Instances of synthetic polymers obtained from renewable feedstock with the possibility of post‐synthesis functionalization are scarce. Herein, the first ever synthesis and drug delivery application ...of amphiphilic block copolymer (mPEG‐b‐PJL) derived from renewable jasmine lactone with free allyl groups on the backbone is presented. The polymer is synthesized via facile ring‐opening polymerization and subsequently, UV mediated thiol‐ene click chemistry is utilized for post‐functionalization. The introduction of hydroxyl, carboxyl, and amine functionality to mPEG‐b‐PJL polymer is successfully established. As a proof‐of‐concept demonstration, doxorubicin (DOX) is conjugated on hydroxyl‐terminated polymer (mPEG‐b‐PJL‐OH) via redox responsive disulfide linkage to obtain PJL‐DOX. PJL‐DOX is readily self‐assembled into micelles with an average hydrodynamic size of ≈150 nm and demonstrates reduction‐responsive DOX release. Micelles are evaluated in vitro for cytocompatibility and selective drug release in cancer cells (MDA‐MB‐231) using 10 mm glutathione as a reducing agent. Cytotoxicity and microscopy results confirm a redox‐triggered release of DOX, which is further confirmed by flow cytometry. The introduction of these novel functional polymers can pave the way forward in designing polymer‐drug conjugate‐based smart nano‐carriers.
A novel amphiphilic block copolymer with a pendant allyl group has been synthesized using renewable jasmine lactone. The polymer offers an opportunity to insert a free functional group of interest via thiol‐ene reaction. The stimuli‐responsive drug delivery potential of hydroxyl‐terminated polymer is evaluated on cancer cells. The reported polymers can find versatile applications in several domains including drug delivery.
Mesoporous silica nanoparticles (MSNs) are extensively explored as drug delivery systems, but in depth understanding of design-toxicity relationships is still scarce. We used zebrafish (Danio rerio) ...embryos to study toxicity profiles of differently surface functionalized MSNs. Embryos with the chorion membrane intact, or dechoroniated embryos, were incubated or microinjected with amino (NH
-MSNs), polyethyleneimine (PEI-MSNs), succinic acid (SUCC-MSNs) or polyethyleneglycol (PEG-MSNs) functionalized MSNs. Toxicity was assessed by viability and cardiovascular function. NH
-MSNs, SUCC-MSNs and PEG-MSNs were well tolerated, 50 µg/ml PEI-MSNs induced 100% lethality 48 hours post fertilization (hpf). Dechoroniated embryos were more sensitive and 10 µg/ml PEI-MSNs reduced viability to 5% at 96hpf. Sensitivity to PEG- and SUCC-, but not NH
-MSNs, was also enhanced. Typically cardiovascular toxicity was evident prior to lethality. Confocal microscopy revealed that PEI-MSNs penetrated into the embryos whereas PEG-, NH2- and SUCC-MSNs remained aggregated on the skin surface. Direct exposure of inner organs by microinjecting NH
-MSNs and PEI-MSNs demonstrated that the particles displayed similar toxicity indicating that functionalization affects the toxicity profile by influencing penetrance through biological barriers. The data emphasize the need for careful analyses of toxicity mechanisms in relevant models and constitute an important knowledge step towards the development of safer and sustainable nanotherapies.
