Nanoengineered injectable hydrogels derived from layered double hydroxides and alginate for sustained release of protein therapeutics in tissue engineering applications.

Chronic Kidney Disease (CKD) which involves gradual loss of kidney function is characterized by low levels of a glycoprotein called Erythropoietin (EPO) that leads to red blood cell  deficiency and anemia. Recombinant human EPO (rhEPO) injections that are administered intravenously or subcutaneously is the current gold standard for treating CKD. The rhEPO injections have very short half-lives and thus demands frequent administration with a risk of high endogenous EPO levels leading to severe side effects that could prove fatal. To this effect, this work provides a novel approach of using lamellar inorganic solids with a brucite-like structure for controlling the release of protein therapeutics such as rhEPO in injectable hydrogels. The nanoengineered injectable system was formulated by incorporating two-dimensional layered double hydroxide (LDH) clay materials with a high surface area into alginate hydrogels for sustained delivery. The inclusion of LDH in the hydrogel network not only improved the mechanical properties of the hydrogels (5-30 times that of alginate hydrogel) but also exhibited a high binding affinity to proteins without altering their bioactivity and conformation. Furthermore, the nanoengineered injectable hydrogels (INHs) demonstrated quick gelation, injectability, and excellent adhesion properties on human skin. The in vitro release test of EPO from conventional alginate hydrogels (Alg-Gel) showed 86% EPO release within 108 h while INHs showed greater control over the initial burst and released only 24% of EPO in the same incubation time. INH-based ink was successfully used for 3D printing, resulting in scaffolds with good shape fidelity and stability in cell culture media. Controlled release of EPO from INHs facilitated superior angiogenic potential in ovo (chick chorioallantoic membrane) compared to Alg-Gel. When subcutaneously implanted in albino mice, the INHs formed a stable gel in vivo without inducing any adverse effects. The results suggest that the proposed INHs in this study can be utilized as a minimally invasive injectable platform or as 3D printed patches for the delivery of protein therapeutics to facilitate tissue regeneration.

Self-Assembled Amphiphilic Starch Based Drug Delivery Platform: Synthesis, Preparation, and Interactions with Biological Barriers.

Core-shell structured nanoparticles (NPs) render the simultaneous coloading capacity of both hydrophobic and hydrophilic drugs and may eventually enhance therapeutic efficacy. In this study, we employed a facile squalenoylation technology to synthesize a new amphiphilic starch derivative from partially oxidized starch, which self-assembled into core-shell starch NPs (StNPs) only at a squalenyl degree of substitution (DoS) of ∼1%. The StNPs characteristics could be tuned as the functions of the polymer molecular weight, DoS, and NPs concentration. The biopharmaceutical features of the StNPs, including colloidal stability, carrier properties, and biocompatibility, were carefully investigated. The interaction study between StNPs and mucin glycoproteins, the main organic component of mucus, revealed a moderate mucin interacting profile. Furthermore, the StNPs also showed good penetration through Pseudomonas aeruginosa biofilms. These results nominate StNPs as a versatile drug delivery platform with potential applications for mucosal drug delivery and the treatment of persistent infections.

Bioinspired pH- and Temperature-Responsive Injectable Adhesive Hydrogels with Polyplexes Promotes Skin Wound Healing.

