Macromolecular Carriers Research Articles

Chlorogenic Acid-Cucurbit[n]uril Nanocomplex Delivery System: Synthesis and Evaluations for Potential Applications in Osteoporosis Medication.

Based on nanomedicine strategies, this study employed cucurbit[7]uril (Q[7]) as the macromolecular carrier to synthesize nanocomplex drug delivery system for chlorogenic acid (CGA). The nanocomplex drug delivery system is intended to overcome the unsatisfactory biocompatibility and bioavailability of CGA and realizing its potential role in long-term osteoporosis (OP) medication. The nanocomplex was synthesized by the reflux stirring method. The chemical structure of the nanocomplex was characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction analysis (XRD), UV-visible spectrophotometry (UV-vis), zeta potential analysis and transmission electronic microscope (TEM). The Cell Counting Kit-8 (CCK-8) assay, Live/Dead staining assay, and cytoskeleton staining were conducted to testify the biocompatibility of the nanocomplex. The release assay, Ferric Reducing Ability of Plasma (Frap) assay and Reactive oxygen species (ROS) staining were implemented to evaluate the release profile of CGA as well as its remaining antioxidative levels. CGA and Q[7] formed hydrogen bonding through an exclusion interaction, with the binding ratio more than 1:1. The nanocomplex had a crystalline and spherical-like structure and improved thermal stability. The nanocomplex demonstrated better biocompatibility than free CGA. The release profile of CGA from the nanocomplex was much steadier, and 70% of CGA was released in 5 days. The CGA released from the nanocomplex maintained its antioxidative properties at high levels and effectively eliminated the accumulated ROS in MC3T3-E1 cells under oxidative stress. Q[7] has been demonstrated to be an ideal nanocarrier for CGA and the nanocomplex delivery system holds the potential for the long-term medication strategy of OP.

Specific anti-toxic immunotherapy: use in medical practice and perspectives

The results of use of approaches and means of antitoxic immunotherapy in medical practice are summarized: passive transfer of various variants of antibodies specific to toxic compounds, vaccination – specific active immunization with vaccines carrying determinants of the immunochemical specificity of target toxic compounds. The practical effectiveness of the known approaches of passive transfer and vaccination is associated with the ability of specific antibodies, by binding target bioactive compounds with pronounced toxicity, to change the availability of corresponding structures in the body-targets and, in the presence of a sufficient number of specific antibodies with high binding ability to the target compounds, neutralize their toxicity. In medical practice, polyspecific heterologous antisera or the gamma globulin fraction of antisera (extremely rare monoclonal antibodies of narrow specificity) are widely used for passive transfer as antidotes in the treatment of victims in order to prevent deaths and extensive necrosis of soft tissues at the site of the bite of poisonous snakes and insects. Active immunization – vaccination with appropriate antigenic drugs should create in immunized individuals a state of humoral immunity with the corresponding characteristics of antibody formation specific to the target compound. When a target toxic compound enters an immunized organism, it is also possible to neutralize its toxicity. The most successful experience in using the principles of active immunization as a technology for specific antitoxic therapy is associated with the practice of using toxoids for toxinemic infections. Specific practical techniques used to achieve the effectiveness of possible approaches to specific antitoxic immunotherapy in the form of passive transfer of specific antibodies or their fragments are considered: to combat lethal infections in the pathogenesis of which the toxic effects of bacterial exotoxins are significant; when treating victims of snake and insect bites, exposure to poisons of marine organisms, algae and plant toxins; in the treatment of severe intoxication with certain low molecular weight toxic substances: digoxin, colchicine, tricyclic antidepressants. The most successful experiences of using the principles of active immunization as a technology for specific antitoxic therapy, based on the use of toxoids with specificity for diphtheria, tetanus, botulism, cholera, typhoid fever, dysentery, gas gangrene and other toxinemic infections, are also considered. The fairly high immunogenicity of toxoids with the possibility of activating both constitutional and adaptive immunity has become the basis for their use as macromolecular carriers of hapten analogues of narcotic substances – a promising direction in drug addiction, in the implementation of which a number of experimental molecular and combined vaccines of opiates, methamphetamine, cocaine, and nicotine. This variant of practical efforts in medicine can be regarded as a new direction of specific antitoxic immunotherapy – an option to combat drug addiction by vaccinating drug addicts.

