Blood Circulation Time Research Articles

Liposomes with Water as a pH‐Responsive Functionality for Targeting of Acidic Tumor and Infection Sites

AbstractA lipid named DCPA was synthesized under microwave‐assisted heating. DCPA possesses a pyridine betaine, hydrophilic group that can be complexed with water through hydrogen bonding (DCPA‐H2O). DCPA‐H2O liposomes became protonated relatively fast already at pH<6.8, due to the high HOMO binding energy of DCPA‐H2O. In murine models, DCPA‐H2O liposomes had longer blood circulation times than natural DPPC or cationic DCPM liposomes, while after tail‐vein injection DCPA‐H2O liposomes targeted faster to solid tumors and intra‐abdominal infectious biofilms. Therapeutic efficacy in a murine, infected wound‐healing model of tail‐vein injected ciprofloxacin‐loaded DCPA‐H2O liposomes exceeded the ones of clinically applied ciprofloxacin as well as of ciprofloxacin‐loaded DPPC or DCPM liposomes.

Pharmacokinetics, Biodistribution, and Biosafety of PEGylated Gold Nanoparticles In Vivo

Despite the obvious advantages of gold nanoparticles for biomedical applications, controversial and incomplete toxicological data hamper their widespread use. Here, we present the results from an in vivo toxicity study using gold nanoparticles coated with polyethylene glycol (PEG-AuNPs). The pharmacokinetics and biodistribution of PEG-AuNPs were examined in the rat’s liver, lung, spleen, and kidney after a single i.v. injection (0.7 mg/kg) at different time intervals. PEG-AuNPs had a relatively long blood circulation time and accumulated primarily in the liver and spleen, where they remained for up to 28 days after administration. Increased cytoplasmic vacuolation in hepatocytes 24 h and 7 days after PEG-AuNPs exposure and apoptotic-like cells in white splenic pulp 24 h after administration has been detected, however, 28 days post-exposure were no longer observed. In contrast, at this time point, we identified significant changes in lipid metabolism, altered levels of liver injury markers, and elevated monocyte count, but without marked biological relevance. In blood cells, no DNA damage was present in any of the studied time intervals, with the exception of DNA breakage transiently detected in primary kidney cells 4 h post-injection. Our results indicate that the tissue accumulation of PEG-AuNPs might result in late toxic effects.

Impact of Poly (Styrene-Acrylic Acid) Latex Nanoparticles on Colorectal and Cervical Cancer Cells.

Polymer nanoparticles are a promising approach for cancer treatment and detection, due to their biocompatibility, biodegradability, targeting capabilities, capacity for drug loading and long blood circulation time. This study aims to evaluate the impact of poly (styrene–acrylic acid) latex particles on colorectal and cervical cancer cells for anti-tumor efficiency. Latex particles were synthesized by a surfactant-free radical emulsion polymerization process and the obtained polymer particles were characterized in terms of size, size distribution, morphology using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and electrokinetic property (i.e., zeta potential). Human colorectal and cervical cancer, and normal cell lines, were then treated with different concentrations of poly (styrene–acrylic acid) latex particles. The cell morphology changes were pointed out using an optical microscope and the nanoparticles’ (NPs) cell cytotoxicity was evaluated using MTT assay. The obtained results showed that poly (styrene–acrylic acid) latex particles are effective against colorectal and cervical cancer cells if treated with an appropriate particle concentration for 48 h. In addition, it showed that normal cells are the least affected by this treatment. This indicates that these NPs are safe as a drug delivery carrier when used at a low concentration.

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective.

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.

Salicylic acid-based nanomedicine with self-immunomodulatory activity facilitates microRNA therapy for metabolic skeletal disorders

