Tumor-specific activatable biopolymer nanoparticles stabilized by hydroxyethyl starch prodrug for self-amplified cooperative cancer therapy.

Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.

Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer.

Combination therapy system has become a promising strategy for achieving favorable antitumor efficacy. Herein, a novel oral drug delivery system with colon localization and tumor targeting functions was designed for orthotopic colon cancer chemotherapy and photothermal combinational therapy. The polydopamine coated nanodiamond (PND) was used as the photothermal carrier, through the coupling of sulfhydryl-polyethylene glycol-folate (SH-PEG-FA) on the surface of PND to achieve systematic colon tumor targeting, curcumin (CUR) was loaded as the model drug, and then coated with chitosan (CS) to achieve the long gastrointestinal tract retention and colon localization functions to obtain PND-PEG-FA/CUR@CS nanoparticles. It has high photothermal conversion efficiency and good photothermal stability and exhibited near-infrared (NIR) laser-responsive drug release behavior. Folate (FA) modification effectively promotes the intracellular uptake of nanoparticles by CT26 cells, and the combination of chemotherapy and photothermal therapy (CT/PTT) can enhance cytotoxicity. Compared with free CUR group, nanoparticles prolonged the gastrointestinal tract retention time, accumulated more in colon tumor tissues, and exhibited good photothermal effect in vivo. More importantly, the CT/PTT group exhibited satisfactory tumor growth inhibition effects with good biocompatibility in vivo. In summary, this oral drug delivery system is an efficient platform for chemotherapy and photothermal combinational therapy of orthotopic colon cancer.

Nanotechnology for Topical Drug Delivery to the Anterior Segment of the Eye.

Topical drug delivery is one of the most challenging aspects of eye therapy. Eye drops are the most prevalent drug form, especially for widely distributed anterior segment eye diseases (cataracts, glaucoma, dry eye syndrome, inflammatory diseases, etc.), because they are convenient and easy to apply by patients. However, conventional drug formulations are usually characterized by short retention time in the tear film, insufficient contact with epithelium, fast elimination, and difficulties in overcoming ocular tissue barriers. Not more than 5% of the total drug dose administered in eye drops reaches the interior ocular tissues. To overcome the ocular drug delivery barriers and improve drug bioavailability, various conventional and novel drug delivery systems have been developed. Among these, nanosize carriers are the most attractive. The review is focused on the different drug carriers, such as synthetic and natural polymers, as well as inorganic carriers, with special attention to nanoparticles and nanomicelles. Studies in vitro and in vivo have demonstrated that new formulations could help to improve the bioavailability of the drugs, provide sustained drug release, enhance and prolong their therapeutic action. Promising results were obtained with drug-loaded nanoparticles included in in situ gel.

Mesoporous polydopamine nanoparticles carrying peptide RL-QN15 show potential for skin wound therapy.

BACKGROUND: Skin wound healing remains a considerable clinical challenge, thus stressing the urgent need for the development of new interventions to promote repair. Recent researches indicate that both peptides and nanoparticles may be potential therapies for the treatment of skin wounds. METHODS: In the current study, the mesoporous polydopamine (MPDA) nanoparticles were prepared and the peptide RL-QN15 that was previously identified from amphibian skin secretions and exhibited significant potential as a novel prohealing agent was successfully loaded onto the MPDA nanoparticles, which was confirmed by results of analysis of scanning electron microscopy and fourier transform infrared spectroscopy. The encapsulation efficiency and sustained release rate of RL-QN15 from the nanocomposites were determined. The prohealing potency of nanocomposites were evaluated by full-thickness injured wounds in both mice and swine and burn wounds in mice. RESULTS: Our results indicated that, compared with RL-QN15 alone, the prohealing potency of nanocomposites of MPDA and RL-QN15 in the full-thickness injured wounds and burn wounds in mice was increased by up to 50 times through the slow release of RL-QN15. Moreover, the load on the MPDA obviously increased the prohealing activities of RL-QN15 in full-thickness injured wounds in swine. In addition, the obvious increase in the prohealing potency of nanocomposites of MPDA and RL-QN15 was also proved by the results from histological analysis. CONCLUSIONS: Based on our knowledge, this is the first research to report that the load of MPDA nanoparticles could significantly increase the prohealing potency of peptide and hence highlighted the promising potential of MPDA nanoparticles-carrying peptide RL-QN15 for skin wound therapy.