Influence of nanopesticide surface chemistry on adsorption to plant cuticle and wax layer: The role of zeta potential and wetting

Nanopesticidal adsorption on plant surfaces is a critical determinant of their application efficacy, persistence, and ecological impact. In this study, we systematically investigate the impact of surface chemistry on the attachment of nanopesticides for seven different nanocarriers: ethyl lauroyl arginate (ELA, cationic), cocamidopropyl betaine (CAPB, zwitterionic), tween 80 (TW80, nonionic), β-cyclodextrin (βCD), sodium dodecyl sulfate (SDS, anionic), whey protein isolate (WPI), and poloxamer 407 (PXL, nonionic). Azadirachtin from neem seed extract was employed as a model pesticide active ingredient. The nanopesticides were characterized using dynamic light scattering, UV–visible spectroscopy, static contact angle (SCA, θ), and zeta (ζ) potential measurements. Pepper leaves (ζ = −11.6 mV) and candelilla wax (ζ = −2.6 mV) films were utilized to analyze the effect of nanocarrier chemical composition on nanopesticide adsorption. Fluorescence microscopy was utilized to quantify the adsorption of nanopesticides (with fluorophore tagging) on the substrates. It was found that the choice of nanocarrier significantly influenced the adsorption behavior. Nanopesticides with ELA corona, which was cationic with a zeta potential of ∼+19 mV and θ of ∼ 61°, exhibited the highest affinity towards the leaf cuticle and wax substrates, attributed to favorable electrostatic interactions forces. Conversely, nanopesticides with SDS (ζ = −48 mV; θ = 45°), WPI (ζ = −24 mV; θ = 54°), and PXL (ζ = −31 mV; θ = 64°) corona demonstrated the least adsorption. These findings indicate a weak correlation between the wetting behavior of nanopesticide suspensions and nanopesticide adsorption on plant and wax surfaces, as well as a strong correlation between nanopesticide zeta potential and nanopesticide adsorption. These findings heuristically recommend that aqueous cationic and zwitterionic nanocarriers for pesticides provide superior adsorption characteristics on pepper leaves and candelilla wax surfaces. Aqueous macromolecular carriers such as PXL and WPI have performed less effectively in adherence compared to shorter chain amphiphiles with similar zeta potential and wetting characteristics, indicating that the steric and osmotic chain effects of hydrophilic macromolecules hinder the adsorption relative to shorter chains.

Synthesis and Structure Optimization of Star Copolymers as Tunable Macromolecular Carriers for Minimal Immunogen Vaccine Delivery.

Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.

Preparation of novel sulfated polysaccharide-carboxymethyl-5-fluorouracil-folic acid conjugates for targeted anticancer drug delivery

GFP1, a sulfated polysaccharide extracted from Grateloupia filicina, exhibits remarkable immunomodulatory activity. To reduce the side effects of 5-fluorouracil (5-FU), GFP1 was employed as a macromolecular carrier to synthesize of GFP1-C-5-FU by reacting with carboxymethyl-5-fluorouracil (C-5-FU). Subsequently, this new compound was reacted with folic acid (FA) through an ester bond, forming novel conjugates named GFP1-C-5-FU-FA. Nuclear magnetic resonance analysis confirmed the formation of GFP1-C-5-FU-FA. In vitro drug release studies revealed that the cumulative release rate of C-5-FU reached 46.9 % in phosphate buffer (pH 7.4) after 96 h, a rate significantly higher than that of the control groups, indicating the controlled drug release behavior of GFP1-C-5-FU-FA. Additionally, in vitro anticancer assays demonstrated the potent anticancer activity of GFP1-C-5-FU-FA conjugates, as evidenced by the reduced viability of HeLa and AGS cancer cells, along with increased levels of apoptosis and cellular uptake. Western blot analysis indicated that the GFP1-C-5-FU-FA conjugate effectively enhanced phosphorylation in cancer cells through the NF-kB and MAPK pathways, thereby promoting apoptosis. These findings highlight the potential of folate-targeted conjugates in efficiently treating HeLa and AGS cancer cells in vitro and lay a robust theoretical groundwork for future in vivo anti-cancer research involving these cells.