Despite great potential, the delivery of genetic materials into cells or tissues of interest remains challenging owing to their susceptibility to nuclease degradation, lack of permeability to the cell membrane, and short in vivo half-life, which severely restrict their widespread use in therapeutics. To surmount these shortcomings, we developed a bioinspired in situ-forming pH- and temperature-sensitive injectable hydrogel depot that could control the delivery of DNA-bearing polyplexes for versatile biomedical applications. A series of multiblock copolymer, comprised of water-soluble poly(ethylene glycol) (PEG) and pH- and temperature-responsive poly(sulfamethazine ester urethane) (PSMEU), has been synthesized as in situ-forming injectable hydrogelators. The free-flowing PEG-PSMEU copolymer sols at high pH and room temperature (pH 8.5, 23 °C) were transformed to stable gel at the body condition (pH 7.4, 37 °C). Physical and mechanical properties of hydrogels, including their degradation rate and viscosity, are elegantly controlled by varying the composition of urethane ester units. Subcutaneous administration of free-flowing PEG-PSMEU copolymer sols to the dorsal region of Sprague-Dawley rats instantly formed hydrogel depot. The degradation of the hydrogel depot was slow at the beginning and found to be bioresorbable after two months. Cationic protein or DNA-bearing polyplex-loaded PEG-PSMEU copolymer sols formed stable gel and controlled its release over 10 days in vivo. Owing to the presence of urethane linkages, the PEG-PSMEU possesses excellent adhesion strength to wide range of surfaces including glass, plastic, and fresh organs. More importantly, the hydrogels effectively adhered on human skin and peeled easily without eliciting an inflammatory response. Subcutaneous implantation of PEG-PSMEU copolymer sols effectively sealed the ruptured skin, which accelerated the wound healing process as observed by the skin appendage morphogenesis. The bioinspired in situ-forming pH- and temperature-sensitive injectable adhesive hydrogel may provide a promising platform for myriad biomedical applications as controlled delivery vehicle, adhesive, and tissue regeneration.

Stimuli-Sensitive Injectable Hydrogels Based on Polysaccharides and Their Biomedical Applications.

Stimuli-sensitive injectable polymeric hydrogels are one of the promising delivery vehicles for the controlled release of bioactive agents. In aqueous solutions, these polymers are able to switch sol-to-gel transitions in response to various stimuli including pH, temperature, light, enzyme and magnetic field. Therapeutic agents, including chemotherapeutic agents, protein drugs or cells, are easily mixed with the low-viscous polymer solution at room temperature. Therapeutic-agents-containing solutions are readily injected into target sites through syringe or catheter, which could form hydrogel depot and serve as bioactive molecules release carriers. In particular, they are convenient for in vivo injection in a minimally invasive manner. Owing to their ease of handling, hydrogel scaffolds encapsulated with a wide array of therapeutic agents including growth factors, cells or fillers have been used in regeneration or filling of the defect area. Therefore, injectable hydrogels found a variety of biomedical applications, such as drug delivery and tissue engineering. Here, we summarize the chemical designs and recent developments of polysaccharide-based injectable hydrogels, giving a special attention to hydrogels prepared using amphiphilic polysaccharides for biomedical applications. Advantages and future perspectives of polysaccharide-based injectable hydrogels are highlighted.

Bioreducible shell-cross-linked hyaluronic acid nanoparticles for tumor-targeted drug delivery.

The major issues of self-assembled nanoparticles as drug carriers for cancer therapy include biostability and tumor-targetability because the premature drug release from and nonspecific accumulation of the drug-loaded nanoparticles may cause undesirable toxicity to normal organs and lower therapeutic efficacy. In this study, we developed robust and tumor-targeted nanocarriers based on an amphiphilic hyaluronic acid (HA)-polycaprolactone (PCL) block copolymer, in which the HA shell was cross-linked via a bioreducible disulfide linkage. Doxorubicin (DOX), chosen as a model anticancer drug, was effectively encapsulated into the nanoparticles with high drug loading efficiency. The DOX-loaded bioreducible HA nanoparticles (DOX-HA-ss-NPs) greatly retarded the drug release under physiological conditions (pH 7.4), whereas the drug release rate was markedly enhanced in the presence of glutathione, a thiol-containing tripeptide capable of reducing disulfide bonds in the cytoplasm. Furthermore, DOX-HA-ss-NPs could effectively deliver the DOX into the nuclei of SCC7 cells in vitro as well as to tumors in vivo after systemic administration into SCC7 tumor-bearing mice, resulting in improved antitumor efficacy in tumor-bearing mice. Overall, it was demonstrated that bioreducible shell-cross-linked nanoparticles could be used as a potential carrier for cancer therapy.

Triple-Hybrid BioScaffold Based on Silk Fibroin, Chitosan, and nano-Biphasic Calcium Phosphates: Preparation, Characterization of Physiochemical and Biopharmaceutical Properties.