Multifunctional Size-Expandable Nanomedicines Enhance Tumor Accumulation and Penetration for Synergistic Chemo-Photothermal Therapy.

Size expansion can effectively improve tumor accumulation of nanocarriers where precise control is required. A dual-responsive nanocarrier stimulated by both endogenous pH and exogenous heat stimuli can change its size. Herein, a nanoparticle composed of poly(N,N-diethyl acrylamide) (PDEAA) and poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) is developed. The antitumor drug celastrol (CLT) and the photosensitizer indocyanine green (ICG) are then loaded in it to form CIPP. ICG generates heat under near-infrared (NIR) stimulation to kill tumor cells and enhance CIPP penetration. Meanwhile, CIPP expands in response to hyperthermia and acid tumor microenvironments, preventing itself from returning to the blood flow, thus accumulating in tumor sites. Ultimately, the acidic lysosomal environment in tumor cells disintegrates CIPP to release CLT, directly inducing immunogenic cell death and sensitizing tumor cells for hyperthermia by disrupting the interaction of heat shock protein 90 and P50cdc37. Most of the tumors in B16F10-bearing mice are eradicated after single laser irradiation. The dual-responsive CIPP with multiple functions and simple design displays a synergistic antitumor effect. This study provides a basis for developing size-expandable stimulus-responsive drug delivery systems against tumors.

Vacancy Engineering to Regulate Photocatalytic Activity of Polymer Photosensitizers for Amplifying Photodynamic Therapy against Hypoxic Tumors.

Polymer photosensitizers (PPSs) with the distinctive properties of good light-harvesting capability, high photostability, and excellent tumor retention effects have aroused great research interest in photodynamic therapy (PDT). However, their potential translation into clinic was often constrained by the hypoxic nature of tumor microenvironment, the aggregation-caused reduced production of reactive oxygen species (ROS), and the tedious procedure of manufacture. As a powerful and versatile strategy, vacancy engineering possesses the unique capability to effectively improve the photogenerated electron efficiency of nanomaterials for high-performance O2 and ROS production. Herein, by introducing vacancy engineering into the design of PPSs for PDT for the first time, we synthesized a novel PPS of Au-decorated polythionine (PTh) nanoconstructs (PTh@Au NCs) with the unique integrated features of distinguished O2 self-evolving function and highly efficient ROS generation for achieving the greatly enhanced PDT efficacy toward hypoxic tumor both in vitro and in vivo. The incorporation of Au into PTh leads to the special PTh-Au heterostructure-induced sulfur vacancies in PTh@Au NCs, which results in an efficient electron-hole separation performance and also plays a key role in a long lifetime of free electrons and holes. Accordingly, an ∼2- to 3-fold ROS generation and an ∼1.5-fold increase of O2 self-supply than the pure PTh nanoparticles (NPs) were obtained even under hypoxic conditions upon exposure to 650 nm light. By combining such superior ROS generation and O2 self-supply performances with the outstanding cellular internalization and tumor accumulation capacities, an advanced antitumor effect with the achievement of almost complete hypoxic tumor elimination in vivo or 88% cell destruction in vitro was acquired by the PTh@Au NCs. In addition, the distinctive facile one-step redox strategy for PTh@Au NCs synthesis compared to the reported PPSs for PDT also makes it beneficial for potential practical application. The first introduction of vacancy engineering concept into PPSs in the field of PDT proposed in this work offers a new strategy for the development and design highly efficient PPSs for PDT applications.

Effects of the Blending Ratio on the Design of Keratin/Poly(butylene succinate) Nanofibers for Drug Delivery Applications.