Nonextractable Polyphenols from Fu Brick Tea Alleviates Ulcerative Colitis by Controlling Colon Microbiota-Targeted Release to Inhibit Intestinal Inflammation in Mice.

This study was designed to elucidate the colon microbiota-targeted release of nonextractable bound polyphenols (NEPs) derived from Fu brick tea and to further identify the possible anti-inflammatory mechanism in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. 1.5% DSS drinking water-induced C57BL/6J mice were fed rodent chow supplemented with or without 8% NEPs or dietary fibers (DFs) for 37 days. The bound p-hydroxybenzoic acid and quercetin in NEPs were liberated up to 590.5 ± 70.6 and 470.5 ± 51.6 mg/g by in vitro human gut microbiota-simulated fermentation, and released into the colon of the mice supplemented with NEPs by 4.4- and 1.5-fold higher than that of the mice supplemented without NEPs, respectively (p < 0.05). Supplementation with NEPs also enhanced the colonic microbiota-dependent production of SCFAs in vitro and in vivo (p < 0.05). Interestingly, Ingestion of NEPs in DSS-induced mice altered the gut microbiota composition, reflected by a dramatic increase in the relative abundance of Dubosiella and Enterorhabdus and a decrease in the relative abundance of Alistipes and Romboutsia (p < 0.05). Consumption of NEPs was demonstrated to be more effective in alleviating colonic inflammation and UC symptoms than DFs alone in DSS-treated mice (p < 0.05), in which the protective effects of NEPs against UC were highly correlated with the reconstruction of the gut microbiome, formation of SCFAs, and release of bound polyphenols. These findings suggest that NEPs as macromolecular carriers exhibit targeted delivery of bound polyphenols into the mouse colon to regulate gut microbiota and alleviate inflammation.

Superfluorinated, Highly Water-Soluble Polyphosphazenes as Potential 19F Magnetic Resonance Imaging (MRI) Contrast Agents.

"Hot spot" 19F magnetic resonance imaging (MRI) has garnered significant attention recently for its ability to image various disease markers quantitatively. Unlike conventional gadolinium-based MRI contrast agents, which rely on proton signal modulation, 19F-MRI's direct detection has a unique advantage in vivo, as the human body exhibits a negligible background 19F-signal. However, existing perfluorocarbon (PFC) or PFC-based contrast materials suffer from several limitations, including low longitudinal relaxation rates and relatively low imaging efficiency. Hence, we designed a macromolecular contrast agent featuring a high number of magnetically equivalent 19F-nuclei in a single macromolecule, adequate fluorine nucleus mobility, and excellent water solubility. This design utilizes superfluorinated polyphosphazene (PPz) polymers as the 19F-source; these are modified with sodium mercaptoethanesulfonate (MESNa) to achieve water solubility exceeding 360 mg/mL, which is a similar solubility to that of sodium chloride. We observed substantial signal enhancement in MRI with these novel macromolecular carriers compared to non-enhanced surroundings and aqueous trifluoroacetic acid (TFA) used as a positive control. In conclusion, these novel water-soluble macromolecular carriers represent a promising platform for future MRI contrast agents.

Advancements in the preparation technology of small molecule artificial antigens and their specific antibodies: a comprehensive review.

Small molecules find extensive application in medicine, food safety, and environmental studies, particularly in biomedicine. Immunoassay technology, leveraging the specific recognition between antigens and antibodies, offers a superior alternative to traditional physical and chemical analysis methods. This approach allows for the rapid and accurate detection of small molecular compounds, owing to its high sensitivity, specificity, and swift analytical capabilities. However, small molecular compounds often struggle to effectively stimulate an immune response due to their low molecular weight, weak antigenicity, and limited antigenic epitopes. To overcome this, coupling small molecule compounds with macromolecular carriers to form complete antigens is typically required to induce specific antibodies in animals. Consequently, the preparation of small-molecule artificial antigens and the production of efficient specific antibodies are crucial for achieving precise immunoassays. This paper reviews recent advancements in small molecule antibody preparation technology, emphasizing the design and synthesis of haptens, the coupling of haptens with carriers, the purification and identification of artificial antigens, and the preparation of specific antibodies. Additionally, it evaluates the current technological shortcomings and limitations while projecting future trends in artificial antigen synthesis and antibody preparation technology.

