3D printing tissue-engineered scaffolds for auricular reconstruction.

Congenital microtia is the most common cause of auricular defects, with a prevalence of approximately 5.18 per 10,000 individuals. Autologous rib cartilage grafting is the leading treatment modality at this stage of auricular reconstruction currently. However, harvesting rib cartilage may lead to donor site injuries, such as pneumothorax, postoperative pain, chest wall scarring, and deformity. Therefore, in the pursuit of better graft materials, biomaterial scaffolds with great histocompatibility, precise control of morphology, non-invasiveness properties are gradually becoming a new research hotspot in auricular reconstruction. This review collectively presents the exploit and application of 3D printing biomaterial scaffold in auricular reconstruction. Although the tissue-engineered ear still faces challenges before it can be widely applied to patients in clinical settings, and its long-term effects have yet to be evaluated, we aim to provide guidance for future research directions in 3D printing biomaterial scaffold for auricular reconstruction. This will ultimately benefit the translational and clinical application of cartilage tissue engineering and biomaterials in the treatment of auricular defects.

Pd Loaded NiCo Hydroxides for Biomass Electrooxidation: Understanding the Synergistic Effect of Proton Deintercalation and Adsorption Kinetics.

The key issue in the 5-hydroxymethylfurfural oxidation reaction (HMFOR) is to understand the synergistic mechanism involving the protons deintercalation of catalyst and the adsorption of the substrate. In this study, a Pd/NiCo catalyst was fabricated by modifying Pd clusters onto a Co-doped Ni(OH)2 support, in which the introduction of Co induced lattice distortion and optimized the energy band structure of Ni sites, while the Pd clusters with an average size of 1.96 nm exhibited electronic interactions with NiCo support, resulting in electron transfer from Pd to Ni sites. The resulting Pd/NiCo exhibited low onset potential of 1.32 V and achieved a current density of 50 mA/cm2 at only 1.38 V. Compared to unmodified Ni(OH)2 , the Pd/NiCo achieved an 8.3-fold increase in peak current density. DFT calculations and in situ XAFS revealed that the Co sites affected the conformation and band structure of neighboring Ni sites through CoO6 octahedral distortion, reducing the proton deintercalation potential of Pd/NiCo and promoting the production of Ni3+ -O active species accordingly. The involvement of Pd decreased the electronic transfer impedance, and thereby accelerated Ni3+ -O formation. Moreover, the Pd clusters enhanced the adsorption of HMF through orbital hybridization, kinetically promoting the contact and reaction of HMF with Ni3+ -O.

Cerebral delivery of redox-responsive lenalidomide prodrug plus methotrexate for primary central nerve system lymphoma combination therapy.

Primary central nervous system lymphoma (PCNSL) is an extremely malignant CNS tumor with high incidence and mortality rates. Its chemotherapy in the clinic has been restricted owing to unsatisfactory drug distribution in the cerebral tissues. In this study, a redox-responsive prodrug of disulfide-lenalidomide-methoxy polyethylene glycol (LND-DSDA-mPEG) was successfully developed for the cerebral delivery of lenalidomide (LND), and methotrexate (MTX) via subcutaneous (s.c.) administration at the neck for combined anti-angiogenesis and chemotherapy on PCNSL. Both the subcutaneous xenograft tumor model and orthotopic intracranial tumor model demonstrated that the co-delivery of LND and MTX nanoparticles (MTX@LND NPs) may significantly inhibit the growth of lymphoma and effectively prevent liver metastasis by downregulating CD31 and VEGF expression. Moreover, an orthotopic intracranial tumor model further verified that through s.c. administration at the neck, redox-responsive MTX@LND NPs could bypass the blood-brain barrier (BBB), efficiently distribute into brain tissues, and effectively inhibit lymphoma growth in the brain, as detected by magnetic resonance imaging (MRI). Taken together, this biodegradable, biocompatible, and redox-responsive nano-prodrug with highly effective targeted delivery of LND and MTX in the brain through the lymphatic vasculature may provide a facile and feasible treatment strategy for PCNSL in the clinic.

