Stem cell technology for antitumor drug loading and delivery in oncology

The main aim of antineoplastic treatment is to maximize patient benefit by augmenting the drug accumulation within affected organs and tissues,thus incrementing drug effects and,at the same time,reducing the damage of non-involved tissues to cytotoxic agents.Mesenchymal stromal cells(MSC)represent a group of undifferentiated multipotent cells presenting wide self-renewal features and the capacity to differentiate into an assortment of mesenchymal family cells.During the last year,they have been proposed as natural carriers for the selective release of antitumor drugs to malignant cll,s thus optimizing cytotoxic action on cancer cll,while significantly reducing adverse side efect on healthy cells.MSC chemotherapeutic drug loading and delivery is an encouraging new area of cell therapy for several tumors,especially for those with unsatisfactory prognosis and limited treatment options available.Although some experim ental models have been sucesfuly developed,phase I dinical studies are needed to confirm this potential application of cell therapy,in particular in the case of primary and secondary lung cancers.

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

Drug delivery via intra-articular(IA)injection has proved to be effective in osteoarthritis(OA)therapy,limited by the drug efficiency and short retention time of the drug delivery systems(DDSs).Herein,a series of modified cross-linked dextran(Sephadex,S0)was fabricated by respectively grafting with linear alkyl chains,branched alkyl chains or aromatic chain,and acted as DDSs after ibuprofen(Ibu)loading for OA therapy.This DDSs expressed sustained drug release,excellent anti-inflammatory and chondroprotective effects both in IL-1βinduced chondrocytes and OA joints.Specifically,the introduction of a longer hydrophobic chain,particularly an aromatic chain,distinctly improved the hydrophobicity of S0,increased Ibu loading efficiency,and further led to significantly improving OA therapeutic effects.Therefore,hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.

A drug-loaded flexible substrate improves the performance of conformal cortical electrodes

Cortical electrodes are a powerful tool for the stimulation and/or recording of electrical activity in the nervous system.However,the inevitable wound caused by surgical implantation of electrodes presents bacterial infection and inflammatory reaction risks associated with foreign body exposure.Moreover,inflammation of the wound area can dramatically worsen in response to bacterial infection.These consequences can not only lead to the failure of cortical electrode implantation but also threaten the lives of patients.Herein,we prepared a hydrogel made of bacterial cellulose(BC),a flexible substrate for cortical electrodes,and further loaded antibiotic tetracycline(TC)and the anti-inflammatory drug dexamethasone(DEX)onto it.The encapsulated drugs can be released from the BC hydrogel and effectively inhibit the growth of Gram-negative and Gram-positive bacteria.Next,therapeutic cortical electrodes were developed by integrating the drug-loaded BC hydrogel and nine-channel serpentine arrays;these were used to record electrocorticography(ECoG)signals in a rat model.Due to the controlled release of TC and DEX from the BC hydrogel substrate,therapeutic cortical electrodes can alleviate or prevent symptoms associated with the bacterial infection and inflammation of brain tissue.This approach facilitates the development of drug delivery electrodes for resolving complications caused by implantable electrodes.

Development of a concentration-controlled sequential nanoprecipitation for making lipid nanoparticles with high drug loading

Lipid-based nanostructures have garnered considerable interests over the last two decades,and have achieved tremendous clinical success including thefirst clinical approval of a liposome(Doxil)for cancer therapy in 1995 and the recent COVID-19 mRNA lipid nanoparticle vaccines.Compared to liposomes which have a lipid bilayer surrounding an aqueous core,lipid nanoparticles with a particle structure have several attractive advantages for encapsulating poorly water-soluble drugs such as better stability due to the particle structure,high drug encapsulation efficiency because of a pre-or co-drug-loading strategy.While many studies have reported the synthesis of lipid nanoparticles for hydrophobic drug encapsulation,the pre-cise control of drug loading and encapsulation efficiency remains a significant challenge.This work reports a new concentration-controlled nanoprecipitation plat-form technology for fabricating lipid nanoparticles with tunable drug loading up to 70 wt%.This method is applicable for encapsulating a wide range of drugs from very hydrophobic to slightly hydrophilic.Using this facile method,nanoparticles with tunable drug loading exhibited excellent properties such as small particle size,narrow size distribution,good particle stability,showing great promise for future drug delivery applications.