In recent years there has been a growing interest in the use of proteins as biocompatible and environmentally friendly biomolecules for the design of wound healing and drug delivery systems. Keratin is a fascinating protein, obtainable from several keratinous biomasses such as wool, hair or nails, with intrinsic bioactive properties including stimulatory effects on wound repair and excellent carrier capability. In this work keratin/poly(butylene succinate) blend solutions with functional properties tunable by manipulating the polymer blending ratios were prepared by using 1,1,1,3,3,3-hexafluoroisopropanol as common solvent. Afterwards, these solutions doped with rhodamine B (RhB), were electrospun into blend mats and the drug release mechanism and kinetics as a function of blend composition was studied, in order to understand the potential of such membranes as drug delivery systems. The electrophoresis analysis carried out on keratin revealed that the solvent used does not degrade the protein. Moreover, all the blend solutions showed a non-Newtonian behavior, among which the Keratin/PBS 70/30 and 30/70 ones showed an amplified orientation ability of the polymer chains when subjected to a shear stress. Therefore, the resulting nanofibers showed thinner mean diameters and narrower diameter distributions compared to the Keratin/PBS 50/50 blend solution. The thermal stability and the mechanical properties of the blend electrospun mats improved by increasing the PBS content. Finally, the RhB release rate increased by increasing the keratin content of the mats and the drug diffused as drug-protein complex.

3D printing and enteric coating of a hollow capsular device with controlled drug release characteristics prepared using extruded Eudragit® filaments.

This work focuses on the extrusion of a brittle, tacky, cationic copolymer i.e. Eudragit® E-100 to prepare filament and subsequent 3D printing of hollow capsular device using the extruded filament. An optimum amount of talc and triethyl citrate was used for the possible extrusion of the polymer. There was no thermal and chemical degradation of the polymer observed after extrusion confirmed by DSC and FTIR analysis. Microscopic analysis of the printed capsule showed the layer-by-layer manner of 3D printing. Capsule parts were printed according to the set dimensions (00 size) with minimal deviation. Printed capsule showed the soluble behaviour in gastric fluid pH 1.2 where within 15 min the encapsulated drug encounters with the dissolution medium and almost 70% drug was dissolved within 4 hr. In case of phosphate buffer pH 6.8, the printed capsule showed a longed swelling behaviour up to 12 hr and then gradually bursting of capsule occurred wherein more than 90% encapsulated drug was dissolved within 36 hr. Enteric coating of the printed capsule showed similar behaviour in alkaline medium that observed with non-enteric capsule. This indicates the potential application of this printed capsules for both gastric and intestinal specific delayed drug delivery by a single step enteric coating process.

Preparation and Characterization of a Lutein Solid Dispersion to Improve Its Solubility and Stability.

Lutein has been used as a dietary supplement for the treatment of eye diseases, especially age-related macular degeneration. For oral formulations, we investigated lutein stability in artificial set-ups mimicking different physiological conditions and found that lutein was degraded over time under acidic conditions. To enhance the stability of lutein upon oral intake, we developed enteric-coated lutein solid dispersions (SD) by applying a polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF), through a solvent-controlled precipitation method. The SD were characterized in crystallinity, morphology, and drug entrapment. In the dissolution profile of lutein SD, a F80 formulation showed resistance toward the acidic environment under simulated gastric conditions while exhibiting a bursting drug release under simulated intestinal conditions. Our results highlight the potential use of HPMCAS-LF as an effective matrix to enhance lutein bioavailability during oral delivery and to provide novel insights into the eye-care supplement industry, with direct benefits for the health of patients.

Imaging-Guided Chemo-Photothermal Polydopamine Carbon Dots for EpCAM-Targeted Delivery toward Liver Tumor.

We demonstrate a versatile nanoparticle with imaging-guided chemo-photothermal synergistic therapy and EpCAM-targeted delivery of liver tumor cells. EpCAM antibody (anti-EpCAM) and Pt(IV) were grafted onto the polydopamine carbon dots (PDA-CDs) by the amidation reaction. The EpCAM antibody of particles enables the targeted interaction with liver progenitor cells due to their overexpressed EpCAM protein. The tetravalent platinum prodrug [Pt(IV)] induces apoptosis with minimum toxic side effects through the interaction between cisplatin and tumor cell DNA. The nanoparticles displayed stable photothermal property and considerable anti-tumor therapeutic effect in vivo. Coupling with cellular imaging due to their fluorescence property, anti-EpCAM@PDA-CDs@Pt(IV) offers a convenient and effective platform for imaging-guided chemo-photothermal synergistic therapy toward liver cancers in the near future.

