NPs for enhanced HCC therapy in vitro and in vivo. • Prolonged blood circulation outperforms active targeting for enhanced HCC in vivo. • The obtained conclusion could promote the generation of DDSs for enhanced HCC therapy. [ABSTRACT FROM AUTHOR]

Liposomes are highly advantageous platforms for drug delivery. To improve the colloidal stability and avoid rapid uptake by the mononuclear phagocytic system of conventional liposomes while controlling the release of encapsulated agents, modification of liposomes with well-designed polymers to modulate the physiological, particularly the interfacial properties of the drug carriers, has been intensively investigated. Briefly, polymers are incorporated into liposomes mainly using "grafting" or "coating", defined according to the configuration of polymers at the surface. Polymer-modified liposomes preserve the advantages of liposomes as drug-delivery carriers and possess specific functionality from the polymers, such as long circulation, precise targeting, and stimulus-responsiveness, thereby resulting in improved pharmacokinetics, biodistribution, toxicity, and therapeutic efficacy. In this review, we summarize the progress in polymer-modified liposomes for drug delivery, focusing on the change in physiological properties of liposomes and factors influencing the overall therapeutic efficacy. [ABSTRACT FROM AUTHOR]

To utilize the multiple functions and give full play of ginsenosides, a variety of ginsenosides with different structures were prepared into liposomes and evaluated for their effect on the stability, pharmacokinetics and tumor targeting capability of liposomes. The results showed that the position and number of glycosyl groups of ginsenosides have significant effect on the in vitro and in vivo properties of their liposomes. The pharmacokinetics of ginsenosides liposomes indicated that the C-3 sugar group of ginsenosides is beneficial to their liposomes for longer circulation in vivo. The C-3 and C-6 glycosyls can enhance the uptake of their liposomes by 4T1 cells, and the glycosyls at C-3 position can enhance the tumor active targeting ability significantly, based on the specific binding capacity to Glut 1 expressed on the surface of 4T1 cells. According to the results in the study, ginsenoside Rg3 and ginsenoside Rh2 are potential for exploiting novel liposomes because of their cholesterol substitution, long blood circulation and tumor targeting capabilities. The results provide a theoretical basis for further development of ginsenoside based liposome delivery systems. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ferroptosis could effectively kill cancer cells because of their high-loaded reactive oxygen species (ROS), metabolic mutations, and increased requirement for an iron supply. • Ferric metal–organic frameworks (Fe-MOFs) function as nanoplatforms to co-deliver iron ions and a ferroptosis inducer, atorvastatin (ATV), to cancer cells. • The glutathione (GSH)-degradable zwitterionic polymer membrane (PMPC) coated on the surface endowed Fe-MOFs with enhanced stability and long circulation time. • When internalized by cancer cells, these nanoparticles were degraded by GSH, to deplete GSH and release ATV and Fe2+. • The ferroptosis mechanism of this nanoplatform was elucidated. Ferroptosis inhibits tumor growth by iron-dependently accumulating lipid peroxides (LPO) to a lethal extent, which can result from iron overload and glutathione peroxidase 4 (GPX4) inactivation. In this study, we developed biodegradable zwitterionic polymer-cloaked atorvastatin (ATV)-loaded ferric metal–organic frameworks (Fe-MOFs) for cancer treatment. Fe-MOFs served as nanoplatforms to co-deliver ferrous ions and ATV to cancer cells; the zwitterionic polymer membrane extended the circulation time of the nanoparticles and increased their accumulation at tumor sites. In cancer cells, the structure of the Fe-MOFs collapsed in the presence of glutathione (GSH), leading to the depletion of GSH and the release of ATV and Fe2+. The released ATV decreased mevalonate biosynthesis and GSH, resulting in GPX4 attenuation. A large number of reactive oxygen species were generated by the Fe2+-triggered Fenton reaction. This synergistic effect ultimately contributed to a lethal accumulation of LPO, causing cancer cell death. The findings both in vitro and in vivo suggested that this ferroptosis-inducing nanoplatform exhibited enhanced anticancer efficacy and preferable biocompatibility, which could provide a feasible strategy for anticancer therapy. [ABSTRACT FROM AUTHOR]

Minimizing the interaction of nanomedicines with the mononuclear phagocytic system (MPS) is a critical challenge for their clinical translation. Conjugating polyethylene glycol (PEG) to nanomedicines is regarded as an effective approach to reducing the sequestration of nanomedicines by the MPS. However, recent concerns about the immunogenicity of PEG highlight the demand of alternative low‐fouling polymers as innovative coating materials for nanoparticles. Herein, a highly hydrophilic sulfoxide‐containing polymer—poly(2‐(methylsulfinyl)ethyl acrylate) (PMSEA)—is used for the surface coating of iron oxide nanoparticles (IONPs). It is found that the PMSEA polymer coated IONPs have a more hydrophilic surface than their PEGylated counterparts, and demonstrate remarkably reduced macrophage cellular uptake and much less association with human plasma proteins. In vivo study of biodistribution and pharmacokinetics further reveals a much‐extended blood circulation (≈2.5 times longer in terms of elimination half‐life t1/2) and reduced accumulation (approximately two times less) in the organs such as the liver and spleen for IONPs coated by PMSEA than those by PEG. It is envisaged that the highly hydrophilic sulfoxide‐containing polymers have huge potential to be employed as an advantageous alternative to PEG for the surface functionalization of a variety of nanoparticles for long circulation and improved delivery. [ABSTRACT FROM AUTHOR]