Tumor Microenvironment Mediated Spermidine-Metal-Immunopeptide Nanocomplex for Boosting Ferroptotic Immunotherapy of Lymphoma.

Immunotherapy as an alternative treatment strategy for B-cell lymphoma is undesirable because of tumor heterogeneity and immune surveillance. Spermidine (SPM), as a regulator of the tumor microenvironment (TME), can facilitate the release of damage-associated molecular patterns (DAMPs) from cancer cells, promote immune recognition, and thus alleviate immune surveillance in the TME. Hence, in this work, self-assembled spermidine-based metal-immunopeptide nanocomplexes (APP-Fe NCs; APP is anti-programmed death ligand-1 peptide) with pH-responsive release kinetics were prepared via the flash nanocomplexation (FNC) technique based on the noncovalent interaction between APP-SPM-dextran (DEX) and sodium tripolyphosphate (TPP) and coordination between Fe3+ and TPP. An in vitro study suggested that APP-Fe NCs effectively induce strong oxidative stress and mitochondrial dysfunction and subsequently lead to ferroptosis in cells by interfering with homeostasis in lymphoma cells. Further investigation on lymphoma mice models demonstrated that APP-Fe NCs effectively inhibited the growth and liver metastasis of lymphomas. Mechanistically, by triggering ferroptosis in tumor tissues, these spermidine-containing APP-Fe NCs efficiently facilitated the release of DAMPs and ultimately reshaped TME to enhance immunotherapy efficacy in lymphoma. Combined with its good histocompatibility and facile preparation technique, this pH-responsive APP-Fe NCs with regulation on TME may hold potential for cascade amplification on the combinative immunotherapy of lymphoma in the clinic.

Facile synthesis of poly(disulfide)s through one-step oxidation polymerization for redox-responsive drug delivery.

Poly(disulfide)s-based systems with repetitive disulfide bonds in their backbones are emerging as promising tumor microenvironment responsive platforms for drug delivery. However, complicated synthesis and purification processes have restricted their further application. Herein, we developed redox-responsive poly(disulfide)s (PBDBM) by one-step oxidation polymerization of a commercially available monomer, 1,4-butanediol bis(thioglycolate) (BDBM). PBDBM can self-assemble with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)3400 (DSPE-PEG3.4k) by the nanoprecipitation method and be formulated into PBDBM NPs (sub 100 nm). It can also be loaded with docetaxel (DTX), a first-line chemotherapy agent for breast cancer, to form DTX@PBDBM NPs with a loading capacity of 6.13%. DTX@PBDBM NPs with favorable size stability and redox-responsive capability exhibit superior antitumor activity in vitro. In addition, owing to the different glutathione (GSH) levels in normal and tumor cells, PBDBM NPs with disulfide bonds could synergistically increase intracellular ROS levels, further inducing apoptosis and cell cycle arrest in the G2/M phase. Moreover, in vivo studies revealed that PBDBM NPs could accumulate in tumors, suppress 4T1 tumor growth, and significantly attenuate the systemic toxicity of DTX. Thus, a novel redox-responsive poly(disulfide)s nanocarrier was successfully and facilely developed for cancer drug delivery and effective breast cancer therapy.

Nanomaterial-Based Antivascular Therapy in the Multimodal Treatment of Cancer.

Abnormal tumor vasculature and a hypoxic tumor microenvironment (TME) limit the effectiveness of conventional cancer treatment. Recent studies have shown that antivascular strategies that focus on antagonizing the hypoxic TME and promoting vessel normalization effectively synergize to increase the antitumor efficacy of conventional therapeutic regimens. By integrating multiple therapeutic agents, well-designed nanomaterials exhibit great advantages in achieving higher drug delivery efficiency and can be used as multimodal therapy with reduced systemic toxicity. In this review, strategies for the nanomaterial-based administration of antivascular therapy combined with other common tumor treatments, including immunotherapy, chemotherapy, phototherapy, radiotherapy, and interventional therapy, are summarized. In particular, the administration of intravascular therapy and other therapies with the use of versatile nanodrugs is also described. This review provides a reference for the development of multifunctional nanotheranostic platforms for effective antivascular therapy in combined anticancer treatments.