Macromolecular carrier with long retention and body-temperature triggered nitric oxide release for corneal alkali burn therapy via leptin-related signaling

Corneal injuries, such as alkali burn, are a common ocular trauma worldwide and usually cause corneal opacification and even loss of sight, if without timely treatments. Eye drops have long been regarded as the best media for treating ocular surface diseases. However, their effectiveness was seriously dampened by natural self-cleaning mechanism of the eye. Herein, we designed and prepared polyamino acid-based poly-S-nitrosothiols (PGlu-TEPA-SNAP) as long-acting eye drops to treat corneal alkali burns. The cationic polymeric NO donor demonstrated good retention on the negatively charged surface of cornea without causing obvious biotoxicity. Meanwhile, the polymer can release NO in a temperature-dependent manner, by remaining relatively stable at 4 ℃ and 25 ℃, while rapidly releasing NO at around 35 ℃. In vivo study proved that the eye-drop with proper concentration effectively mitigated alkali-induced corneal damage in mice, via leptin related STAT3/MAPK/AKT signaling pathway. It selectively promoted epithelium regeneration without inducing neovascularization by utilization of the difference in cell sensitivity towards NO. Overall, the combined strategy of temperature-dependent drug release and strong retention of carriers can indeed fasten the healing of damaged cornea. It may serve as an inspiration for future NO or leptin-based work for ocular surface therapy.

Exploring the Potential of siRNA Delivery in Acute Myeloid Leukemia for Therapeutic Silencing.

We investigated the feasibility of using siRNA therapy for acute myeloid leukemia (AML) by developing macromolecular carriers that facilitated intracellular delivery of siRNA. The carriers were derived from low-molecular-weight (<2 kDa) polyethyleneimine (PEI) and modified with a range of aliphatic lipids. We identified linoleic acid and lauric acid-modified PEI as optimal carriers for siRNA delivery to AML cell lines KG1 and KG1a, as well as AML patient-derived mononuclear cells. As they have been proven to be potent targets in the treatment of AML, we examined the silencing of BCL2L12 and survivin and showed how it leads to the decrease in proliferation of KG1 and stem-cell-like KG1a cells. By optimizing the transfection schedule, we were able to enhance the effect of the siRNAs on proliferation over a period of 10 days. We additionally showed that with proper modifications of PEI, other genes, including MAP2K3, CDC20, and SOD-1, could be targeted to decrease the proliferation of AML cells. Our studies demonstrated the versatility of siRNA delivery with modified PEI to elicit an effect in leukemic cells that are difficult to transfect, offering an alternative to conventional drugs for more precise and targeted treatment options.

Polymerizable 2-Propionic-3-methylmaleic Anhydrides as a Macromolecular Carrier Platform for pH-Responsive Immunodrug Delivery.

The design of functional polymers coupled with stimuli-triggered drug release mechanisms is a promising achievement to overcome various biological barriers. pH trigger methods yield significant potential for controlled targeting and release of therapeutics due to their simplicity and relevance, especially upon cell internalization. Here, we introduce reactive polymers that conjugate primary or secondary amines and release potential drugs under acidic conditions. For that purpose, we introduced methacrylamide-based monomers with pendant 2-propionic-3-methylmaleic anhydride groups. Such groups allow the conjugation of primary and secondary amines but are resistant to radical polymerization conditions. We, therefore, polymerized 2-propionic-3-methylmaleic anhydride amide-based methacrylates via reversible addition-fragmentation chain transfer (RAFT) polymerization. Their amine-reactive anhydrides could sequentially be derivatized by primary or secondary amines into hydrophilic polymers. Acidic pH-triggered drug release from the polymeric systems was fine-tuned by comparing different amines. Thereby, the conjugation of primary amines led to the formation of irreversible imide bonds in dimethyl sulfoxide, while secondary amines could quantitatively be released upon acidification. In vitro, this installed pH-responsiveness can contribute to an effective release of conjugated immune stimulatory drugs under endosomal pH conditions. Interestingly, the amine-modified polymers generally showed no toxicity and a high cellular uptake. Furthermore, secondary amine-modified immune stimulatory drugs conjugated to the polymers yielded better receptor activity and immune cell maturation than their primary amine derivatives due to their pH-sensitive drug release mechanism. Consequently, 2-propionic-3-methylmaleic anhydride-based polymers can be considered as a versatile platform for pH-triggered delivery of various (immuno)drugs, thus enabling new strategies in macromolecule-assisted immunotherapy.