Assessment of the Potential for Veverimer Drug-Drug Interactions.

Veverimer is a polymer being developed as a potential treatment of metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral, or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiologic concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. SIGNIFICANCE STATEMENT: Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.

Polymeric Nanoreactors as Emerging Nanoplatforms for Cancer Precise Nanomedicine.

How to precisely detect and effectively cure cancer which is defined as precise nanomedicine has drawn great attention worldwide. Polymeric nanoreactors which can in situ catalyze inert species into activated ones, can greatly increase imaging quality and enhance therapeutic effects along with decreased background interference and reduced serious side effects. After a brief introduction, the design and preparation of polymeric nanoreactors are discussed from the following aspects, that is, solvent-switch, pH-tuning, film rehydration, hard template, electrostatic interaction, and polymerization-induced self-assembly (PISA). Subsequently, the biomedical applications of these nanoreactors in the fields of cancer imaging, cancer therapy, and cancer theranostics are highlighted. The last but not least, conclusions and future perspectives about polymeric nanoreactors are given. It is believed that polymeric nanoreactors can bring a great opportunity for future fabrication and clinical translation of precise nanomedicine.

Investigating the Influence of Tablet Location Inside Dissolution Test Apparatus on Polymer Erosion and Drug Release of a Surface-Erodible Sustained-Release Tablet Using Computational Simulation Methods.

The objective of this work was to investigate the influence of tablet location along the bottom of a USP apparatus II vessel on polymer erosion and drug release of surface-erodible sustained-release tablets using computational simulation methods. Computational fluid dynamics (CFD) methods were performed to simulate the velocity distribution. A mathematical model was developed to describe polymer erosion and tablet deformation according to the mass transfer coefficient. Numerical analysis was used to simulate drug release controlled by drug diffusion and polymer erosion. The results indicated that tablets located at the off-center position deformed faster than the tablets located at the center position. However, tablet location had no profound impact on drug release rate since all drug release profiles were "similar" according to the f2 similarity values which were above 50. Hence, our simulation supported that the USP apparatus II was a reliable and robust device for the dissolution testing of surface-erodible sustained-release tablets.

Design of biotin decorated enterocyte targeting muco-inert nanocomplexes for enhanced oral insulin delivery.

The natural mucus cover has been a major obstacle to prevent enterocyte targeting particles from contact with the receptors. Thus, mucus penetration and intestinal targeting should be designed into one system. Based on the concept that biotin specifically recognizes epithelium receptors, enterocyte targeting muco-inert nanocomplexes were designed. Firstly, biotinylated chitosan (CS-Biotin) copolymers with different degree of substitution were synthesized and characterized. The nanocomplexes between CS-Biotin and insulin were prepared via self-assembly method. Thereafter, the nanocomplexes were fabricated by coating with various molecular weight hyaluronic acid (HA), which improved penetration efficiency in the mucus layer and small intestine in a HA molecular weight dependent manner. In vivo study indicated that hypoglycemic effect of the nanocomplexes was biotin modification degree and HA molecular weight dependent, with HA (200)-coated CS-Biotin21.8%/Insulin polyelectrolyte complex presenting the best performance. In conclusion, biotin decorated muco-inert nanocomplexes with HA coating are a promising platform for oral insulin delivery.

Polymer-based hydrogels with local drug release for cancer immunotherapy.

Immunotherapy that boosts the body's immune system to treat local and distant metastatic tumors has offered a new treatment option for cancer. However, cancer immunotherapy via systemic administration of immunotherapeutic agents often has two major issues of limited immune responses and potential immune-related adverse events in the clinic. Hydrogels, a class of three-dimensional network biomaterials with unique porous structures can achieve local delivery of drugs into tumors to trigger the antitumor immunity, resulting in amplified immunotherapy at lower dosages. In this review, we summarize the recent development of polymer-based hydrogels as drug release systems for local delivery of various immunotherapeutic agents for cancer immunotherapy. The constructions of polymer-based hydrogels and their local delivery of various drugs in tumors to achieve sole immunotherapy, and chemotherapy-, and phototherapy-combinational immunotherapy are introduced. Furthermore, a brief conclusion is given and existing challenges and further perspectives of polymer-based hydrogels for cancer immunotherapy are discussed.