Tomato based gelatin methacryloyl hydrogel as an effective natural and low-cost scaffold for accelerative wound healing.

Oxidative stress and infection are the main reasons for postponement of wound healing rate. They can potentially lead to serious inflammation and eventually lead to a longer and more painful recovery phase. Although wound dressings based on synthetic materials with antioxidative property have been proved to exhibit remarkable effect in controlling ROS level and improving wound healing, issues, such as high cost in raw materials, complicated procedures, usage of various toxic additives, and potential allergies, have significantly confined further clinical applications. In this study, a novel type of tissue engineering scaffold, based on tomatoes (Solanum lycopersicon) and gelatin methacryloyl (GelMA), was prepared via facile lyophilization and photo cross-link method (SL/GelMA). By taking advantages of various antioxidative components, such as carotenoids, flavonoids, phenolic acids, vitamin E, and vitamin C in tomatoes, SL/GelMA can effectively regulate ROS level, relieve the oxidative stress in wound bed, promote cell migration and angiogenesis, contribute to collagen deposition, and thus accelerate the rate of wound enclosure. Along with its high biocompatibility and low allergic potential, we believe that the food-derived wound dressing with facile preparation method, easy accessibility, and high cost-effectiveness can be translated for clinical treatments of various chronic wounds.

Metal-Cyclic Dinucleotide Nanomodulator-Stimulated STING Signaling for Strengthened Radioimmunotherapy of Large Tumor.

Combined treatment of immunotherapy and radiotherapy shows promising therapeutic effects for the regression of a variety of cancers. However, even multi-modality therapies often fail to antagonize the regression of large tumors due to the extremely immunosuppressive tumor microenvironment (TME). Here, a radioimmunotherapeutic paradigm based on stimulator of interferon genes (STING)-dependent signaling is applied to preclude large tumor progression by utilizing the metal-cyclic dinucleotide (CDN) nanoplatform, which integrates STING agonist c-di-AMP and immunomodulating microelement manganese (II) within the tannic acid nanostructure (TMA-NPs). As observed by magnetic resonance imaging, the localized administration of TMA-NPs effectively relieves hypoxia within TME and causes radical oxygen species overproduction and apoptosis in cancer cells after exposure to X-ray irradiation. The DNA fragments released from the apoptotic cells after the combined treatment augment the production of endogenous CDNs in cancer cells, hence significantly activating the STING-mediated pathway for stronger anti-tumor immunity. The localized therapy of TMA-NPs + X-ray not only inhibits the primary large tumor progression but also retards distant tumor growth by promoting dendritic cell maturation and activating cytotoxic immune cells whil suppressing immunosuppressive cells. Therefore, this work represents the combinatorial potency of TMA-NPs and X-rays on large tumor regression through strengthened STING-mediated radioimmunotherapeutics.

Stimuli-responsive cyclodextrin-based supramolecular assemblies as drug carriers.

Cyclodextrins (CDs) are widely employed in biomedical applications because of their unique structures. Various biomedical applications can be achieved in a spatiotemporally controlled manner by integrating the host-guest chemistry of CDs with stimuli-responsive functions. In this review, we summarize the recent advances in stimuli-responsive supramolecular assemblies based on the host-guest chemistry of CDs. The stimuli considered in this review include endogenous (pH, redox, and enzymes) and exogenous stimuli (light, temperature, and magnetic field). We mainly discuss the mechanisms of the stimuli-responsive ability and present typical designs of the corresponding supramolecular assemblies for drug delivery and other potential biomedical applications. The limitations and perspectives of CD-based stimuli-responsive supramolecular assemblies are discussed to further promote the translation of laboratory products into clinical applications.

Poly(disulfide)s: From Synthesis to Drug Delivery.