Highlights: Soft mesoporous organosilica nanoplatforms modified with hyaluronic acid and cyanine 5.5 are constructed. Therapeutic efficacy of the soft nanoplatforms on tumor is higher both in vitro and in vivo after loading photosensitizer chlorin e6 compared to that of stiff counterparts.To date, the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration. Herein, a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared, denoted SMONs-HA-Cy5.5, and comparative studies between SMONs-HA-Cy5.5 (24.2 MPa) and stiff counterparts (79.2 MPa) are conducted. Results indicate that, apart from exhibiting a twofold increase in tumor cellular uptake, the soft nanoplatforms also display a remarkable pharmacokinetic advantage, resulting in considerably improved tumor accumulation. Moreover, SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration, achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts. Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels, diffuse farther in the dense extracellular matrix, and reach deeper tumor tissues compared to the stiff ones. Specifically, the soft nanoplatforms generate a 16-fold improvement (43 vs. 2.72 μm) in diffusion distance in tumor parenchyma. Based on the significantly improved blood circulation and tumor accumulation/penetration, a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5. The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones. [ABSTRACT FROM AUTHOR]

Abstract Aims This study aims to develop and evaluate oleuropein loaded surface functionalized folate-targeted – PEG liposomes for the effective management of prostate cancer in an animal model. Materials and methods Film hydration-cum-extrusion technique was used to produce liposomes. Particle size, entrapment efficiency, drug loading, electron microscopy, and drug release study were performed for the characterization. Cell viability and various in vitro studies (phosphatidylserine internalization, TUNEL assay, measurement of mitochondrial membrane potential and caspase-3 assay) were performed to compare the anticancer and apoptotic effects of developed liposomes against the plain oleuropein. Comparative pharmacokinetic profiling and anticancer efficacy studies including a change in tumor volume, body weight, and survival analysis were performed in mice model. Key findings The developed liposomes (OL-FML) showed the particle size of 184.2 ± 9.16 nm, the zeta potential of 1.41 ± 0.24 mV, entrapment efficiency of 63.52 ± 4.15% and drug loading of 21.31 ± 2.37%. OL-FML showed higher in vitro anti-proliferative effect and apoptosis on 22Rv1 cells. In vivo pharmacokinetic study revealed a nearly 6 fold increase in the bioavailability of OL-FML (AUC 0→∞ = 641.78 ± 103.764 μg/mL·hr) as compared to OL solution (AUC 0→∞ = 104.11 ± 18.374 μg/mL·hr) in mice. Increased tumor suppression, weight loss resistance, and survival probability were observed in 22Rv1 induced tumor-bearing mice with OL-FML treatment as compared to OL. Significance The study provides conclusive evidence for the utilization of combining passive and active targeting strategy to enhance the anticancer effect of OL. [ABSTRACT FROM AUTHOR]

Abstract Cell membrane coating has emerged as an intriguing biomimetic strategy to endow nanomaterials with functions and properties inherent to source cells for various biomedical applications. Hybrid membrane of different types of cells could be coated onto nanoparticle surface to achieve additional functions. Herein, we fused red blood cell (RBC) membrane together with MCF-7 cell membrane and fabricated an erythrocyte-cancer (RBC-M) hybrid membrane-camouflaged melanin nanoparticle (Melanin@RBC-M) platform for enhancing therapeutic efficacy of photothermal therapy (PTT). The fused RBC-M hybrid membrane vesicles retained both RBC and MCF-7 cell membrane proteins and the resultant Melanin@RBC-M exhibited prolonged blood circulation and homotypic targeting to source MCF-7 cells simultaneously. Interestingly, increasing MCF-7 membrane components in RBC-M significantly enhanced the homotypic targeting function of Melanin@RBC-M while increasing RBC membrane components in RBC-M effectively reduced the cellular uptake of Melanin@RBC-M by macrophages and improved their circulation time in the blood. After intravenous injection into MCF-7 tumor-bearing athymic nude mice, Melanin@RBC-M with 1:1 membrane protein weight ratio of RBC to MCF-7 exhibited significantly higher tumor accumulation and better PTT efficacy compared with other Melanin@RBC-M with different membrane protein weight ratios as well as pristine melanin nanoparticles, due to the optimal balance between prolonged blood circulation and homotypic targeting. In addition, in vitro photoacoustic results revealed that Melanin@RBC-M had a photoacoustic signal enhancement with the increase of nanoparticle size (64 → 148 nm) and the photoacoustic amplitudes increased linearly with nanoparticle concentration at the excitation wavelength ranged from 680 nm to 800 nm, which could be used for quantification of Melanin@RBC-M in vivo. Looking forward, coating hybrid membrane onto nanoparticles could add flexibility and controllability in enhancing nanoparticles functionality and offer new opportunities for biomedical applications. [ABSTRACT FROM AUTHOR]