Bioscaffolds, which promote cell regeneration and restore tissues' functions, have emerged as significant need in clinic. The hybrid of several biomaterials in a bioscaffold renders clinically advanced and relevant properties for applications yet add challenges in cost efficiency, production, and clinical investigation. This study proposes a facile and sustainable method to formulate a triple-hybrid bioscaffold based on Vietnamese cocoon origin Silk Fibroin, Chitosan, and nano-Biphasic Calcium Phosphates (nano-BCP) that can be easily molded, has high porosity (55-80%), and swelling capacity that facilitates cell proliferation and nutrient diffusion. Notably, their mechanical properties, in particular compressive strength, can easily be tuned in a range from 50 - 200 kPa by changing the amount of nano-BCP addition, which is comparable to the successful precedents for productive cell regeneration. The latter parts investigate the biopharmaceutical properties of a representative bioscaffold, including drug loading and release studies with two kinds of active compounds, salmon calcitonin and methylprednisolone. Furthermore, the bioscaffold is highly biocompatible as the results of hemocompatibility and hemostasis tests, as well as ovo chick chorioallantoic membrane investigation. The findings of the study suggest the triple-hybrid scaffold as a promising platform for multi-functional drug delivery and bone defect repair.

Orally ingestible medication utilizing layered double hydroxide nanoparticles strengthened alginate and hyaluronic acid-based hydrogel bead for bowel disease management.

In the treatment of bowel diseases such as ulcerative colitis through oral administration, an effective drug delivery system targeting the colon is crucial for enhancing efficacy and minimizing side effects of therapeutic agents. This study focuses on the development of a novel nanocomposite hydrogel bead comprising a synergistic blend of biological macromolecules, namely sodium alginate (ALG) and hyaluronic acid (HA), reinforced with layered double hydroxide nanoparticles (LDHs) for the oral delivery of dual therapeutics. The synthesized hydrogel bead exhibits significantly enhanced gel strength and controllable release of methylprednisolone (MP) and curcumin (CUR), serving as an anti-inflammatory drug and a mucosal healing agent, compared to native ALG or ALG/HA hydrogel beads without LDHs. The physicochemical properties of the synthesized LDHs and hydrogel beads were characterized using various techniques, including scanning electron microscopy, zeta potential measurement, transmission electron microscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy. In vitro release studies of MP and CUR under simulated gastrointestinal tract (GIT) conditions demonstrate the superior controlled release property of the nanocomposite hydrogel bead, particularly in minimizing premature drug release in the upper GIT environment while sustaining release of over 82 % of drugs in the colonic environment. Thus, the modularly engineered carrier designed for oral colon targeting holds promise as a potential candidate for the treatment of ulcerative colitis.

Electric Field-Responsive Gold Nanoantennas for the Induction of a Locoregional Tumor pH Change Using Electrolytic Ablation Therapy.

Electrolytic ablation (EA) is a burgeoning treatment for solid tumors, in which electrical energy catalyzes a chemical reaction to generate reactive species that can eradicate cancer cells. However, the application of this technique has been constrained owing to the limited spatial effectiveness and complexity of the electrode designs. Therefore, the incorporation of nanotechnology into EA is anticipated to be a significant improvement. Herein, we present a therapeutic approach based on difructose dianhydride IV-conjugated polyethylenimine-polyethylene glycol-modified gold nanorods as electric nanoantennas and nanoelectrocatalysts for EA. We demonstrate that square-wave direct current (DC) fields trigger a reaction between water molecules and chloride ions on the gold nanorod surface, generating electrolytic products including hydrogen, oxygen, and chlorine gases near the electrodes, changing the pH, and inducing cell death. These electric nanoantennas showed significant efficacy in treating colorectal cancer both in vitro and in vivo after DC treatment. These findings clearly indicate that gold nanoantennas enhance the effectiveness of EA by creating a localized electric field and catalyzing electrolytic reactions for the induction of locoregional pH changes within the tumor. By overcoming the limitations of traditional EA and offering an enhanced level of tumor specificity and control, this nanotechnology-integrated approach advances further innovations in cancer therapies.

Amphiphilic polysialic acid derivatives: synthesis, characterization, and in-vitro cytotoxicity.