Bioresponsive polymers have been widely used in drug delivery because of their degradability. For example, poly(disulfide)s with repeating disulfide bonds in the main chain have attracted considerable research attention. The characteristics of the disulfide bonds, including their dynamic and reversible properties and their responsiveness to stimuli such as reductants, light, heat, and mechanical force, make them ideal platforms for on-demand drug delivery. This review introduces the synthesis methods and applications of poly(disulfide)s. Furthermore, the synthesis methods of poly(disulfide)s are classified on the basis of the monomers used: oxidative step-growth polymerization with dithiols, ring-opening polymerization with cyclic disulfides, and polymerization with linear disulfides. In addition, recent advances in poly(disulfide)s for the delivery of small-molecule or biomacromolecular drugs are discussed. Quantum-dot-loaded poly(disulfide) delivery systems for imaging are also included. This review provides an overview of the various design strategies employed in the construction of poly(disulfide) platforms to inspire new applications in the field of drug delivery.

Sustained Release Systems for Delivery of Therapeutic Peptide/Protein.

Peptide/protein therapeutics have been significantly applied in the clinical treatment of various diseases such as cancer, diabetes, etc. owing to their high biocompatibility, specificity, and therapeutic efficacy. However, due to their immunogenicity, instability stemming from its complex tertiary and quaternary structure, vulnerability to enzyme degradation, and rapid renal clearance, the clinical application of protein/peptide therapeutics is significantly confined. Though nanotechnology has been demonstrated to prevent enzyme degradation of the protein therapeutics and thus enhance the half-life, issues such as initial burst release and uncontrollable release kinetics are still unsolved. Moreover, the traditional administration method results in poor patient compliance, limiting the clinical application of protein/peptide therapeutics. Exploiting the sustained-release formulations for more controllable delivery of protein/peptide therapeutics to decrease the frequency of injection and enhance patient compliance is thus greatly meaningful. In this review, we comprehensively summarize the substantial advancements of protein/peptide sustained-release systems in the past decades. In addition, the advantages and disadvantages of all these sustained-release systems in clinical application together with their future challenges are also discussed in this review.

Therapeutic nanovaccines sensitize EBV-associated tumors to checkpoint blockade therapy.

For successful treatment of EBV-associated tumors immune tolerance must be broken. While most studies of EBV-associated tumor vaccines have focused on augmenting tumor-specific effector T cells, the effects of these vaccines on the immune-suppressive tumor microenvironment have not been investigated. Here, we describe the manufacture of a nanovaccine using tannic acid (TA) and a newly constructed protein antigen for EBV-associated tumors with interferon-α (IFN-α) or CpG as adjuvants. TA as a biocompatible material from plant self-assembles with antigens and adjuvants via hydrogen bonding to form well-defined nanoparticulate vaccines by flash nanocomplexation, a scalable yet controllable technique. By targeting lymph nodes, the nanovaccine co-loaded with CpG adjuvant induces strong immune activation and exhibits efficient inhibition tumorigenesis. Moreover, the nanovaccine combining with anti-PD-L1 results a marked decrease in tumor size and prolonged survival of tumor-bearing mice by decreasing infiltration of regulatory T cells to the tumor lesion. This suggests that the nanovaccine can reverse immune checkpoint inhibitor resistance by remodeling the tumor microenvironment. Thus, this study shows a promising strategy for treatment of EBV-positive tumors in patients.

A polyphenol-metal nanoparticle platform for tunable release of liraglutide to improve blood glycemic control and reduce cardiovascular complications in a mouse model of type II diabetes.