Improving the supply of O 2 and the circulation lifetime of photosensitizers for photodynamic therapy (PDT) in vivo would be a promising approach to eliminate hypoxic tumors. Herein, by taking advantage of the significant gas-adsorption capability of metal-organic frameworks (MOFs), a biomimetic O 2 -evolving photodynamic therapy (PDT) nanoplatform with long circulating properties was fabricated. Zirconium (IV)-based MOF (UiO-66) was used as a vehicle for O 2 storing, then conjugated with indocyanine green (ICG) by coordination reaction, and further coated with red blood cell (RBC) membranes. Upon 808 nm laser irradiation, the initial singlet oxygen ( 1 O 2 ) generated by ICG would decompose RBC membranes. At the same time, The photothermal property of ICG could facilitate the burst release of O 2 from UiO-66. Subsequently, the generated O 2 could significantly improve the PDT effects on hypoxic tumor. Owing to the advantages of long circulation and O 2 self-sufficient, the designed nanotherapeutic agent can improve the efficiency of treatment against hypoxia tumor via PDT. Hence, this study presents a new paradigm for co-delivery of O 2 and photosensitizers, and provides a new avenue to eliminate hypoxic tumors. [ABSTRACT FROM AUTHOR]

As current tumor chemotherapy faces many challenges, it is important to develop drug delivery systems with increased tumor-targeting ability, enhanced therapeutic effects and reduced side effects. In this study, a pH-sensitive liposome was constructed containing CHEMS-anchored PEG2000 for extended circulation and NGR peptide as the targeting moiety. The NGR-modified docetaxel-loaded pH-sensitive extended-circulation liposomes (DTX/NGR-PLL) prepared possess suitable physiochemical properties, including particle size of approximately 200 nm, drug encapsulation efficiency of approximately 70%, and pH-sensitive drug release properties. Experiments performed in vitro and in vivo on human fibrosarcoma cells (HT-1080) and human breast adenocarcinoma cells (MCF-7) verified the specific targeting ability and enhanced antitumor activity to HT-1080 cells. The results of intravenous administration demonstrated that NGR-modified liposomes can significantly and safely accumulate in tumor tissue in xenografted nude mice. In conclusion, the liposomes constructed hold promise as a safe and efficient drug delivery system for specific tumor treatment. [ABSTRACT FROM AUTHOR]

Phospholipids and cholesterols are being spotlighted as raw materials for preparing liposomes, one of the key compounds for drug delivery systems (DDS), and as base compounds for converting water-soluble drugs to fat-soluble drugs. Other applications of phospholipids also are being explored. Nippon Fine Chemical, aware of the future of such lipids, has developed new processes for synthesizing and purifying phospholipids and is supplying them on an industrial scale. These products – used worldwide – are highly regarded as raw materials for preparing liposomes. In particular, Nippon Fine Chemical’s innovative research led to the development of “Presome®”, a base agent that facilitates the preparation of liposome solutions. To further this research, Nippon Fine Chemical has established an “Advanced Lipid Technology”. [ABSTRACT FROM AUTHOR]

Among a broad spectrum of medical treatments, protein therapeutics holds tremendous opportunities for the treatment of metabolic disorders, cancer, autoimmune diseases and etc. Broad adaption of protein therapeutics, however, still remain challenging, not only because of poor protein stability, but they also experience fast clearance after administrated and elicit immune responses, resulting in undesirable biodistribution and short blood residence time. In this study, we demonstrate a novel protein delivery method via encapsulating therapeutic proteins within thin shells of poly( N -vinylpyrrolidone) (PVP), which leads to significantly improved protein stability, reduced macrophage uptake, prolonged circulation time and reduced immunogenicity. Exemplified with urate oxidase (UOx), the enzyme used for hyperuricemia treatment, as-formed UOx nanocapsules, n(UOx), exhibits enhanced stability, more significant therapeutic effects, and a more than 10-fold improvement in circulation time when compared with native UOx. This technology not only demonstrates the use of UOx nanocapsules for hyperuricemia management, but also provides a general approach for a broad spectrum of therapeutic proteins for in vivo applications. [ABSTRACT FROM AUTHOR]

Polysarcosine (PS), a non-ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural α-amino acid, has been used to stabilize gold nanoparticles (AuNPs) due to its excellent hydrophilicity and biocompatibility. Disulfide functionalized polysarcosines with different molecular weight were synthesized and used to cap AuNPs by traditional ligand exchange. The grafting of PS on AuNPs was evidenced by Fourier transform infrared (FTIR) spectroscopy and the alternation of surface zeta potential. The polysarcosine coated AuNPs (Au@PS) showed good stabilities in wide pH range and saline condition. They had strong resistance to ligand competition of dithiothreitol (DTT). They showed good stability in serum, with a molecular weight dependent interaction pattern with proteins. The Au@PS had very low cytotoxicity and cell uptake in vitro . Based on the results in vitro , polysarcosine with molecular weight of 5 kD with the best ability to stabilize AuNPs was used for in vivo test. The Au@PS had a longer circulation time in blood after intravenous injection than that of Au@PEG, indicating a better stealth-like property of polysarcosine. The Au@PS did not cause obvious toxicity in vivo , suggesting potential applications in disease diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Context: Baicalin has many pharmacological activities, including protective function against myocardial ischemia by antioxidant effects and free radical scavenging activity. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy. Objective: Novel baicalin-loaded PEGylated nanostructured lipid carriers (BN-PEG-NLC) were developed to improve bioavailability of BN, to prolong retention timein vivoand to enhance its protective effect. Methods: In this study, BN-PEG-NLC were prepared by the emulsion-evaporation and low temperature-solidification method using a mixture of glycerol monostearate and polyethylene glycol monostearate as solid lipids, and oleic acid as the liquid lipid. The physicochemical properties of NLC were characterized. The pharmacokinetic and pharmacodynamic behaviors of BN-PEG-NLC or BN-NLC were evaluated in acute MI rats. Results and discussion: The particle size, zeta potential, and entrapment efficiency for BN-PEG-NLC were observed as 83.9 nm, −32.1 mV, and 83.5%, respectively. The release profiles of BN from both BN-PEG-NLC and BN-NLC were fitted to the Ritger–Peppas modal, which presented burst release initially and prolonged release afterwards. Pharmacokinetics results indicated that BN-PEG-NLC exhibited a 7.2-fold increase in AUC in comparison to BN solution, while a 3-fold increase in comparison to BN-NLC. Biodistribution results revealed that BN-PEG-NLC exhibited higher heart drug concentration compared with BN-NLC as well as BN solution. In the present study, BN-PEG-NLC significantly ameliorated infarct size. Conclusion: The results of the present study imply that PEG-NLC could be the biocompatible carriers for heart-targeted drug delivery to improve myocardial ischemia. [ABSTRACT FROM AUTHOR]