Metabolic skeletal disorders remain a major clinical challenge. The complexity of this disease requires a strategy to address the net effects of both inflammation and impaired bone formation. microRNA-based gene therapy provides several therapeutic advantages to tackle these issues. Herein, we describe a microRNA-21 (miR-21) delivery system with an additional therapeutic effect from that of the delivery carrier itself. Poly (salicylic acid) (PSA) is, for the first time, synthesized via polycondensation of salicylic acid (SA), a bioactive ingredient widely used for anti-inflammation in medicine. PSA can self-assemble into nanoparticles (PSA-NPs) and can effectively deliver genes both in vitro and in vivo. The carrier was then attached to repetitive sequences of aspartate, serine, serine (DSS)6 for delivering miRNAs specifically to bone-formation surfaces. In vitro studies showed that miR-21@PSA-NP could effectively realize the intracellular delivery of miR-21 with low toxicity, while in vivo results indicated that the miR-21@PSA-NP-DSS6 prolonged blood circulation time, enhanced bone accumulation, and significantly improved the efficacy of miR-21-based bone anabolic therapy in osteoporotic mice. The constructed delivery system (miR-21@PSA-NP-DSS6) inherited the advantages of both SA and miR-21, which could ameliorate bone-inflamed niche and rescued the impaired bone formation ability. The synergy of anti-inflammatory and pro-osteogenic effects significantly improved trabecular bone microstructure in osteoporotic mice. Statement of significanceThe complexity of metabolic skeletal disorders requires a strategy to address the net effects of both inflammation and impaired bone formation. microRNA-based gene therapy provides several therapeutic advantages to tackle these issues. We develop a novel microRNA-21 delivery system with additional therapeutic effect from that of the gene carrier itself. Poly (salicylic acid) (PSA) nanoparticles, for the first time, synthesized via polycondensation of salicylic acid and can effectively deliver genes both in vitro and in vivo. The constructed delivery system (miR-21@PSA-NP-DSS6) inherited the advantages of both SA (commonly used anti-inflammation drug in medicine) and miR-21 (a pro-osteogenic molecule), which could ameliorate bone-inflamed niche, rescued impaired bone formation ability and significantly improved trabecular bone microstructure in osteoporotic mice.

Multifunctional nanoplatforms as cascade-responsive drug-delivery carriers for effective synergistic chemo-photodynamic cancer treatment

Synergistic chemo-photodynamic therapy has garnered attention in the field of cancer treatment. Here, a pH cascade-responsive micellar nanoplatform with nucleus-targeted ability, for effective synergistic chemo-photodynamic cancer treatment, was fabricated. In this micellar nanoplatform, 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin (Por), a photodynamic therapy (PDT) agent was utilized for carrying the novel anticancer drug GNA002 to construct a hydrophobic core, and cyclic RGD peptide (cRGD)-modified polyethylene glycol (PEG) (cRGD-PEG) connected the cell-penetrating peptide hexaarginine (R6) through a pH-responsive hydrazone bond (cRGD-PEG-N = CH-R6) to serve as a hydrophilic shell for increasing blood circulation time. After passively accumulating in tumor sites, the self-assembled GNA002-loaded nanoparticles were actively internalized into cancer cells via the cRGD ligands. Once phagocytosed by lysosomes, the acidity-triggered detachment of the cRGD-PEG shell led to the formation of R6-coated secondary nanoparticles and subsequent R6-mediated nucleus-targeted drug delivery. Combined with GNA002-induced nucleus-specific chemotherapy, reactive oxygen species produced by Por under 532-nm laser irradiation achieved a potent synergistic chemo-photodynamic cancer treatment. Moreover, our in vitro and in vivo anticancer investigations revealed high cancer-suppression efficacy of this ideal multifunctional nanoplatform, indicating that it could be a promising candidate for synergistic anticancer therapy.

Gemini Cationic Lipid-Type Nanovectors Suitable for the Transfection of Therapeutic Plasmid DNA Encoding for Pro-Inflammatory Cytokine Interleukin-12.

Ample evidence exists on the role of interleukin-12 (IL-12) in the response against many pathogens, as well as on its remarkable antitumor properties. However, the unexpected toxicity and disappointing results in some clinical trials are prompting the design of new strategies and/or vectors for IL-12 delivery. This study was conceived to further endorse the use of gemini cationic lipids (GCLs) in combination with zwitterionic helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphatidyl ethanol amine) as nanovectors for the insertion of plasmid DNA encoding for IL-12 (pCMV-IL12) into cells. Optimal GCL formulations previously reported by us were selected for IL-12-based biophysical experiments. In vitro studies demonstrated efficient pCMV-IL12 transfection by GCLs with comparable or superior cytokine levels than those obtained with commercial control Lipofectamine2000*. Furthermore, the nanovectors did not present significant toxicity, showing high cell viability values. The proteins adsorbed on the nanovector surface were found to be mostly lipoproteins and serum albumin, which are both beneficial to increase the blood circulation time. These outstanding results are accompanied by an initial physicochemical characterization to confirm DNA compaction and protection by the lipid mixture. Although further studies would be necessary, the present GCLs exhibit promising characteristics as candidates for pCMV-IL12 transfection in future in vivo applications.