Polysialic acid (PSA), a natural hydrophilic polysaccharide, is a potential alternative to poly(ethylene glycol) as the hydrophilic constituent of the polymeric amphiphiles for biomedical applications. In this study, amphiphilic block copolymers were prepared based on PSA as the hydrophilic block and polycaprolactone (PCL) as the hydrophobic block. The block copolymers formed micelles with spherical shapes in an aqueous environment. The average sizes of the nanoparticles were in the range of 270-390 nm, depending on the block length of PCL. The zeta potential values of the micelles were approximately -20 mV due to the negatively charged carboxylic acids of PSA. The nanoparticles showed good stability for five days in a physiological solution (pH 7.4), and had low critical micelle concentration values (1.68-8.54 microg/ml). The in-vitro cytotoxicity tests confirmed that the PSA-PCL micelles had little cytotoxicity. All these results suggest that the PSA-PCL block copolymers can form nano-sized micelles with high stability and low toxicity, implying their high potential for biomedical application.

Carboxymethyl dextran-cyclodextrin conjugate as the carrier of doxorubicin.

The carboxymethyl dextran-y-cyclodextrin (CMD-yCD) conjugate was prepared as the carrier for the delivery of the poorly water-soluble anticancer drug, doxorubicin (DOX). The conjugate could form self-assembled nanoparticles (315 nm in diameter) in an aqueous solution, which might be due to the hydrogen bonding among yCD molecules in the conjugate. DOX was effectively encapsulated into CMD-yCD nanoparticles (CMD-NPs) by the emulsion method. In particular, regardless of the feed amount of DOX, its loading efficiencies were always greater than 70%. CMD-NPs released DOX in a sustained manner, owing to the inclusion complex formation between DOX and yCD. When Cy5.5-labeled CMD-NPs were treated with SCC7 cancer cells, strong fluorescence signals were observed at the cytosol, indicating effective intracellular uptake. In addition, DOX-loaded CMD-NPs exhibited dose-dependent cytotoxicity to SCC7 cancer cells. However, the empty nanoparticles did not show toxicity to the cells, implying their high biocompatibility. Overall, these results suggest that the CMD-gammaCD conjugate could be a useful carrier for the delivery of DOX.

Recent strategies to develop pH-sensitive injectable hydrogels.

"Smart" biomaterials that are responsive to pathological abnormalities are an appealing class of therapeutic platforms for the development of personalized medications. The development of such therapeutic platforms requires novel techniques that could precisely deliver therapeutic agents to the diseased tissues, resulting in enhanced therapeutic effects without harming normal tissues. Among various therapeutic platforms, injectable pH-responsive biomaterials are promising biomaterials that respond to the change in environmental pH. Aqueous solutions of injectable pH-responsive biomaterials exhibit a phase transition from sol-to-gel in response to environmental pH changes. The injectable pH-responsive hydrogel depot can provide spatially and temporally controlled release of various bioactive agents including chemotherapeutic drugs, peptides, and proteins. Therapeutic agents are imbibed into hydrogels by simple mixing without the use of toxic solvents and used for long-term storage or in situ injection using a syringe or catheter that could form a stable gel and acts as a controlled release depot in a minimally invasive manner. Tunable physicochemical properties of the hydrogels, such as biodegradability, ability to interact with drugs and mechanical properties, can control the release of the therapeutic agent. This review highlights the advances in the design and development of biodegradable and in situ forming injectable pH-responsive biomaterials that respond to the physiological conditions. Special attention has been paid to the development of amphoteric pH-responsive biomaterials and their utilization in biomedical applications. We also highlight key challenges and future directions of pH-responsive biomaterials in clinical translation.

Injectable hydrogel imbibed with camptothecin-loaded mesoporous silica nanoparticles as an implantable sustained delivery depot for cancer therapy.