Nanotherapeutics have been investigated for years, but only modest survival benefits were observed clinic. This is partially attributed to the short and rapid elimination of nanodrug after intravenous administration. In this study, a long circulation single wall carbon nanotube (SWCNT) complex was successfully fabricated through a new SWCNT dispersion agent, evans blue (EB). The complex was endowed with fluorescent imaging and photodynamic therapy ability by self-assembly loading an albumin coupled fluorescent photosensitizer, Chlorin e6 (Ce6) via the high affinity between EB and albumin. The yielding multifunctional albumin/Ce6 loaded EB/carbon nanotube-based delivery system, named ACEC, is capable of providing fluorescent and photoacoustic imaging of tumors for optimizing therapeutic time window. Synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) were carried out as guided by imaging results at 24 h post-injection and achieved an efficient tumor ablation effect. Compared to PDT or PTT alone, the combined phototherapy managed to damage tumor and diminish tumor without recurrence. Overall, our study presents a SWCNT based theranostic system with great promising in dual modalities imaging guided PTT/PDT combined treatment of tumor. The applications of EB on SWCNT functionalization can be easily extended to the other nanomaterials for improving their in vivo stability and circulation time. [ABSTRACT FROM AUTHOR]

Star-branched amphiphilic copolymer nanocarriers with high-density zwitterionic shell show great promise in drug delivery due to their controllable small size and excellent anti-biofouling properties. This gives the hydrophobic cargo with high stability and long blood circulation in vivo . In the present study, star-branched polylactic acid and poly(2-methacryloyloxyethyl phosphorylcholine) copolymers with (AB 3 ) 3 –type architecture (PLA- b -PMPC 3 ) 3 were conceived as drug vectors, and the copolymers were synthesized by an “arm-first” approach via the combination of ring opening polymerization (ROP), atom transfer radical polymerization (ATRP) and the click reaction. The self-assembled star-branched copolymer micelles (sCPM) had an average diameter of about 64.5 nm and exhibited an ultra-hydrophilic surface with an ultralow water contact angle of about 12.7°, which efficiently suppressed the adhesion of serum proteins. In vivo experiments showed that the sCPM loading strongly enhanced the blood circulation time of DiI and the plasma half-life of DiI in sCPM was 19.3 h. The relative accumulation concentration in tumor of DiI delivered by sCPM was 2.37-fold higher than that of PLA-PEG, at 4 h after intravenous injection. These results demonstrated that the star-branched copolymer (PLA- b -PMPC 3 ) 3 is a promising alternative carrier material for intravenous delivery versus classic PEG-modified strategies. [ABSTRACT FROM AUTHOR]

Limited blood circulation and poor tumor penetration are two main obstacles hampering the clinical translation of conventional nanosized drug delivery systems (NDDS). Here, red-blood-cell (RBC)-mimetic nanoparticles (NPs) with long circulation and peptide-enhanced tumor penetration for treating metastatic breast cancer are reported. The RBC-mimetic NPs are composed of a paclitaxel (PTX)-loaded polymeric core and a hydrophilic RBC vesicle shell. The RBC-mimetic NPs display dramatically elongated blood circulation with an elimination half time of 32.8 h, 5.8-fold higher than that of the parental polymeric NPs (i.e., 5.6 h). Moreover, the experimental results demonstrate that the tumor penetration ability of the RBC-mimetic NPs can be significantly improved by coadministrating with a tumor-penetrating peptide iRGD. Antitumor studies using a metastatic 4T1 breast tumor model show that RBC-mimetic NPs in combination with iRGD significantly inhibit over 90% of the tumor growth and suppress 95% of the lung metastasis, much more efficient than PTX-loaded polymer NP alone or the combination of polymer NPs and iRGD. The results reveal the importance of both long circulation and tumor penetration of nanosized drugs for efficient cancer therapy, which can provide a new insight for NDDS design. [ABSTRACT FROM AUTHOR]