Self-Folding Macromolecular Drug Carrier for Cancer Imaging and Therapy.

Nano-sized contrast agents (NCAs) hold potential for highly specific tumor contrast enhancement during magnetic resonance imaging. Given the quantity of contrast agents loaded into a single nano-carrier and the anticipated relaxation effects, the current molecular design approaches its limits. In this study, a novel molecular mechanism to augment the relaxation of NCAs is introduced and demonstrated. NCA formation is driven by the intramolecular self-folding of a single polymer chain that possesses systematically arranged hydrophilic and hydrophobic segments in water. Utilizing this self-folding molecular design, the relaxivity value can be elevated with minimal loading of gadolinium complexes, enabling sharp tumor imaging. Furthermore, the study reveals that this NCA can selectively accumulate into tumor tissues, offering effective anti-tumor results through gadolinium neutron capture therapy. The efficacy and versatility of this self-folding molecular design underscore its promise for cancer diagnosis and treatment.

Colon-Targeted Release of Turmeric Nonextractable Polyphenols and Their Anticolitis Potential via Gut Microbiota-Dependent Alleviation on Intestinal Barrier Dysfunction in Mice.

Solid evidence has emerged supporting the role of nonextractable polyphenols (NEPs) and dietary fibers (DFs) as gut microbiota modulators. This study aims to elucidate gut microbiota-dependent release of turmeric NEPs and examine the possible anti-inflammatory mechanism in the dextran sulfate sodium-induced ulcerative colitis (UC) model. 1.5% DSS drinking water-induced C57BL/6J mice were fed a standard rodent chow supplemented with or without 8% extractable polyphenols (EPs), NEPs, or DFs for 37 days. The bound curcumin, demethoxycurcumin, and bisdemethoxycurcumin in NEPs were released up to 181.5 ± 10.6, 65.2 ± 6.0, and 69.5 ± 7.6 μg/mL by in vitro gut microbiota-simulated fermentation and released into the colon of NEP-supplemented mice by 5.7-, 11.0-, and 7.8-fold higher than pseudo germ-free mice, respectively (p < 0.05). NEPs also enhanced the colonic microbiota-dependent production of short-chain fatty acids in vitro and in vivo (p < 0.05). Interestingly, NEP feeding significantly improved the DSS-caused gut microbiota disorder, epithelial barrier damage, and inflammation of UC mice better than EPs or DFs (p < 0.05). Meanwhile, the pseudo germ-free mice supplemented with NEPs failed to ameliorate UC symptoms. These findings manifest that turmeric NEPs as macromolecular carriers exert the target delivery of polyphenols into the colon for regulating gut microbiota to restore the impaired gut barrier function for alleviation of inflammation.

Designing Site Specificity in the Mechanochemical Cargo Release of Small Molecules.

Mechanical force can trigger the predictable and precise release of small molecules from macromolecular carriers. In this article, based on mechanochemical simulations, we show that norborn-2-en-7-one (NEO), I, and its derivatives can selectively release CO, N2, and SO2 and produce two distinctly different products, A ((3E,5Z,7E)-dimethyl-5,6-diphenyldeca-3,5,7-triene-1,10-diyl bis(2-bromo-2-methylpropanoate)) and B (4',5'-dimethyl-4',5'-dihydro-[1,1':2',1''-terphenyl]-3',6'-diyl)bis(ethane-2,1-diyl) bis(2-bromo-2-methylpropanoate). Site-specific design in the pulling points (PP) ensures that by changing the regioselectivity, either A or B can be exclusively generated. Controlling the rigidity of the NEO scaffold by replacing a 6-membered ring with an 8-membered ring and concomitantly tuning the pulling groups makes it mechanolabile toward the selective formation of B. The diradical intermediate formed during I → A is predicted to be persistent for ∼150 fs. The structural design holds the key to the trade-off between mechanochemical rigidity and lability.