Nanogels (Ng) are crosslinked polymer-based hydrogel nanoparticles considered to be next-generation drug delivery systems due to their superior properties, including high drug loading capacity, low ...toxicity, and stimuli responsiveness. In this study, dually thermo-pH-responsive plasmonic nanogel (AuNP@Ng) was synthesized by grafting poly (N-isopropyl acrylamide) (PNIPAM) to chitosan (CS) in the presence of a chemical crosslinker to serve as a drug carrier system. The nanogel was further incorporated with gold nanoparticles (AuNP) to provide simultaneous drug delivery and photothermal therapy (PTT). Curcumin's (Cur) low water solubility and low bioavailability are the biggest obstacles to effective use of curcumin for anticancer therapy, and these obstacles can be overcome by utilizing an efficient delivery system. Therefore, curcumin was chosen as a model drug to be loaded into the nanogel for enhancing the anticancer efficiency, and further, its therapeutic efficiency was enhanced by PTT of the formulated AuNP@Ng. Thorough characterization of Ng based on CS and PNIPAM was conducted to confirm successful synthesis. Furthermore, photothermal properties and swelling ratio of fabricated nanoparticles were evaluated. Morphology and size measurements of nanogel were determined by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Nanogel was found to have a hydrodynamic size of ~167 nm and exhibited sustained release of curcumin up to 72 h with dual thermo-pH responsive drug release behavior, as examined under different temperature and pH conditions. Cytocompatibility of plasmonic nanogel was evaluated on MDA-MB-231 human breast cancer and non-tumorigenic MCF 10A cell lines, and the findings indicated the nanogel formulation to be cytocompatible. Nanoparticle uptake studies showed high internalization of nanoparticles in cancer cells when compared with non-tumorigenic cells and confocal microscopy further demonstrated that AuNP@Ng were internalized into the MDA-MB-231 cancer cells via endosomal route.
cytotoxicity studies revealed dose-dependent and time-dependent drug delivery of curcumin loaded AuNP@Ng/Cur. Furthermore, the developed nanoparticles showed an improved chemotherapy efficacy when irradiated with near-infrared (NIR) laser (808 nm)
. This work revealed that synthesized plasmonic nanogel loaded with curcumin (AuNP@Ng/Cur) can act as stimuli-responsive nanocarriers, having potential for dual therapy i.e., delivery of hydrophobic drug and photothermal therapy.
Cancer is an exceptionally confounding disease that demands the development of powerful drug/drugs, without inducing heavy adverse side effects. Thus, different approaches have been applied to ...improve the targeted delivery of cancer drugs: for example by using nanocarriers. However, nanocarriers are foreign materials, which need further validation for their biocompatibility and biodegradability. In this study, we have chemically conjugated the hydrophilic anticancer drug doxorubicin (DOX) with the hydrophobic drug paclitaxel (PTX) through a redox-sensitive disulfide bond, abbreviated to DOX-S-S-PTX. Subsequently, due to its amphiphilic characterization, the prodrug can self-assemble into nanoparticles under microfluidic nanoprecipitation. These novel prodrug nanoparticles have a super-high drug loading degree of 89%, which is impossible to achieve by any nanocarrier systems, and can be tailored to 180 nm to deliver themselves to the target, and release DOX and PTX under redox conditions, which are often found in cancer cells. By evaluating cell viability in MDA-MB-231, MDA-MB-231/ADR and MEF cell lines, we observed that the prodrug nanoparticles effectively killed the cancer cells, and selectively conquered the MDA-MB-231/ADR. Meanwhile, MEF cells were spared due to their lack of a redox condition. The cell interaction results show that the reduced intermediate of the prodrug can also bind to parent drug biological targets. The hemolysis results show that the nanoparticles are biocompatible in blood. Computer modelling suggested that the prodrug is unlikely to bind to biological targets that parent drugs still strongly interact with. Finally, we confirm that the prodrug nanoparticles have no therapeutic effect in blood or healthy cells, but can selectively eliminate the cancer cells that meet the redox conditions to cleave the disulfide bond and release the drugs DOX and PTX.