While ursolic acid (UA), one of the most broadly known triterpene compounds, has proved to be effective in cancer therapy, the applications of UA is limited due to its poor aqueous solubility and low bioavailability. The aim of our study was to prolong circulation time and enhance uptake of liposomes in tumor tissues through the modification of UA liposomes via water-soluble polyethylene glycol (PEG). In addition, this research also focuses on physicochemical properties of the liposome formulations, including encapsulation efficiency, particle morphology, size, stability, release rate in vitro and cytotoxicity test. The obtained liposomes were spherical particles with mean particle diameters around 100–200 nm. And the Fourier transform infrared spectroscopy (FTIR) indicated that PEG had been anchored successfully to the liposomes. Based on our experimental data achieved, PEG-modified UA liposomes possessed higher stability than conventional liposomes, and the release rate of UA from PEG-modified liposomes was slower when compared with those of UA solution and conventional liposomes. Meanwhile, the liposomal UA showed relatively low cytotoxic effect than UA conventional liposomes within 24 h, which was consistent with their release rates. [ABSTRACT FROM AUTHOR]

The study was aimed to evaluate the antitumor potential of the Ala-Pro-Arg-Pro-Gly (APRPG)-modified angiogenic vessel targeting drug delivery system using paclitaxel (PTX) as a model drug. In this study, an angiogenesis homing peptide APRPG was conjugated to the amphipathic copolymer PLGA–PEG and the synthesized copolymer APRPG–PEG–PLGA was used to prepare PTX encapsulated micelles (APRPG–PEG-Mic). The micelles were uniform spherical and exhibited a unimodal particle size distribution and a slight negative zeta-potential. The in vitro drug release result demonstrated a significant sustained release property of APRPG–PEG-Mic. Compared to Taxol ® and Cont-PEG-Mic, APRPG–PEG-Mic showed a stronger cytotoxicity against two cancerous cell lines. In the cell uptake studies, the APRPG-modified micelles enhanced intracellular fluorescent intensity in EA.hy926 cells. The biodistribution study revealed the accumulation of APRPG–PEG-Mic in tumor tissues as a result of passive accumulation and active targeting. In comparison with Taxol ® and Cont-PEG-Mic, APRPG–PEG-Mic reduced the tumor volume more significantly and prolonged the survival time of tumor-bearing mice, indicating a higher antitumor efficacy and lower systematic side effects of APRPG–PEG-Mic. The results indicated that APRPG-modified micelles could be an efficient target-delivery method to angiogenic vessels and a highly promising therapeutic system in anticancer therapy. [ABSTRACT FROM AUTHOR]

Highlights: [•] Emulsion–evaporation and low temperature-solidification method was used to prepare nanostructured lipid carriers. [•] High drug loading and sustained release were achieved by nanostructured lipid carriers. [•] Long circulation was realized by the modification of PEG. [•] Drug residence time in vivo was extended and the bioavailability of Amoitone B was enhanced by long circulating nanostructured lipid carriers. [Copyright &y& Elsevier]

[Display omitted] Targeting delivery and prolonging action duration of artemisinin drugs are effective strategies for improving antimalarial treatment outcomes. Here, dihydroartemisinin (DHA) loaded poly (lactic- co -glycolic acid) (PLGA) nanoparticles (PDNs) were prepared and further cloaked with red blood cell (RBC) membranes via electrostatic interactions to yield RBC membrane-cloaked PDNs (RPDNs). The prepared RPDNs displayed a notable "core-shell" structure, with a negative surface charge of −29.2 ± 4.19 mV, a relatively uniform size distribution (86.4 ± 2.54 nm, polydispersity index of 0.179 ± 0.011), an average encapsulation efficiency (70.1 ± 0.79%), and a 24-h sustained-release behavior in vitro. Compared with PDNs, RPDNs showed markedly decreased phagocytic activity by RAW 264.7 cells and had prolonged blood circulation duration. The Pearson correlation coefficient of RPDNs distribution in infected red blood cells (iRBCs) was 0.7173, suggesting that RPDNs could effectively target Plasmodium -iRBCs. In Py By265-infected mice, RPDNs showed a higher inhibition ratio (88.39 ± 2.69%) than PDNs (83.13 ± 2.12%) or DHA (58.74 ± 3.78%), at the same dose of 8.8 μmol/kg. The ED 90 of RPDNs (8.13 ± 0.18 μmol/kg) was substantially lower than that of PDNs (14.48 ± 0.23 μmol/kg) and DHA (17.67 ± 3.38 μmol/kg). Furthermore, no apparent abnormalities were detected in routine blood examination, liver function indexes, and pathological analysis of tissue sections of Py By265-infected mice following RPDNs treatment. In conclusion, the prepared RPDNs exhibited enhanced antimalarial efficacy, prolonged circulation, targeted delivery to Plasmodium -iRBCs, and satisfactory biocompatibility. [ABSTRACT FROM AUTHOR]

Abstract: The non-specific interaction between nanoparticles (NPs) and plasma proteins occurs immediately after NPs enter the blood, resulting in the formation of the protein corona that thereafter replaces the original NPs and becomes what the organs and cells really see. Consequently, the in vivo fate of NPs and the biological responses to the NPs are changed. This is one substantial reason for the two main problems of the NPs based drug delivery system, i.e. nanotoxicity and rapid clearance of NPs from the blood after intravenous injection. Here, we demonstrate the successful application of the preformed albumin corona in inhibiting the plasma proteins adsorption and decreasing the complement activation, and ultimately in prolonging the blood circulation time and reducing the toxicity of the polymeric PHBHHx NPs. Since the interaction of proteins with various nano-materials and/or -particles is ubiquitous, pre-forming albumin corona has a great potential to be a versatile strategy for optimizing the NPs based drug delivery system. [Copyright &y& Elsevier]