In recent years, injectable stimuli-sensitive hydrogels are employed as suitable drug delivery carriers for the release of various anti-cancer drugs. However, large pore size of the microporous hydrogel trigger release of small molecular anticancer drug that limits hydrogel application in cancer therapy. Therefore, introducing reinforcing fillers such as mesoporous silica nanoparticles (MSNs) can not only load different type of anticancer drugs but also prevent the premature release of drugs due to the strengthening of the networks. Furthermore, high specific surface area, suitable size, large pore volume, and stable physicochemical properties of MSNs can improve the therapeutic efficacy. In this study, to sustain the release of hydrophobic anticancer drug, camptothecin (CPT) was loaded into MSNs, and then imbibed into the physiological stimuli-sensitive poly(ethylene glycol)-poly(ß-aminoester urethane) (PAEU) hydrogels. MSN-imbibed PAEU hydrogels exhibited prolonged release of CPT than MSNs and PAEU hydrogel alone. Furthermore, MSN-imbibed PAEU copolymers form stable viscoelastic gel depot into the subcutaneous layers of Sprague-Dawley rats and found to be safe and not induced toxicity to healthy organs, implying biodegradability and safety of the hydrogels. Interestingly, CPT-loaded hydrogels shown dose-dependent toxicity to A549 and B16F10 cells. These results demonstrated that MSN-imbibed PAEU hydrogel with biocompatible, biodegradable, and in situ gel forming property could be a useful drug delivery depot for sustained release of anticancer drugs.

Antibody-conjugated and streptomycin-chitosan oligosaccharide-modified gold nanoshells for synergistic chemo-photothermal therapy of drug-resistant bacterial infection.

Despite the many advanced strategies that are available, rapid gene mutation in multidrug-resistant bacterial infections remains a major challenge. Combining new therapeutic strategies such as chemo-photothermal therapy (PTT) with high antibacterial efficiency against drug-resistant Listeria monocytogenes (LM) is urgently needed. Here, we report synergistic chemo-PTT against drug-resistant LM based on antibody-conjugated and streptomycin-chitosan oligosaccharide-modified gold nanoshells (anti-STR-CO-GNSs) as all-in-one nanotheranostic agents for the first time, which was used for accurate antibacterial applications. The anti-STR-CO-GNSs showed excellent photothermal conversion efficiency (31.97 %) and were responsive to near-infrared (NIR) and pH dual stimuli-triggered antibiotic release, resulting in outstanding chemo-photothermal effects against LM. In vitro chemo-photothermal effect of anti-STR-CO-GNSs with laser irradiation caused a greater antibacterial effect (1.37 %), resulting in more rapid killing of LM and prevention of LM regrowth. Most importantly, the mice receiving the anti-STR-CO-GNSs with laser irradiation specifically at the sites of LM infections healed almost completely, leaving only scars on the surface of the skin and resulting in superior inhibitory effects from combined chemo-PTT. Overall, our findings suggest that chemo-PTT using smart biocompatible anti-STR-CO-GNSs is a favorable potential alternative to combat the increasing threat of drug-resistant LM, which opens a new door for clinical anti-infection therapy in the future.

Biocompatible Calcium Ion-Doped Magnesium Ferrite Nanoparticles as a New Family of Photothermal Therapeutic Materials for Cancer Treatment.

Novel biocompatible and efficient photothermal (PT) therapeutic materials for cancer treatment have recently garnered significant attention, owing to their effective ablation of cancer cells, minimal invasiveness, quick recovery, and minimal damage to healthy cells. In this study, we designed and developed calcium ion-doped magnesium ferrite nanoparticles (Ca2+-doped MgFe2O4 NPs) as novel and effective PT therapeutic materials for cancer treatment, owing to their good biocompatibility, biosafety, high near-infrared (NIR) absorption, easy localization, short treatment period, remote controllability, high efficiency, and high specificity. The studied Ca2+-doped MgFe2O4 NPs exhibited a uniform spherical morphology with particle sizes of 14.24 ± 1.32 nm and a strong PT conversion efficiency (30.12%), making them promising for cancer photothermal therapy (PTT). In vitro experiments showed that Ca2+-doped MgFe2O4 NPs had no significant cytotoxic effects on non-laser-irradiated MDA-MB-231 cells, confirming that Ca2+-doped MgFe2O4 NPs exhibited high biocompatibility. More interestingly, Ca2+-doped MgFe2O4 NPs exhibited superior cytotoxicity to laser-irradiated MDA-MB-231 cells, inducing significant cell death. Our study proposes novel, safe, high-efficiency, and biocompatible PT therapeutics for treating cancers, opening new vistas for the future development of cancer PTT.

Challenges and progress toward tumor-targeted therapy by systemic delivery of polymer-complexed oncolytic adenoviruses.