Preparation, characterization, antioxidant and antianemia activities of Poria cocos polysaccharide iron (III) complex

As a new natural antioxidant with high safety and non-toxic side effects, polysaccharide can also be used as a critical macromolecular carrier to form a stable iron complex with Fe3+. Our previous study has extracted and purified the homogeneous polysaccharide (PCP1C) from Poria cocos. In this study, the PCP1C-iron (III) complex was synthesized by co-thermal synthesis with PCP1C and ferric trichloride. The chelating capacity, iron releasing capacity, and qualitative identification of complex were evaluated. The complex was characterized by scanning electron microscope-energy dispersive spectrometer (SEM-EDS) analysis, particle size distribution, and fourier transform infrared (FTIR) spectroscopy. The antioxidant and iron supplement effects of the complex were also studied in vitro and in the iron deficiency anemia (IDA) rat model. The results showed that the iron content in the PCP1C-iron (III) complex was 28.14% with no free iron, and the iron release rate was 95.3%. The structure analysis showed that the iron core of the PCP1C-iron (III) complex existed in the form of β-FeOOH and the surface of the complex become smooth and particle size increased, which indicated the high iron content of polysaccharide iron and slow release. Furthermore, we found that the PCP1C iron (III) complex had positive scavenging effect on DPPH, ABTS, MDA, and hydroxyl radical in vitro study and significantly increased the levels of red blood cell (RBC), Hemoglobin (Hb), and red blood cell specific volume (HCT) in IDA rat model. Therefore, our results suggested that the PCP1C-iron (III) complex is expected to develop into a new comprehensive iron supplement and antioxidant.

Targeted drug delivery strategy: a bridge to the therapy of diabetic kidney disease

Diabetic kidney disease (DKD) is the main complication in diabetes mellitus (DM) and the main cause of end-stage kidney disease worldwide. However, sodium glucose cotransporter 2 (SGLT2) inhibition, glucagon-like peptide-1 (GLP-1) receptor agonist, mineralocorticoid receptor antagonists and endothelin receptor A inhibition have yielded promising effects in DKD, a great part of patients inevitably continue to progress to uremia. Newly effective therapeutic options are urgently needed to postpone DKD progression. Recently, accumulating evidence suggests that targeted drug delivery strategies, such as macromolecular carriers, nanoparticles, liposomes and so on, can enhance the drug efficacy and reduce the undesired side effects, which will be a milestone treatment in the management of DKD. The aim of this article is to summarize the current knowledge of targeted drug delivery strategies and select the optimal renal targeting strategy to provide new therapies for DKD.

A novel sulfated mannan-carboxymethyl-5-fluorouracil-folic acid conjugates for targeted anticancer drug delivery

CFP2 is a sulfated polysaccharide isolated from Codium fragile that shows excellent immunomodulatory activity. To reduce the side effects of 5-fluorouracil (5-FU), CFP2 was used as a macromolecular carrier to react with carboxymethyl-5-fluorouracil (C-5-FU) to form CFP2-C-5-FU, which further reacted with folic acid (FA) via an ester bond to form novel conjugates (CFP2-C-5-FU-FA). CFP2-C-5-FU-FA was confirmed by nuclear magnetic resonance (NMR) analysis. In vitro drug release results showed that the cumulative release rate of C-5-FU was 49.9% in phosphate buffer (pH 7.4) after 96 h, which was much higher than that of the other groups, indicating that CFP2-C-5-FU-FA showed controlled drug release behavior. CFP2-C-5-FU-FA also exhibited enhanced apoptosis and cellular uptake in vitro. Further, intravenous administration of CFP2-C-5-FU-FA in an HCT-116 cell-bearing xenograft mouse showed that the conjugates were safe and effective drug delivery systems. These results suggest that folate-targeted conjugates can be used effectively for efficient chemotherapy of colorectal cancer.