Abstract: The clinical application of salvianolic acid B (Sal B), a potential therapeutic agent for cardiovascular diseases isolated from Salvia miltiorrhiza, is greatly restricted by its short half-life and low bioavailability. To improve therapeutic effects and prolong the systemic circulation time of Sal B, liposomes, composed of soybean phosphatidylcholine and cholesterol were prepared by reverse-phase evaporation method. In addition, polyethylene glycol 2000-disteroylphosphoethanolamine (PEG-DSPE 2000) was included to give steric barrier to liposomes. A central composite design was employed to optimize liposomal formulation with high encapsulation efficiency and small particle size. Physicochemical characteristics such as particle size, zeta potential, encapsulation efficiency and in vitro release were investigated. In vivo pharmacokinetic properties of Sal B in beagle dogs and the effect of PEG on the blood circulation time of Sal B-loaded liposomes were also evaluated. An optimized formulation with encapsulation efficiency of 73.68% and mean particle size of 136.6nm were developed. Encapsulation of Sal B into conventional and PEGylated liposomes could prolong the half-life of Sal B by 5.8- and 17.5-fold and enhance the AUC0-t of Sal B by 6.7- and 13.3-fold compared with free Sal B, respectively. Therefore, the use of PEGylated liposomes could prolong the circulation time in blood and longevity effect of liposomes on Sal B was increased by PEG. [Copyright &y& Elsevier]

Polymeric surfaces in contact with blood in vivo are foreign bodies and are quickly isolated from blood by the non-specific defense systems. Nanoparticles (NP) used as drug carriers are normally quickly taken up by phagocytes and sequestered in liver and spleen to which they can deliver drugs. Long-circulating and/or low complement activating core-shell NPs can be obtained from PEO/PEG amphiphilic copolymers forming brush or loops on the surface. Core-shell NPs can also be obtained from polysaccharidic graft or block amphiphilic copolymers. Complement activation by the NPs and protein adsorption both depend on the structure, nature and molecular weight of the polysaccharide chains composing the shell. NPs showing low complement activation can be obtained if the polysaccharide on the surface is long and in a brush configuration. Fragile molecules such as hemoglobin or siRNA can be loaded and protected by appropriate brush shells without modifying the low complement activation properties. [ABSTRACT FROM AUTHOR]

Abstract: In liposomal drug delivery, polyethylene glycol (PEG) modification is known to prolong the circulation time of liposomes in the blood stream, and hence, this method has been employed for liposomes in clinical use. To achieve effective prolongation of liposomal circulation time using PEG-modification, it is of importance to control not only the average amount of PEG chains incorporated in the liposomes but also the deviation in PEG amount among PEG-modified liposomes (PEGylated liposomes). Therefore, evaluation of PEG-modification is essential for the quality control of PEGylated liposomes. In this study, we developed a novel method to estimate PEG-modification for PEGylated liposomes using chromatography with an anion-exchange column. We applied this method to liposomes with varying PEG-lipid contents and found that the chromatography could successfully separate PEGylated liposomes on the basis of the PEG-lipid content of their liposome membranes. Results demonstrate that the established method can be potentially used to control the quality of PEGylated liposomes not only for research and but also for manufacturing processes. [Copyright &y& Elsevier]

Abstract: A multifunctional mixed micelle was assembled for drug targeting delivery by combining two newly synthesized amphiphilic polymers, which were octreotide-polyethylene glycol-monostearate (OPMS) and N-octyl-N-succinyl-O-carboxymethyl chitosan (OSCC), respectively. The mixed micelle was designed to be characterized with long circulation, somatostatin receptors (SSTR)-mediated endocytosis and pH sensitivity. A series of assembling proportions of OPMS and OSCC was tested to reveal the effect of compositions on the functions. The particle size, zeta potential, drug loading and critical micelle concentration were examined. The dialysis test indicated a pH-triggering release behavior of the doxorubicin-loaded mixed micelle (DLMM), and faster release in acidic media (pH 4.0–6.0) in response to the protonation of carboxyl group. In addition, the PEG segments could efficiently protect the mixed micelle from plasma protein adsorption in vitro, and the DLMM composed of 20% OPMS and 80% OSCC provided the longest residence time after intravenous injection in rats in vivo. Due to SSTR mediated endocytosis, the significantly higher uptake of DLMM was observed in the tumor cells (SMMC-7721), compared with that in the normal cells (CHO) without SSTR expression. All the results suggested that the mixed micelle with multifunctional characteristics could be used as an effective approach for tumor treatment. [Copyright &y& Elsevier]

Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocyte-mimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization. [ABSTRACT FROM AUTHOR]