Oncolytic adenovirus (oAd) elicits antitumor activity by preferential viral replication in cancer cells. However, poor systemic administrability or suboptimal intratumoral retainment of the virus remains a major challenge toward maximizing the antitumor activity of oAd in a clinical environment. To surmount these issues, a variety of non-immunogenic polymers has been used to modify the surface of oAds chemically or physically. Complexation of oAd with polymers can effectively evade the host immune response and reduces nonspecific liver sequestration. The tumor-specific delivery of these complexes can be further improved upon by inclusion of tumor-targeting moieties on the surface. Therefore, modification of the Ad surface using polymers is viewed as a potential strategy to enhance the delivery of Ad via systemic administration. This review aims to provide a comprehensive overview of polymer-complexed Ads, their progress, and future challenges in cancer treatment.

Gene Regulations upon Hydrogel-Mediated Drug Delivery Systems in Skin Cancers-An Overview.

The incidence of skin cancer has increased dramatically in recent years, particularly in Caucasian populations. Specifically, the metastatic melanoma is one of the most aggressive cancers and is responsible for more than 80% of skin cancer deaths around the globe. Though there are many treatment techniques, and drugs have been used to cure this belligerent skin cancer, the side effects and reduced bioavailability of drug in the targeted area makes it difficult to eradicate. In addition, cellular metabolic pathways are controlled by the skin cancer driver genes, and mutations in these genes promote tumor progression. Consequently, the MAPK (RAS-RAF-MEK-ERK pathway), WNT and PI3K signaling pathways are found to be important molecular regulators in melanoma development. Even though hydrogels have turned out to be a promising drug delivery system in skin cancer treatment, the regulations at the molecular level have not been reported. Thus, we aimed to decipher the molecular pathways of hydrogel drug delivery systems for skin cancer in this review. Special attention has been paid to the hydrogel systems that deliver drugs to regulate MAPK, PI3K-AKT-mTOR, JAK-STAT and cGAS-STING pathways. These signaling pathways can be molecular drivers of skin cancers and possible potential targets for the further research on treatment of skin cancers.

A pH- and Bioreducible Cationic Copolymer with Amino Acids and Piperazines for Adenovirus Delivery.

Adenoviruses (Ads) are attractive nonviral vectors and show great potential in cancer gene therapy. However, inherent properties of Ads, including immunogenicity, nonspecific toxicity, and coxsackie and adenovirus receptor (CAR)-dependent cell uptake, limit their clinical use. To surmount these issues, we developed a pH- and glutathione-responsive poly(ethylene glycol)-poly(ꞵ-aminoester)-polyethyleneimine (PPA) for conjugation with Ad. The pH sensitivity of the PPA copolymer was elegantly tuned by substitution with different amino acids (arginine, histidine, and tryptophan), piperazines (Pip1, Pip2, and Pip3), and guanidine residues in the backbone of the PPA conjugate. PPA copolymer was further functionalized with short-chain cross-linker succinimidyl 3-(2-pyridyldithio)propionate) (SPDP) to obtain PPA-SPDP for facile conjugation with Ad. The PPA-conjugated Ad (PPA-Ad) conjugate was obtained by reacting PPA-SPDP conjugate with thiolated Ad (Ad-SH). Ad-SH was prepared by reacting Ad with 2-iminothiolane. The size distribution and zeta potential results of PPA-Ad conjugate showed an increasing trend with an increase in copolymer dose. From in vitro test, it was found that the transduction efficiency of PPA-Ad conjugate in CAR-positive cells (A549 and H460 cells) was remarkably increased at the acidic pH condition (pH 6.2) when compared with PPA-Ad conjugate incubated under the physiological condition (pH 7.4). Interestingly, the increase in transduction efficiency was evidenced in CAR-negative cells (MDA-MB-231 and T24 cells). These results demonstrated that biocompatible and biodegradable PPA copolymers can efficiently cover the surface of Ad and can increase the transduction efficiency, and hence PPA copolymers can be a useful nanomaterial for viral vector delivery in cancer therapy.

Polymeric Systems for Cancer Immunotherapy: A Review.