Biodegradable polymers from renewable resources have attracted much attention in recent years within the biomedical field. Lately, poly(δ-decalactone) based copolymer micelles have emerged as a ...potential drug delivery carrier material as a sustainable alternative to fossil-based polymers. However, their intracellular drug delivery potential is not yet investigated and therefore, in this work, we report on the synthesis and cellular uptake efficiency of poly(δ-decalactone) based micelles with or without a targeting ligand. Folic acid was chosen as a model targeting ligand and Rhodamine B as a fluorescent tracer to demonstrate the straightforward functionalisation aspect of copolymers. The synthesis of block copolymers was accomplished by a combination of facile ring-opening polymerisation and click chemistry to retain the structure uniformity. The presence of folic acid on the surface of micelles with diameter ~150 nm upsurge the uptake efficiency by 1.6 fold on folate receptor overexpressing MDA-MB-231 cells indicating the attainment of targeting using ligand functionality. The drug delivery capability of these carriers was ascertained by using docetaxel as a model drug, whereby the in vitro cytotoxicity of the drug was significantly increased after incorporation in micelles 48 h post incubation. We have also investigated the possible endocytosis route of non-targeted micelles and found that caveolae-mediated endocytosis was the preferred route of uptake. This work strengthens the prospect of using novel bio-based poly(δ-decalactone) micelles as efficient multifunctional drug delivery nanocarriers towards medical applications.
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•The extent of HSA adsorption to MSN surface is dependent on surface modification.•PEG in copolymer composition lead to unfolding/denaturation of adsorbed protein.•HSA association on ...mesoporous silica nanoparticles increases the biocompatibility.•MSN do not alter the myogenic differentiation.
The supplementation of stem cell culture medium with fetal bovine serum (FBS) for maintenance and propagation of cell lines in vitro is associated with immunogenicity and disease transmission by prions, bacteria, and viruses. Therefore, establishing xenogenic-free cell culture media for the benefit of rational testing conditions for stem cells in terms of eliminating the disadvantages is essential. In parallel, a number of investigations have been carried out on nanoparticle (NP) aided stem cell-based therapies. To use NP-integrated stem cell therapy in clinical applications, NP behavior in xenogenic-free stem cell cultures needs to be understood in detail. Mesoporous silica nanoparticles (MSN) are profusely used in biomedical applications and have also shown great potential in stem cell therapies. One of the strategies to make them compatible with stem cell therapy is to alter their surface functionalization. In line with this notion, the main interest of the present investigation was to study the impact of human serum albumin (HSA) association with differently surface-modified MSN, and rationalize the MSN utilization in xenogenic-free stem cell culture by employing C2C12 myogenic progenitor cells as a model system. Our results revealed that HSA coating on differently surface-modified MSN is a promising strategy to improve the colloidal stability of MSN, stem cell viability, and imparts no adverse effects on the differentiation of stem cells.
Hydrogels play an important role in tissue engineering due to their native extracellular matrix-like characteristics, but they are insufficient in providing the necessary stimuli to support tissue ...formation. Efforts to integrate bioactive cues directly into hydrogels are hindered by incompatibility with hydrophobic drugs, issues of burst/uncontrolled release, and rapid degradation of the bioactive molecules. Skeletal muscle tissue repair requires internal stimuli and communication between cells for regeneration, and nanocomposite systems offer to improve the therapeutic effects in tissue regeneration. Here, the versatility of mesoporous silica nanoparticles (MSN) was leveraged to formulate a nanoparticle-hydrogel composite and to combine the benefits of controlled delivery of bioactive cues and cellular support. The tunable surface characteristics of MSNs were exploited to optimize homogeneity and intracellular drug delivery in a 3D matrix. Nanocomposite hydrogels formulated with acetylated or succinylated MSNs achieved high homogeneity in 3D distribution, with succinylated MSNs being rapidly internalized and acetylated MSNs exhibiting slower cellular uptake. MSN-hydrogel nanocomposites simultaneously allowed efficient local intracellular delivery of a hydrophobic model drug. To further study the efficiency of directing cell response, a Notch signaling inhibitor (DAPT) was incorporated into succinylated MSNs and incorporated into the hydrogel. MSN-hydrogel nanocomposites effectively downregulated the Notch signaling target genes, and accelerated and maintained the expression of myogenic markers. The current findings demonstrate a proof-of-concept in effective surface engineering strategies for MSN-based nanocomposites, suited for hydrophobic drug delivery in tissue regeneration with guided cues.