Evaluation on the physicochemical and digestive properties of melanoidin from black garlic and their antioxidant activities in vitro.

As the important compounds in black garlic, the physicochemical properties and bioactivities of melanoidin (MLD) were investigated in this study. The results showed that MLD possessed strong metal-ion chelating capacity and radical scavenging activities which were positively correlative with molecular weight (MW). During the simulated digestion in vitro, the ultraviolet absorption, browning degree and MW distribution of MLD remained the same as initial. It proved that the MLD from black garlic could be indigestible like the dietary fiber with little loss of volatile compounds and polysaccharides. Remarkably, the bioactivities of MLD were reduced significantly under the treatment of α-amylase or hydrochloric acid, while they were stable and retained over 60% after adding pepsin and pancreatin. This study provides fundamental evidences for further research and widely application of MLD and black garlic in the production of functional food or food additives.

Fluorophore Selection and Incorporation Contribute to Permeation and Distribution Behaviors of Hyperbranched Polymers in Multi-Cellular Tumor Spheroids and Xenograft Tumor Models.

Improving our understanding of how design choices in materials synthesis impact biological outcomes is of critical importance in the development of nanomedicines. Here, we show that fluorophore labeling of polymer nanomedicine candidates significantly alters their transport and cell association in multi-cellular tumor spheroids and their penetration in breast cancer xenografts, dependent on the type of the fluorophore and their positioning within the macromolecular structure. These data show the critical importance of the biomaterials structure and architecture in their tissue distribution and intracellular trafficking, which in turn govern their potential therapeutic efficacy. The broader implication of these findings suggests that when developing materials for medical applications, great care should be taken early on in the design process as relatively simple choices may have downstream impacts that could potentially skew preclinical biology data.

In vitro characterization of novel multidrug-eluting soy protein wound dressings.

Polymers derived from natural sources are of interest in the scientific and medical communities, especially soy protein which exhibits low immunogenicity and good mechanical properties, and supports cell proliferation. Soy protein is cost-effective compared to other natural polymers and is attractive also due to its non-animal origin and relatively long storage stability. In the current study, hybrid film structures were developed and studied as a novel wound dressing platform with controlled release of three bioactive agents. The dense top layer is designed to provide mechanical support, control the water vapor permeability and to elute the antibiotic drug cloxacillin and the analgesic drug bupivacaine to the wound site. The porous sub-layer is designed to absorb the wound exudates and release the hemostatic agent tranexamic acid for bleeding control. The results show that the formulation parameters, i.e. crosslinker and plasticizer concentrations, affected the mechanical properties of the wound dressings as well as relevant physical properties (water vapor transmission rate and swelling kinetics), but had almost no effect on the drug-release profiles. While the antibiotic drug and the analgesic drug were released within several hours, the hemostatic agent was released within several minutes, according to the well designed hybrid structure. In conclusion, our novel soy protein hybrid wound dressings are biocompatible, can deliver various drugs simultaneously in a controlled fashion for each drug individually, and can be adjusted to suit various types of wounds by altering their properties through formulation effects.

Cytotoxicity study of bakery product melanoidins on intestinal and endothelial cell lines.

Melanoidins contribute to organoleptic properties of processed foods and exert benefits in health. The aim of this study was to isolate and characterize melanoidins from baked products (common bread, soft bread and biscuits), evaluate their cytotoxicity and determine their suitability as functional additives. Extraction yield, spectrophotometric characteristics, colorimetric properties, antioxidant capacity, and cytotoxicity of melanoidins were assessed. Among the studied products, soft bread had the highest extraction throughput. Melanoidins from biscuit showed the highest antioxidant capacity, closely followed by those of soft bread. Melanoidins did not exert cytotoxic effects on Caco-2 and HUVEC cells (viability was >80%). Nevertheless, incubation of HUVEC cells with melanoidins from common bread and biscuit slightly decreased viability, whereas gastrointestinal digestion of such melanoidins softened the decrease in cell viability. This study point to soft bread as a safe and efficient source of melanoidins, that could be potentially used in the future as functional ingredient.