Bilirubin-based ROS responsive hydrophobicity/hydrophilicity switchable hybrid vector for gene delivery

The insufficient endocytosis and the low expression efficiency of the transfected gene in the lesion are still the main challenge for gene therapy. Herein, a novel bilirubin (BR)-based ROS responsive hydrophobicity/hydrophilicity switchable BR-grafted polylysine (PLL)/DNA nanosystem is designed by condensing indocyanine green (ICG) onto the surface of vector through electrostatic interaction between ICG and PLL, which can prolong the blood circulation time of nanocomplexes, and thus enhance the gene transfection efficiency due to the favorable solubility exchange of BR from hydrophobicity to hydrophilicity under ROS stimulus and the increased roughness of coated ICG. The in vitro and in vivo results demonstrate that the BR-based ROS responsive hydrophobicity/hydrophilicity switchable nanosystem with a rough surface can enhance the endocytosis of the nanoparticles, and consequently facilitate the gene therapy in an inflammatory environment. Our delicate design concept can expand to develop an anti-inflammation nanocarrier for efficient gene therapy in an inflammatory setting.

Prolonged activity of exenatide: Detailed comparison of Site-specific linear polyglycerol- and poly(ethylene glycol)-conjugates

Exenatide is a small therapeutic peptide being currently used in clinic for the treatment of diabetes mellitus type II, however, displaying a short blood circulation time which makes two daily injections necessary. Covalent polymer modification of a protein is a well-known approach to overcome this limitation, resulting in steric shielding, an increased size and therefore a longer circulation half-life. In this study, we employed site-selective C-terminal polymer ligation of exenatide via copper-catalyzed azide-alkyne-cycloaddition (CuAAC) to yield 1:1-conjugates of either poly(ethylene glycol) (PEG) or linear polyglycerol (LPG) of different molecular weights. Our goal was to compare the impact of the two polymers on size, structure and activity of exenatide on the in vitro and in vivo level. Both polymers did not alter the secondary structure of exenatide and expectedly increased its hydrodynamic size, where the LPG-versions of exenatide showed slightly smaller values than their PEG-analogs of same molecular weight. Upon conjugation, GLP-1 receptor activation was diminished, however, still enabled maximum receptor response at slightly higher concentrations. Exenatide modified with a 40 kDa LPG (Ex-40-LPG) showed significant reduction of the blood glucose level in diabetic mice for up to 72 h, which was comparable to its PEG-analog, but 9-fold longer than native exenatide (8 h).

Are third-generation active-targeting nanoformulations definitely the best? In vitro and in vivo comparisons of pixantrone-loaded liposomes modified with different sialic acid derivatives.

Treatment with sialic acid-octadecylamine (SA-ODA)-modified pixantrone (Pix) liposomes results in favorable antitumor effects by targeting tumor-associated macrophages (TAMs). To explore the influence of different types of SA decorations on antitumor efficiency, we synthesized a PEGylated SA derivative, SA-PEG2000-DSPE, and combined it with SA-ODA to construct three representative types of SA-modified liposomes (SA-ODA-modified Pix liposomes, SA-ODA-modified Pix liposomes with different PEG densities, and SA-PEG2000-DSPE-modified Pix liposomes, named Pix-SACL, Pix-SPL-0.2/0.5/2.0/5.0, and Pix-SAPL, respectively). All the Pix liposomes were nanoscale formulations, having diameters between 100 and 150nm, high encapsulation efficiencies (> 90%), and slow drug release properties. The in vivo blood circulation time of the PEGylated formulations (Pix-SPL-0.2/0.5/2.0/5.0 and Pix-SAPL) showed an upward trend with increasing PEG density, but there was no significant difference between adjacent groups. All PEGylated formulations displayed increased tumor accumulation when compared with Pix-SACL, but there was no significant difference among them. However, the antitumor activity of SA-modified liposomes was not positively correlated with circulation time or tumor accumulation in S180-bearing mice. Pix-SPL-0.2 displayed the strongest antitumor effect and lowest toxicity among the formulations tested in this study. With Pix-SPL-0.2 treatment, 66.7% of the mice demonstrated tumor shedding and wound healing.