Phase separation-induced nanoprecipitation for making polymer nanoparticles with high drug loading Special Collection:Distinguished Australian Researchers

Increasing drug loading remains a critical challenge in the development and translation of nanomedicine.High drug-loading nanoparticles have demonstrated unique advantages such as less carrier material used,better-controlled drug release,and improved efficacy and safety.Herein,we report a simple and efficient salt concentration screening method for making polymer nanoparticles with exceptionally high drug loading(up to 66.5 wt%)based on phase separation-induced nanoprecipitation.Upon addition of salt,phase separation occurs in a miscible solvent-water solution delaying the precipitation time of drugs and polymers to different extents,facilitating their co-precipitation thus the formation of high drug-loading nanoparticles with high encapsulation efficiency(>90%)and excellent stability(>1 month).This technology is versatile and easy to be adapted to various hydrophobic drugs,different polymers,and solvents.This salt-induced nanoprecipitation strategy offers a novel approach to fabricating polymer nanoparticles with tunable drug loading,and opens great potentials for future nanomedicines.

Functional Amphiphilic Poly(2-oxazoline)Block Copolymers as Drug Carriers:the Relationship between Structure and Drug Loading Capacity

Poly(2-oxazoline)(POx)is a kind of polymeric amides that can be viewed as conformational isomers of polypeptides with excellent cyto-and hemo-compatibility,and is promising to be used as drug carriers.However,the drug loading capacity(DLC)of POx for many drugs is still low except several hydrophobic ones including paclitaxel(PTX).Herein,we prepared a series of amphiphilic POx block copolymers with various functional groups,and investigated the relationship between functional structures and the DLC.Functional POxs with benzyl,carboxyl,and amino groups in the side-chain were synthesized based on a poly(2-methyl-2-oxazoline)-block-poly(2-buty1-2-oxazoline-co-2-buteny1-2-oxazoline)(PMeOx-P(nBuOx-co-ButenOx),PMBEOx)precursor,followed by click reaction between vinyl and the 2-phenylethanethiol,thioglycolic acid and cysteamine.Using thin-film hydration method,eight commonly used drugs with various characteristics were encapsulated within these functional POx polymers.We found that amine-containing drugs were more easily encapsulated by POx with carboxyl groups,while amine functionalities in POx enhanced the loading capacity of drugs with carboxyl groups.In addition,n-n interactions resulted in enhanced DLC of most drugs,except several hydrophobic drugs with aromatic to total carbon ratios less than 0.5.In general,we could successfully encapsulate all the selected drugs with a DLC%over 10%using properly selected functional POxs.The above results confirm that the DLC of polymeric carriers can be adjusted by modifying the functional groups,and the prepared series of functional POxs provide an option for various drug loadings.

High drug loading polymer micelle@ZIF-8 hybrid core–shell nanoparticles through donor–receptor coordination interaction for pH/H_(2)O_(2)-responsive drug release

Smart drug delivery nanocarriers with high drug loading capacity are of great importance in the treatment of diseases,and can improve therapeutic effectiveness as well as alleviate side effects in patients.In this work,a pH and H_(2)O_(2)-responsive drug delivery platform with high doxorubicin(DOX)loading capacity has been established through coordination interaction between DOX and phenylboronic acid containing block polymer.A composited drug nanocarrier is further fabricated by growing a zeolitic imidazolate framework 8(ZIF-8)on the surface of drug-loaded polymer micelles.The study verifies that ZIF-8 shell can act as intelligent“switch”to prevent DOX leaking from core–shell nanoparticles upon H_(2)O_(2) stimulus.However,a burst drug release is detected upon pH and H_(2)O_(2) stimuli due to the further disassociation of ZIF-8 in acid solution.Moreover,the in vitro anti-cancer experiments demonstrate that the DOX-loaded core–shell nanoparticles provide effective treatment towards cancer cells but have negligible effect on normal cells,which results from the high concentration of H_(2)O_(2) and low pH in the microenvironment of tumor cells.