Synthesis and characterization of photo-responsive azobenzene side-chain liquid crystalline polystyrenes with a mesogenic phase of wide temperature range

Polystyrenes (PSs) that provide photochemical stability are commonly used as the chromophore macromolecular carriers. Herein, PS-based alternating copolymers, i.e., alt-P(D-SiH/Ip), alt-P(D-2SiH/Ip) and alt-P(D-SiH/St), are synthesized through anionically copolymerized Si–H functionalized 1,1-diphenylethylene (DPE-SiH/2SiH) with isoprene (Ip)/styrene (St). Anionically polymerized (4-vinylphenyl)-dimethyl-silane is used as the uniform hydrosilylated PS, i.e., Uni.-P(St-SiH). A series of photo-responsive azobenzene side-chain liquid crystalline PSs combine the above PS-based main chains and the mesogenic moiety composed of azobenzene (Azo) and cholesterol (Chol) groups, i.e., Azo-Chol (M), via the hydrosilylation. The polarized optical microscopic (POM) morphologies and thermal properties of Azo-Chol (M) and Azo-Chol-PSs are studied. As desired, they produce the cholesteric phase of wide temperature range due to the PSs and Chol-groups. Moreover, the photo-responsive behavior irradiated under UV-light of different wavelengths are quantitatively evaluated by time-dependent UV–Vis spectroscopy. Azo-Chol-PSs undergo rapid and reversible trans-cis isomerization under the alternating irradiation of UV and visible light. The trans-to-cis isomerization efficiency under 365 nm UV-light is over that under 290–320 nm UV-light, while over 80% of cis-to-trans efficiency can be realized under 400–500 nm Vis-light irradiation This work would provide guidelines for the effective design of photo-responsive anisotropic materials.

Synthesis and characterization of a macromolecular magnetic resonance imaging and delivery system with hyaluronic acid as a carrier

Using hyaluronic acid (HA) as macromolecular drug carriers, a glutathione-responsive imaging drug delivery system HA-SS-a-Gd-DOTA was formed by conjugating gadolinium chelates and cytarabine. This system exhibited T1-reflexivity (21.9 mmol−1 L s−1, 0.5 T) that was higher than that of gadoterate meglumine. In an acidic environment, in vitro drug release reached 63.4% in 24 h. Low cytotoxicity indicated that this system has good biocompatibility. In vivo mouse imaging studies showed that tumor signaling was significantly enhanced. About 58% of the signal enhancement was obtained 50 min after injection of the drug. The degradation of the hyaluronic acid macromolecular chains in vivo makes it an ideal tumor imaging diagnostic agent because it did not cause damage to important organs of the mice.

Passive Macromolecular Translocation Mechanism through Lipid Membranes.

The translocation of biologically active macromolecules through cell membranes is of vital importance for cells and is a key process for drug delivery. Proteins exploit specific conformational changes in their secondary structure to facilitate membrane translocation. For the large class of biological and synthetic macromolecules, where such conformational adaptions are not possible, guidelines to tailor the structure of monomers and macromolecules to aid membrane translocation and cross-membrane drug delivery would be highly desirable. Here, we use alternating amphiphilic macromolecules to systematically investigate the relation between polarity, polymer chain length, lipid chain length, polymer concentration, and temperature on membrane partition and translocation rate. We employed pulse field gradient NMR and confocal fluorescence microscopy to determine membrane adsorption and desorption rate constants and partitioning coefficients. We find that translocation is a two-step process involving a fast adsorption and membrane insertion process and a slower desorption process. Membrane insertion is a key step that determines the molecular weight, concentration, and temperature dependences. Passive translocation is possible on time scales from minutes to hours. Macromolecules with different adapted hydrophilic/hydrophobic comonomer sequences show the same translocation rate, indicating that common optimized translocation conditions can be realized with a variety of monomer chemical structures. The investigated copolymers are biocompatible, biodegradable, and capable of transporting a hydrophobic payload through the lipid membrane. This detailed understanding of the macromolecular translocation mechanism enables to better tailor the delivery of active agents using macromolecular carriers.