Nanotheranostics for the Management of Hepatic Ischemia-Reperfusion Injury.

Hepatic ischemia-reperfusion injury (IRI), in which an insufficient oxygen supply followed by reperfusion leads to an inflammatory network and oxidative stress in disease tissue to cause cell death, always occurs after liver transplantations and sections. Although pharmacological treatments favorably prevent or protect the liver against experimental IRI, there have been few successes in clinical applications for patient benefits because of the incomprehension of complicated IRI-induced signaling events as well as short blood circulation time, poor solubility, and severe side reactions of most antioxidants and anti-inflammatory drugs. Nanomaterials can achieve targeted delivery and controllable release of contrast agents and therapeutic drugs in desired hepatic IRI regions for enhanced imaging sensitivity and improved therapeutic effects, emerging as novel alternative approaches for hepatic IRI diagnosis and therapy. In this review, the application of nanotechnology is summarized in the management of hepatic IRI, including nanomaterial-assisted hepatic IRI diagnosis, nanoparticulate systems-mediated remission of reactive oxygen species-induced tissue injury, and nanoparticle-based targeted drug delivery systems for the alleviation of IRI-related inflammation. The current challenges and future perspectives of these nanoenabled strategies for hepatic IRI treatment are also discussed.

Self-Assembly Iron Oxide Nanoclusters for Photothermal-Mediated Synergistic Chemo/Chemodynamic Therapy.

Methods Superparamagnetic iron oxide nanoclusters (SPIOCs) were located within the core, which resulted in high photothermal conversion and outstanding generation of reactive oxygen species (ROS). The shell consisted of a human serum albumin- (HSA-) paclitaxel (PTX) layer, which extended the blood circulation time and ensured the effectiveness of the chemotherapy. Arg-Gly-Asp peptides (RGD) were linked to the naked cysteine moieties in HSA to promote the specific targeting of human glioma U87 cells by αvβ3 integrins. Continuous near-infrared light irradiation triggered and promoted the synergistic chemo/CDT therapy through the photothermal effect. Results Our SPIOCs@HSA-RGD nanoplatform showed well biocompatibility and could target glioma specifically. Photothermal conversion and ROS burst were detected after continuous 808 nm light irradiation, and a significant antitumor effect was achieved. Conclusion Experimental in vitro and in vivo evaluations showed that our photothermal-mediated chemo/CDT therapy could efficiently inhibit tumor growth and is therefore promising for cancer therapy.

Poly(2-ethyl-2-oxazoline) bottlebrushes: How nanomaterial dimensions can influence biological interactions

Biocompatible polymers are crucial components of successful nano-sized carriers, which enable the delivery of otherwise largely ineffective therapeutics. Poly(2-ethyl-2-oxazoline) (PEtOx) is one polymer that has shown potential for this application due to its demonstrated low fouling nature and biocompatibility comparable to the current gold standard carrier, poly(ethylene glycol). PEtOx based bottlebrushes, in particular, are promising therapeutic carriers due to their anisotropic nature, which can be easily fine-tuned. Despite this potential, little is known about the interaction of PEtOx bottlebrushes with biological systems. The present study provides a detailed insight into the cellular interactions and biodistribution of PEtOx bottlebrushes in a mouse model. Three PEtOx bottlebrushes of varied side-chain and backbone lengths were designed to highlight the effect that the degree of polymerisation (DP) of each aspect may have on both cellular interaction and biodistribution. Herein we show that PEtOx bottlebrushes display no adverse effects to either cells or mice over 48 h at doses that would be relevant to drug delivery applications. Furthermore, increasing either the backbone or side-chain length of PEtOx bottlebrushes leads to a reduction in cellular association in vitro and an increase in blood circulation times in vivo. The fact that small changes to the dimensions of the PEtOx bottlebrushes have a marked effect on biodistribution and blood circulation times may prove to be a highly beneficial insight for the design of next-generation PEtOx bottlebrushes nanocarriers with tailor-made profiles dependent on the application required.