ZnO Incorporated Acrylamide Grafted Chitosan Based Composite Film for Advanced Wound Healing Applications

This study was carried out to prepare ZnO nanoparticles incorporated acrylamide grafted chitosan composite film for possible biomedical application especially drug loading in wound healing. ZnO nanoparticles were prepared by co-precipitation method from zinc acetate di-hydrate and incorporated in acrylamide grafted chitosan. FT-IR and TGA of the prepared composite film confirmed the successful incorporation of ZnO nanoparticles in the acrylamide-grafted polymer matrix. SEM images showed that the ZnO nanoparticles were homogeneously distributed on the porous matrix of the composite film. Water uptake and buffer uptake analysis revealed that the composite film could hold water and buffer sufficiently, which facilitated the absorption of exudate from the wound site. Amoxicillin was loaded in the prepared composite film and the maximum loading efficiency was found to be 67.33% with drug concentration of 300 ppm. In vitro studies showed greater antimicrobial activity of drug-loaded composite film compared to both pure film and standard antibiotic disc. Finally, the In vivo mouse model showed maximum healing efficiency compared to conventional gauge bandages because the loading of antibiotic in the film produced a synergistic effect and healing time was reduced.

Characterization and Performance of Magnesium Doped Bioactive Glass Nanoparticles

The bioactive glass and related biomaterials have become increasingly popular, and have also attracted the research interest of many researchers in recent years due its special performance and tissue engineering application. In this study, to create a material with a variety of properties Mg doped hollow bioactive glass (Mg-HBG) of 80SiO2-5P2O5-10CaO-5MgO system had been produced by using a sol-gel method. The porous structure nanoparticles were specifically made by employing the cetyltrimethylammonium bromide (CTAB) as a surfactant. Magnesium was selected as a doped material with HBG, because it is the most existing cations in the human body which helps for bone metabolism as well as it has antibacterial property. Based on different investigations resulted nanoparticle with the inclusion of the lower molar fractions magnesium has good tested result. For a drug model vancomycin hydrochloride (VAN) was used in this study and it has also good antibacterial activity effect. These findings help the possibility of using Mg-HBG nanoparticles to treat infectious bone abnormalities by demonstrating their compatibility with antibiotics, drug loading and release behavior.

Preparation and in vitro Release Properties of Mercaptopurine Drug-loaded Magnetic Microspheres

Magnetic Fe304 nanoparticles were synthesized by co-precipitation method and the mercaptopurine （MER） drug-loaded magnetic microspheres were obtained through emulsion cross-linking methods. The efficiency of this approach was evaluated in terms of drug loading content （DLC）, encapsulation efficiency （EE） and delivery properties in vitro, determined by high performance liquid chromatograph （HPLC）. The microspheres showed good DLC values of 11.8%, as well as good EE values of 79.4%. The in vitro drug release study was carried out in phosphate buffer solution （PBS） simulated body fluid, at 37 ~C with pH=7.4. The release profiles showed an initial fast release rate, which decreased as time progressed and about 84 % had been released after 48 h. The experimental results indicated that the prepared magnetic microspheres may be useful for potential applications of MER for magnetically targeted chemotherapy.

Polymeric Hydrogel Nanocapsules: A Thermo and pH Dual-responsive Carrier for Sustained Drug Release

Hydrogel capsules show attractive prospects in drug delivery recently because of high drug loading and sustained release behavior. In this study we reported a simple and convenient route to fabricate poly(acrylic acid)-poly(N-isopropylacrylamide)(PAA-PNIPAm) hydrogel capsules by using hydroxypropylcellulose-poly(acrylic acid)(HPC-PAA) complexes as the templates. The capsules showed a high drug loading(～280% to the weight of capsules) for Doxorubicin hydrochloride. The release of drug from the capsules was responsive to the temperature and p H of the surroundings, showing a low-rate but sustained release behavior favorable for low-toxic and long-term therapy. Together with the convenient preparation, high drug loading, dual responsivity as well as the sustained release feature, it is implied that this polymeric hydrogel capsule might be a promising candidate for new drug carriers.

Preparation and Crystal Modification of Ibuprofen-Loaded Solid Lipid Microparticles

An emulsion-congealing technique is used to prepare solid lipid microparticles （SLM） containing ibuprofen with glyceryl behenate, tripalmitin and beewax as excipients. The difference of the solubility parameters between the excipients and ibuprofen are used to analyze their compatibility. Both the solubility parameter analysis and the experimental results show that glyceryl behenate is the best among the three excipients. The solid particles disperse well in aqueous phase when the drug loading reaches 10% （relative to lipid only）. Glycerides exhibit marked polymorphism and their rapid rates of crystallization accelerate the formation of metastable crystal modification. The metastable crystal modification characterizes high drug loading capacity but less stability. Increasing the content of lipophilic drug in a lipid matrix facilitates the transformation of excipients to more stable polymorphic forms.