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Multifunctional biomaterial inks are in high demand for adapting hydrogels in biomedical applications through three‐dimensional (3D) printing. Our previously developed xeno‐free system consisting of ...anionic cellulose nanofibers (T‐CNF) and methacrylated galactoglucomannan (GGMMA) as a photo(bio)polymer provides high‐performance ink fidelity in extrusion‐based 3D printing. The fusion between nanoparticles and this biomaterial‐ink system is a promising yet challenging avenue worth exploring, due to the colloidal stability of T‐CNF being sensitive to electrostatic interactions. Mesoporous silica nanoparticles (MSNs), with their robust ceramic matrix and fine‐tunable surface chemistries, are well‐established nanocarriers for different biologicals. Here, we fabricated MSNs with different surface modifications resulting in a net surface charge ranging from highly negative to highly positive to develop printable MSNs‐laden nanocomposite biomaterial inks. We utilized rheology as a comprehensive tool to address the matrix interactions with differently surface‐charged MSNs. Fluorescently labeled bovine serum albumin (FITC‐BSA) was used as a model protein for MSN loading, whereby negatively or neutral‐charged MSNs were found suitable to formulate FITC‐BSA‐loaded biomaterial inks of T‐CNF/GGMMA. Depending on the particles’ surface charge, FITC‐BSA showed different release profiles and preserved its stability after release. Lastly, the proof‐of‐concept to deliver large‐sized biological cargo with MSN‐laden nanocomposite biomaterial inks was established via the 3D printing technique.
Multifunctional biomaterial inks are suitable for semi‐solid extrusion 3D printing and are designed using differently surface‐charged mesoporous silica nanoparticles (MSNs) and woody biomaterials consisting of anionic cellulose nanofibers (T‐CNF) and methacrylated galactoglucomannan (GGMMA). The surface charge property of MSNs plays a key role in dictating the particle‐protein and particle‐matrix interactions, as well as the release of the loaded protein from the formulated biomaterial ink.
Hierarchically organized hybrid MOF particles were developed to meet the stable luminescence requirements of lanthanide complexes for applications in biological media. Anionic terbium (Tb) complexes ...sensitized by tridentate pyridine-tetrazolate (pytz) ligands ( i.e. Tb(pytz) 3 ) were encapsulated in zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (∼150 nm). TIF-1Zn (Zn(DMBIM) 2 ) frameworks were then hybridized with ZIF-8 by the mediation of a hydrophobic ligand, i.e. DMBIM (5,6-dimethylbenzimidazole). A bio-inspired polymer, i.e. polydopamine, was utilized for imparting the particles with hydrophilicity and functionalization ability. An unprecedentedly high quantum yield (82.0%) and luminescence stability in PBS buffer were realized by the hierarchical structure.
Cancer stem cells (CSCs) are a challenge in cancer treatment due to their therapy resistance. We demonstrated that enhanced Notch signaling in breast cancer promotes self-renewal of CSCs that display ...high glycolytic activity and aggressive hormone-independent tumor growth in vivo. We took advantage of the glycolytic phenotype and the dependence on Notch activity of the CSCs and designed nanoparticles to target the CSCs. Mesoporous silica nanoparticles were functionalized with glucose moieties and loaded with a γ-secretase inhibitor, a potent interceptor of Notch signaling. Cancer cells and CSCs in vitro and in vivo efficiently internalized these particles, and particle uptake correlated with the glycolytic profile of the cells. Nanoparticle treatment of breast cancer transplants on chick embryo chorioallantoic membranes efficiently reduced the cancer stem cell population of the tumor. Our data reveal that specific CSC characteristics can be utilized in nanoparticle design to improve CSC-targeted drug delivery and therapy.
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