Progress in Application of Nanotechnology in Sorafenib.

Dysregulation of the tyrosine kinase signaling pathway is closely related to tumor development, and tyrosine kinase inhibitors are important targets for potential anticancer strategies. In particular, sorafenib, as a representative drug of multitarget tyrosine kinase inhibitors, has an important clinical status and is widely used for treating various solid tumors and diabetic complications. However, poor aqueous solubility of sorafenib, poor bioavailability of commonly used oral dose forms, poor accumulation at tumor sites, and severe off-target effects that tend to induce intolerable systemic side effects in patients have greatly reduced its therapeutic efficiency and limited its extensive clinical application. To improve the properties of sorafenib, increase the efficiency of clinical treatment, and overcome the increasingly prominent phenomenon of sorafenib resistance, multiple investigations have been conducted. Numerous studies have reported that the properties of nanomaterials, such as small particle size, large specific surface area, high surface activity and high adsorption capacity, make nanotechnology promising for the construction of ideal sorafenib nanodelivery systems to achieve timed and targeted delivery of sorafenib to tumors, prolong the blood circulation time of the drug, improve the utilization efficiency of the drug and reduce systemic toxic side effects. This review summarizes the progress of research applications in nanotechnology related to sorafenib, discusses the current problems, and expresses expectations for the prospect of clinical applications of sorafenib with improved performance.

Enhancement of target toxin neutralization effect in vivo by PEGylation of multifunctionalized lipid nanoparticles

Protein–protein (e.g., antibody–antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.

Optimizing the Polymer Cloak for Upconverting Nanoparticles: An Evaluation of Bioactivity and Optical Performance.

The ability of upconversion nanoparticles (UCNPs) to convert low-energy near-infrared (NIR) light into high-energy visible-ultraviolet light has resulted in their development as novel contrast agents for biomedical imaging. However, UCNPs often succumb to poor colloidal stability in aqueous media, which can be conquered by decorating the nanoparticle surface with polymers. The polymer cloak, therefore, plays an instrumental role in ensuring good stability in biological media. This study aims to understand the relationship between the length and grafting density of the polymer shell on the physicochemical and biological properties of these core-shell UCNPs. Poly(ethylene glycol) methyl ether methacrylate block ethylene glycol methacrylate phosphate (PPEGMEMAn-b-PEGMP3) with different numbers of PEGMEMA repeating units (26, 38, and 80) was prepared and attached to the UCNPs via the phosphate ligand of the poly(ethylene glycol methacrylate phosphate) (PEGMP) block at different polymer densities. The in vitro and in vivo protein corona, cellular uptake in two-dimensional (2D) monolayer and three-dimensional (3D) multicellular tumor spheroid (MCTS) models, and in vivo biodistribution in mice were evaluated. Furthermore, the photoluminescence of single-polymer-coated UCNPs was compared in solid state and cancer cells using laser scanning confocal microscopy (LSCM). Our results showed that the bioactivity and luminescence properties are chain length and grafting density dependent. The UCNPs coated with the longest PPEGMEMA chain, grafted at low brush density, were able to reduce the formation of the protein corona in vitro and in vivo, while these UCNPs also showed the brightest upconversion luminescence in the solid state. Moreover, these particular polymer-coated UCNPs showed enhanced cellular uptake, extended in vivo blood circulation time, and more accumulation in the liver, brain, and heart.

Rationalizing Nanodeliverables for Effective L-Asparaginase Delivery in Chemotherapy: Update 2020

L-asparaginase is used as an effective line of treatment for acute lymphoblastic leukemia and lymphoma, however, the high cost for this treatment restricts the wide-scale clinical application. Genetic engineering technology is used to recombinantly express L-asparaginase, with high yield, which reduced the costs of production, and overall therapy. Despite the effectiveness of this therapy, intravenous injection of L-asparaginase has some side effects, such as allergic reactions, immunosuppression, pancreatitis, neurotoxicity, hepatitis, coagulopathy, and failure to produce antibodies. To overcome this limitation, Nano-delivery systems using nanoparticles as the carrier of L-asparaginase is used as a new type of drug carrier delivery system. It can increase the permeability of biofilms, enhance drug efficacy, reduce drug toxicity, change the distribution of drugs in the body, and improve bioavailability. In this review, we summarized the application of a variety of nano-lipid and polymers as protein recombinant drug carrier systems, and these nano-carrier systems facilitate to increase the blood circulation time, reduce side effects, and improve the biocompatibility of L-asparaginase medicine. The review specifically adds value as there is no article available that has attempted to elevate the emerging Nanodeliverables and their significance in delivering L- sparaginase safely by achieving maximum therapeutic efficacy.