Layered double hydroxide monolayers for controlled loading and targeted delivery of anticancer drugs

Two-dimensional （2D） nanomaterials have gained tremendous attention in the field of biomedicine because of their high specific surface areas and fascinating physicochemical properties. Herein, 2D monolayered double hydroxide （MLDH） nanosheets were employed to localize doxorubicin （DOX）, an anticancer drug, with a loading capacity of as high as 3.6 mg.mg-1 （w/w）. Structural characterizations and theoretical calculations indicate that the DOX molecule is uniformly arranged and oriented at the surface of the MLDHs with a binding energy of 15.90 eV, showing significant electrostatic interaction. With the assistance of the targeting agent folic acid （FA）, DOX-FA/MLDHs demonstrate targeted cellular uptake and superior anticancer behavior based on in vitro tests performed with cancer cells. In addition, this composite material exhibits a selective release toward cancer cells and good biocompatibility with normal cells, which would guarantee its practical applications in cancer therapy.

Utilization of H-bond interaction of nucleobase Uralic with antitumor methotrexate to design drug carrier with ultrahigh loading efficiency and pH-responsive drug release

A novel Uralic(U)-rich linear-hyperbranched mono-methoxy poly(ethylene glycol)-hyperbranched polyglycerol-graft-Uralic(mPEG-HPG-g-U)nanoparticle(NP)was prepared as drug carrier for antitumor methotrexate(MTX).Due to the H-bond interaction of U with MTX and hydrophobic interaction,this NP exhibited high drug loading efficiency of up to 40%,which was significantly higher than that of traditional NPs based on U-absent copolymers(<15%).In addition,MTX-loaded mPEG-HPG-g-U NPs also demonstrated an acidity-accelerated drug release behavior.

Preparation and Properties of Guiqi Polysaccharides/Chitosan/Alginate Composite Hydrogel Microspheres

A series of the Guiqi polysaccharides/chitosan/alginate composite hydrogel microspheres(GPcM)with different particle sizes were prepared with Guiqi polysaccharides(GP),chitosan(CS)and sodium alginate(Alg).The optimum preparation process was also determined by single factor and orthogonal experiment analysis.The GPcM were characterized by fourier transform infrared spectroscopy(FT-IR),scanning electron microscope(SEM),drug loading efficiency test(LE),encapsulation efficiency test(EE)and in vitro release study.The results showed that the Guiqi polysaccharides chitosan hydrogel(GPCH)and sodium alginate hydrogel(SAH)formed a crossover system in GPcM.The GPcM have a uniform particle size ranging from 395.1μm to 841.5μm.The drug loading efficiency and encapsulation efficiency of the GPcM were 56.3%and 72.6%,respectively.The bovine serum albumin(BSA)loaded in the GPcM released slowly within 180 h.The results suggested that the GPcM may have potential application value in drug sustained and controlled release system.

THE PHYSICAL PROPERTIES OF POLY(2-HYDROXYETHYL METHACRYLATE)COPOLYMER HYDROGELS USED AS INTRAVAGINAL RINGS

Poly(2-hydroxyethyl methacrylate)(PHEMA)and poly(2-hydroxyethyl methacrylate-co-sodium methacrylate) [P(HEMA-co-SMA)]hydrogels with different compositions were prepared to be used as intravaginal rings,and their gelation time,water content,mechanical properties and morphology were investigated.The water content of PHEMA and P(HEMA-co-SMA) hydrogels decreased as the concentration of the monomer and the degree of crosslinking increased,while the water content significantly increased as the content of SMA,the hydrophilic monomer,increased.The increasing of the concentration of the crosslinking agent affected the tensile and flexural properties highly.The presence of a proper small amount of SMA also led the tensile and flexural modulus to move to a higher level.The results showed that P(HEMA-co-SMA) hydrogel with high drug load and good mechanical properties at optimum preparation conditions can be prepared for intravaginal rings to deliver nonhormonal contraceptives.These results may be applied to prepare better intravaginal drug delivery devices.