Abstract: We examined the effect on drug delivery of liposomes with surfaces that were modified with branched oligoglycerols (BGLs) and explored possible formulation advantages to increase drug exposure. BGL012 is a branched oligoglycerol derivative with a cascade-like structure of 12 glycerol units, characterized as a widely spread structure in aqueous solution. We prepared BGL-phospholipid derivatives (BGL-PEs), including BGL012, by coupling 1,2-distearoylphosphatidylethanolamine to BGLs. BGL012-PE modification of the liposomes (BGL012L) achieved a long circulation time after intravenous injection in rats. The circulation lifetime of BGL012L was almost the same as that of polyethylene glycol (PEG)-modified liposomes. The surface of BGL012L induced the formation of a fixed aqueous layer and reduced protein adsorption on the liposome surface, without strong interference with the binding reaction on the liposome. Thus, the newly synthesized branched oligoglycerol derivatives are considered to have useful hydrophilic and physical properties for modifying the liposome surface to increase drug exposure. [Copyright &y& Elsevier]

Abstract: A polymeric micelle drug carrier system was applied to the targeting of an MRI (magnetic resonance imaging) contrast agent. A block copolymer, PEG-b-poly(L-lysine), was used for conjugation of gadolinium ions through chelating moieties, DOTA. The DOTA moieties were successfully conjugated to all primary amine groups of the lysine residues. The obtained block copolymer, PEG-b-poly(L-lysine-DOTA), formed a polymeric micelle. The polymeric micelle structure was maintained even after partial gadolinium chelation (∼40%) to the DOTA moieties. The prepared polymeric micelle MRI contrast agent was injected into a mouse tail vein at a dose of 0.05 mmol Gd/kg. The polymeric micelle-based MRI contrast agent exhibited stable blood circulation. A considerable amount (6.1±0.3% of ID/g of the polymeric micelle) was found to accumulate at solid tumors 24 h after intravenous injection by means of the EPR effect. An MRI analysis revealed that the signal intensity of the tumor was enhanced 2.0-fold by the use of this contrast agent. [Copyright &y& Elsevier]

Cisplatin is a widely used anticancer drug for various solid tumors. However, the serious adverse effects caused by systemic distribution limit its wide use. In this study, we intend to use biocompatible materials polyethyleneimine (PEI) and poly(L -glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-PEG) to construct nanoparticles to enhance the efficacy of cisplatin and reduce its side effects. The micelle-like nanoparticles were fabricated by a simple two-step method, with a core consisting of PEI and cisplatin and a PLG-g-mPEG coating layer. The obtained nanoparticles have a small particle size (41.79 nm) and high drug loading (16.43%). The coated nanoparticles (NP-II) strengthened the structure of PEI and cisplatin complex (NP-I) and slowed the drug release for less than 20% at pH 7.4 PBS in 24 h. Therefore, it could effectively inhibit the binding of free drug and plasma proteins to achieve the long circulation, and the bioavailability could be increased to about 600% and 285% of cisplatin solution and NP-I respectively. Besides, the cellular uptake of NP-II was enhanced in the acidic tumor microenvironment due to the detachment of coating layer and the increase of positive zeta potential of nanoparticles, which was benefit to reduce the side effect of cisplatin to normal cells. In vivo pharmacodynamic experiments also showed that NP-II improved the efficacy and reduced side effects compared to the cisplatin solution. In conclusion, the two-step fabricating micelle-like nanoparticles with the improved therapeutic efficiency and reduced side effects show great potential for cancer chemotherapy. [Display omitted] • Fabricate the stable micelle-like nanoparticles which coated by polymer material. • Coated nanoparticles have the characteristics of acid-sensitive charge enhancement and accelerated the drug release. • Coated nanoparticles can prolong drug circulation time in the body and increase AUC about 600% than drug solution. • Coated nanoparticles enhanced antitumor efficacy with less system toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Novel series of one-ended monooleate-modified poly(ethylene glycol) with active carboxylic terminal were synthesized by two steps of chemical modification of poly(ethylene glycol) by esterification, one with succinic anhydride to obtain active carboxylic terminal, and the other with oleic acid to obtain sufficiently hydrophobic terminal. The associative polymers were characterized by IR and 1H NMR, their molecular weights were measured by gel permeation chromatography (GPC). The results showed that the synthesis procedure allows us to reach total grafting. The electron microscopy images, associative behaviour of the polymers in aqueous solution and their abilities to prolong the circulation time of emulsion in mice were also investigated. [Copyright &y& Elsevier]

Surface-modified nanoparticles have received much attention as drug carriers. Natural and synthetic polymers are used as the materials to prepare nanoparticles and the properties of these nanoparticles originate with these polymeric materials. In particular, these nanoparticles are modified for specific objectives. The surface characteristics of (shell) nanoparticles are more important than those of the core, because the shell layer directly contacts body fluids and organs. Generally, the nanoparticles are coated with hydrophilic polymer to give long circulation and/or are conjugated with functional ligands or proteins for site-specific delivery. In this review, the preparative methods and the applications of surface modification of polymeric functionalized nanoparticles for long-circulation, site-specific delivery, and oral delivery are discussed. [ABSTRACT FROM AUTHOR]