Surface loading of nanoparticles on engineered or natural erythrocytes for prolonged circulation time: strategies and applications.

Nano drug-delivery systems (DDS) may significantly improve efficiency and reduce toxicity of loaded drugs, but a few nano-DDS are highly successful in clinical use. Unprotected nanoparticles in blood flow are often quickly cleared, which could limit their circulation time and drug delivery efficiency. Elongating their blood circulation time may improve their delivery efficiency or grant them new therapeutic possibilities. Erythrocytes are abundant endogenous cells in blood and are continuously renewed, with a long life span of 100-120 days. Hence, loading nanoparticles on the surface of erythrocytes to protect the nanoparticles could be highly effective for enhancing their in vivo circulation time. One of the key questions here is how to properly attach nanoparticles on erythrocytes for different purposes and different types of nanoparticles to achieve ideal results. In this review, we describe various methods to attach nanoparticles and drugs to the erythrocyte surface, and discuss the key factors that influence the stability and circulation properties of the erythrocytes-based delivery system in vivo. These data show that using erythrocytes as a host for nanoparticles possesses great potential for further development.

Intelligent nanogels with self-adaptive responsiveness for improved tumor drug delivery and augmented chemotherapy

For cancer nanomedicine, the main goal is to deliver therapeutic agents effectively to solid tumors. Here, we report the unique design of self-adaptive ultrafast charge-reversible chitosan-polypyrrole nanogels (CH-PPy NGs) for enhanced tumor delivery and augmented chemotherapy. CH was first grafted with PPy to form CH-PPy polymers that were used to form CH-PPy NGs through glutaraldehyde cross-linking via a miniemulsion method. The CH-PPy NGs could be finely treated with an alkaline solution to generate ultrafast charge-reversible CH-PPy–OH–4 NGs (R-NGs) with a negative charge at a physiological pH and a positive charge at a slightly acidic pH. The R-NGs display good cytocompatibility, excellent protein resistance, and high doxorubicin (DOX) loading efficiency. Encouragingly, the prepared R-NGs/DOX have prolonged blood circulation time, enhanced tumor accumulation, penetration and tumor cell uptake due to their self-adaptive charge switching to be positively charged, and responsive drug delivery for augmented chemotherapy of ovarian carcinoma in vivo. Notably, the tumor accumulation of R-NGs/DOX (around 4.7%) is much higher than the average tumor accumulation of other nanocarriers (less than 1%) reported elsewhere. The developed self-adaptive PPy-grafted CH NGs represent one of the advanced designs of nanomedicine that could be used for augmented antitumor therapy with low side effects.

The Protein Corona Leads to Deformation of Spherical Micelles

AbstractThe formation of a non‐specific protein corona around nanoparticles (NPs) has been identified as one of the culprits for failed nanomedicine. The amount and type of adsorbed protein from the blood plasma are known to determine the fate of NPs and the accessibility of targeting ligands. Herein, we show that the adsorbed protein may not only enlarge the NPs and change their surface properties but also, in the case of soft NPs such as polymer micelles, lead to deformation. Poly(1‐O‐methacryloyl ‐β‐D‐fructopyranose)‐b‐poly(methylmethacrylate) (P(1‐O‐MAFru)‐b‐PMMA) block co‐polymers were self‐assembled into NPs with a spherical core–shell morphology as determined by small angle neutron scattering (SANS). Upon incubation with albumin, TEM, SANS, and small angle X‐ray scattering (SAXS) revealed the adsorption of albumin and deformation of the NPs with a spheroid geometry. Removal of the protein led to the reversal of the morphology back to the spherical core–shell structure. Structural studies and cell studies of uptake of the NPs imply that the observed deformation may influence blood circulation time and cell uptake.