Construction and properties of venlafaxine hydrochloride sustained release system based on hollow mesoporous silica microspheres

The aim of this work is to develop a venlafaxine hydrochloride sustained release system based on hollow mesoporous silica microspheres(HMSMs).HMSMs were innovatively prepared with tetraethyl silicate(TEOS)as the precursor and volatile n-heptane as a soft template.The obtained HMSMs show a well-defined hollow structure with an average size of 967 nm and pore volume of 0.85 cm^(3)/g,implying it is a potential drug carrier.Subsequently,venlafaxine hydrochloride(VF)was absorbed in the HMSMs with a content of 37.67% or so.The sustained release effect is further measured by the dissolution in-strument at 37℃ and 50 rpm in ultrapure water.The results showed that the HMSMs/VF system shows good sustained release properties compared with sustained release tablets with hydroxypropyl meth-ylcellulose as the main component.This HMSMs sustained release system appears to be a promising candidate for a sustained drug release.

Metal-organic frameworks for advanced drug delivery

Metal-organic frameworks(MOFs),comprised of organic ligands and metal ions/metal clusters via coordinative bonds are highly porous,crystalline materials.Their tunable porosity,chemical composition,size and shape,and easy surface functionalization make this large family more and more popular for drug delivery.There is a growing interest over the last decades in the design of engineered MOFs with controlled sizes for a variety of biomedical applications.This article presents an overall review and perspectives of MOFs-based drug delivery systems(DDSs),starting with the MOFs classification adapted for DDSs based on the types of constituting metals and ligands.Then,the synthesis and characterization of MOFs for DDSs are developed,followed by the drug loading strategies,applications,biopharmaceutics and quality control.Importantly,a variety of representative applications of MOFs are detailed from a point of view of applications in pharmaceutics,diseases therapy and advanced DDSs.In particular,the biopharmaceutics and quality control of MOFs-based DDSs are summarized with critical issues to be addressed.Finally,challenges in MOFs development for DDSs are discussed,such as biostability,biosafety,biopharmaceutics and nomenclature.

Bioinspired Andrias davidianus-Derived wound dressings for localized drug-elution

Local drug delivery has received increasing attention in recent years.However,the therapeutic efficacy of local delivery of drugs is still limited under certain scenarios,such as in the oral cavity or in wound beds after resection of tumors.In this study,we introduce a bioinspired adhesive hydrogel derived from the skin secretions of Andrias davidianus(SSAD)as a wound dressing for localized drug elution.The hydrogel was loaded with aminoguanidine or doxorubicin,and its controlled drug release and healing-promoting properties were verified in a diabetic rat palatal mucosal defect model and a C57BL/6 mouse melanoma-bearing model,respectively.The results showed that SSAD hydrogels with different pore sizes could release drugs in a controllable manner and accelerate wound healing.Transcriptome analyses of the palatal mucosa suggested that SSAD could significantly upregulate pathways linked to cell adhesion and extracellular matrix deposition and had the ability to recruit keratinocyte stem cells to defect sites.Taken together,these findings indicate that property-controllable SSAD hydrogels could be a promising biofunctional wound dressing for local drug delivery and promotion of wound healing.

Autologous exosome facilitates load and target delivery of bioactive peptides to repair spinal cord injury

Spinal cord injury(SCI)causes motor,sensory and automatic impairment due to rarely axon regeneration.Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal regenerative ability and disconnection of neural elements after injury,as well as the limited systemic drug delivery efficiency caused by blood spinal cord barrier.To develop an effective non-invasive treatment strategy for SCI in clinic,we generated an autologous plasma exosome(AP-EXO)based biological scaffold where AP-EXO was loaded with neuron targeting peptide(RVG)and growth-facilitating peptides(ILP and ISP).This scaffold can be targeted delivered to neurons in the injured area and elicit robust axon regrowth across the lesion core to the levels over 30-fold greater than naïve treatment,thus reestablish the intraspinal circuits and promote motor functional recovery after spinal cord injury in mice.More importantly,in ex vivo,human plasma exosomes(HP-EXO)loaded with combinatory peptides of RVG,ILP and ISP showed safety and no liver and kidney toxicity in the application to nude SCI mice.Combining the efficacy and safety,the AP-EXO-based personalized treatment confers functional recovery after SCI and showed immense promising in biomedical applications in treating SCI.It is helpful to expand the application of combinatory peptides and human plasma derived autologous exosomes in promoting regeneration and recovery upon SCI treatment.