Immunotherapy holds enormous promise to create a new outlook of cancer therapy by eliminating tumors via activation of the immune system. In immunotherapy, polymeric systems play a significant role in improving antitumor efficacy and safety profile. Polymeric systems possess many favorable properties, including magnificent biocompatibility and biodegradability, structural and component diversity, easy and controllable fabrication, and high loading capacity for immune-related substances. These properties allow polymeric systems to perform multiple functions in immunotherapy, such as immune stimulants, modifying and activating T cells, delivery system for immune cargos, or as an artificial antigen-presenting cell. Among diverse immunotherapies, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cell, and oncolytic virus recently have been dramatically investigated for their remarkable success in clinical trials. In this report, we review the monotherapy status of immune checkpoint inhibitors, CAR-T cell, and oncolytic virus, and their current combination strategies with diverse polymeric systems.

Production of Minor Ginsenoside CK from Major Ginsenosides by Biotransformation and Its Advances in Targeted Delivery to Tumor Tissues Using Nanoformulations.

For over 2000 years, ginseng (roots of Panax ginseng C.A. Meyer) has been used as a traditional herbal medicine. Ginsenosides are bioactive compounds present in ginseng responsible for the pharmacological effects and curing various acute diseases as well as chronic diseases including cardiovascular disease, cancer and diabetes. Structurally, ginsenosides consist of a hydrophobic aglycone moiety fused with one to four hydrophilic glycoside moieties. Based on the position of sugar units and their abundance, ginsenosides are classified into major and minor ginsenosides. Despite the great potential of ginsenosides, major ginsenosides are poorly absorbed in the blood circulation, resulting in poor bioavailability. Interestingly, owing to their small molecular weight, minor ginsenosides exhibit good permeability across cell membranes and bioavailability. However, extremely small quantities of minor ginsenosides extracted from ginseng plants cannot fulfill the requirement of scientific and clinical studies. Therefore, the production of minor ginsenosides in mass production is a topic of interest. In addition, their poor solubility and lack of targetability to tumor tissues limits their application in cancer therapy. In this review, various methods used for the transformation of major ginsenosides to minor ginsenoside compound K (CK) are summarized. For the production of CK, various transformation methods apply to major ginsenosides. The challenges present in these transformations and future research directions for producing bulk quantities of minor ginsenosides are discussed. Furthermore, attention is also paid to the utilization of nanoformulation technology to improve the bioavailability of minor ginsenoside CK.

Recent advances in multifunctional nanomaterials for photothermal-enhanced Fenton-based chemodynamic tumor therapy.

Photothermal (PT)-enhanced Fenton-based chemodynamic therapy (CDT) has attracted a significant amount of research attention over the last five years as a highly effective, safe, and tumor-specific nanomedicine-based therapy. CDT is a new emerging nanocatalyst-based therapeutic strategy for the in situ treatment of tumors via the Fenton reaction or Fenton-like reaction, which has got fast progress in recent years because of its high specificity and activation by endogenous substances. A variety of multifunctional nanomaterials such as metal-, metal oxide-, and metal-sulfide-based nanocatalysts have been designed and constructed to trigger the in situ Fenton or Fenton-like reaction within the tumor microenvironment (TME) to generate highly cytotoxic hydroxyl radicals (•OH), which is highly efficient for the killing of tumor cells. However, research is still required to enhance the curative outcomes and minimize its side effects. Specifically, the therapeutic efficiency of certain CDTs is still hindered by the TME, including low levels of endogenous hydrogen peroxide (H2O2), overexpression of reduced glutathione (GSH), and low catalytic efficacy of Fenton or Fenton-like reactions (pH 5.6-6.8), which makes it difficult to completely cure cancer using monotherapy. For this reason, photothermal therapy (PTT) has been utilized in combination with CDT to enhance therapeutic efficacy. More interestingly, tumor heating during PTT not only causes damage to the tumor cells but can also accelerate the generation of •OH via the Fenton and Fenton-like reactions, thus enhancing the CDT efficacy, providing more effective cancer treatment when compared with monotherapy. Currently, synergistic PT-enhanced CDT using multifunctional nanomaterials with both PT and chemodynamic properties has made enormous progress in cancer theranostics. However, there has been no comprehensive review on this subject published to date. In this review, we first summarize the recent progress in PT-enhanced Fenton-based CDT for cancer treatment. We then discuss the potential and challenges in the future development of PT-enhanced Fenton-based nanocatalytic tumor therapy for clinical application.