Poly(ethylene glycol) (PEG) as a key role can significantly affect the bio-application of imaging sensors or drugs. In this study, iridium (Ir) complexes decorated with PEG chain from 600 Da to 4000 Da were synthesized. Four amphiphilic Ir-based molecules could self-assemble to form micellar nanoparticles (IP600 NPs−IP4000 NPs). TEM results revealed that the size decreased from 76 to 34 nm with the increased PEG length, and the micellar stability increased with longer PEG length. The longer blood circulation time of IP2000 NPs and IP4000 NPs could be ascribed to the decreased serum protein adsorption in theoretically and experimentally. Fluorescence imaging study further exhibited selective tumor accumulation enhancement. Cell fluorescence imaging results revealed that cellular uptake decreased with the PEG length increase. Take multi-factors into consideration, PEG (2000 Da) is suitable for decorating a small molecule. Photodynamic therapy study also exhibited that IP2000 NPs qualified higher therapeutic effect. Biosafety study uncovered the excellent biocompatibility of IP2000 and IP4000 NPs. Our study not only proved that 2000 Da PEG is suitable for the PEGylation of small molecules to fabricate micellar nanoparticles but also supplied a self-assembled strategy for constructing a metabolizable fluorescence-imaging nano-sensors and drug delivery system. Image 1 • A general method for the fabrication of size-adjustable nano micelles. • PEGylated small molecules exhibit remarkable colloidal stability and blood circulation characteristics. • Iridium-based nano-micelles exhibit enhanced tumor fluorescence imaging and photodynamic therapy properties. [ABSTRACT FROM AUTHOR]

Long blood circulation is the basic requirement of advanced drug delivery systems for tumor treatment, which leads to enhanced tumor therapeutic efficiency and reduced side effects. However, the pharmacokinetics of the current nanoparticles in vivo is still unsatisfactory, which leads to limited success to translate nanoparticles into clinical applications. Inspired by the natural cell membrane-coating strategy, a series of zwitterionic polymer membranes are firstly developed and coated onto different kinds of nanoparticles in this work. Intriguingly, the zwitterionic polymer membrane shows stronger protein adsorption resistance and reduced macrophage uptake compared with the corresponding zwitterionic polymer brush or the red blood cell (RBC) membrane, which results in longer blood circulation time and higher tumor accumulation of the coated nanoparticles. Combined with the photothermal effect of model nanoparticles, Fe 3 O 4 , zwitterionic polymer membrane-coated Fe 3 O 4 shows enhanced photothermal therapy (PTT) efficacy on A549 tumors compared with the corresponding zwitterionic polymer brush or RBC membrane-coated Fe 3 O 4. Notably, Fe 3 O 4 coated by carboxybetaine-based biomimic membranes exhibits the ultra-long blood circulation (t 1/2 = 96.0 h) and strongest PTT efficacy compared with those coated by phosphorylcholine-based or sulfobetaine-based biomimic membranes. In addition, the zwitterionic biomimic membrane exhibits rapid glutathione-triggered degradation with the products of low molecular weight (<2000 g mol−1). Therefore, the biodegradable zwitterionic biomimic membrane coating offers a universal platform for the design and application of long-circulating biomedical nanoparticles, which may pave the way for the clinical applications of biomedical nanoparticles in tumor therapy. [ABSTRACT FROM AUTHOR]

Highlights: Soft mesoporous organosilica nanoplatforms modified with hyaluronic acid and cyanine 5.5 are constructed. Therapeutic efficacy of the soft nanoplatforms on tumor is higher both in vitro and in vivo after loading photosensitizer chlorin e6 compared to that of stiff counterparts. To date, the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration. Herein, a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared, denoted SMONs-HA-Cy5.5, and comparative studies between SMONs-HA-Cy5.5 (24.2 MPa) and stiff counterparts (79.2 MPa) are conducted. Results indicate that, apart from exhibiting a twofold increase in tumor cellular uptake, the soft nanoplatforms also display a remarkable pharmacokinetic advantage, resulting in considerably improved tumor accumulation. Moreover, SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration, achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts. Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels, diffuse farther in the dense extracellular matrix, and reach deeper tumor tissues compared to the stiff ones. Specifically, the soft nanoplatforms generate a 16-fold improvement (43 vs. 2.72 μm) in diffusion distance in tumor parenchyma. Based on the significantly improved blood circulation and tumor accumulation/penetration, a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5. The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones. [ABSTRACT FROM AUTHOR]

Due to the non-targeted release of anti-cancer agent gamabufotalin (CS-6), conventional chemotherapy using this drug can cause serious side effects, which accordingly result in poor therapeutic efficiency. Recently, the development of smart nanodrug systems has attracted more and more attention due to their significant advantages of high loading efficiency, controllable release behavior and targeted accumulation at tumor sites. In this study, a nanodrug system named as HA@RBC@PB@CS-6 NPs (HRPC) was constructed. In this system, Prussian blue nanoparticles (PB NPs) with hollow porous structure were used as the carrier for CS-6 and photothermal sensitizer simultaneously. The result indicated that the encapsulation of erythrocyte membrane on the PB NPs prolonged the blood circulation life to 10 h and improved the immune evasion ability for more than 60%, as well, which is beneficial for the targeting molecule (HA) to achieve high concentration accumulation of HRPCs at tumor sites. Moreover, we also disclosed that loading drug of CS-6 performed its ultra-strong anti-tumor function partly through markedly suppressing the expression of HSP70, which conversely amplified the efficiency of photothermal therapy. The in vivo study demonstrated the outstanding performance of HRPC in synergistic photothermal/chemotherapy of cancer without side effect to normal tissues. [ABSTRACT FROM AUTHOR]