Liraglutide is a GLP-1 receptor agonist recently approved for Type-II diabetes (T2D) treatment with superior hypoglycemic effect while also improving cardiovascular function for the patients. However, its application has been limited by its short half-life (~13 h), which requires daily injections to maintain effective drug concentrations in blood, thus increasing the risk of poor patient compliance and complications. In this study, we developed a ternary liraglutide/tannic acid (TA)/Al3+ nanoparticle system based on hydrogen bond formation between liraglutide and TA and stabilized by complex coordination interaction between TA and Al3+. This ternary nanoparticle formulation offers sustained release of liraglutide for >8 days by optimizing the concentration of TA during nanoparticle assembly. A flash nanocomplexation (FNC) process was adopted to confer homogeneous mixing of the three components and control the assembly kinetics, thus enabling efficient encapsulation, a tunable drug release profile, improved nanoparticle size uniformity, and a high degree of colloidal stability. Upon a single intraperitoneal (i.p.) administration, the optimized formulation effectively lowered the high blood glucose level in a T2D db/db mice model to the normal range (8-10 mmol/L) within 6 h, maintained it for 60 more hours, and kept it lower than the original level for >6 days. In a 30-day treatment study, the nanoparticle formulation with a dosage frequency of once every 5 days exhibited similar or better control of blood sugar level (20% reduction in HbA1c) and weight control than daily injection of free liraglutide at the same treatment dose. The extended glycemic control led to distinctive improvements on reducing cardiomyopathy, including inhibition in lipo-toxicity by decreasing 40% of triglyceride, 30% of diacylglycerol and 50% of PKC level in the heart, as well as ameliorating oxidative stress and cell apoptosis activities through positive regulation on superoxidase, malondialdehyde, caspase-3 and Bax. This nanoparticle system demonstrates improved therapeutic potential owing to its long-acting glycemic control with improved cardiovascular function and reduced tissue toxicity in multiple organs.

Surface Coating Approach to Overcome Mucosal Entrapment of DNA Nanoparticles for Oral Gene Delivery of Glucagon-like Peptide 1.

Oral delivery of nucleic acid therapy is a promising strategy in treating various diseases because of its higher patient compliance and therapeutic efficiency compared to parenteral routes of administration. However, its success has been limited by the low transfection efficiency resulting from nucleic acid entrapment in the mucus layer and epithelial barrier of the gastrointestinal (GI) tract. Herein, we describe an approach to overcome this phenomenon and improve oral DNA delivery in the context of treating type II diabetes (T2D). Linear PEI (lPEI) was used as a carrier to form complexes with plasmid DNA encoding glucagon-like peptide 1 (GLP-1), a common target in T2D treatments. These nanoparticles were then coated with a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-rac-glycero-3-methoxy poly(ethylene glycol)-2000 (DMG-PEG) to render the nanoparticle surface hydrophilic and electrostatically neutral. The surface-modified lPEI/DNA nanoparticles showed higher diffusivity and transport in the mucus layer of the GI tract and mediated high levels of transfection efficiency in vitro and in vivo. Moreover, these modified nanoparticles demonstrated high levels of GLP-1 expression for more than 24 h in the liver, lungs, and intestine in a T2D murine model after a single dose, as well as controlled blood glucose levels within a normal range for at least 18 h with repeatable therapeutic effects upon multiple dosages. Taken together, this work demonstrates the feasibility of an oral plasmid DNA delivery approach in the treatment of T2D through a facile surface modification to improve the mucus permeability and delivery efficiency of the nanoparticles.

Sustained release of exendin-4 from tannic acid/Fe (III) nanoparticles prolongs blood glycemic control in a mouse model of type II diabetes.

Exendin-4 has been clinically adopted as an effective drug for treating type 2 diabetes (T2D), but its short circulation half-life in the blood requires two injections per day to maintain effective glycemic control. This significantly limits its clinical application. In this study, we developed a tannic acid/exendin-4/Fe3+ ternary nanoparticle system to provide sustained release of exendin-4 in vivo. The formation of these nanoparticles relies on TA/exendin-4 complexation and stabilization through TA-Fe3+ coordination, where the rapid reaction kinetics can benefit from efficient mixing of all three components. Adapting our recently developed flash nanocomplexation (FNC) method, we formulated nanoparticles with high encapsulation efficiency (~ 100%) of exendin-4, high payload capacity, and high degrees of uniformity and stability because the rapid turbulent mixing facilitated a homogeneous distribution of all three components in the complexation process. Intraperitoneal injection in mice showed that exendin-4 released from the nanoparticles had an AUC 7.2-fold higher than the free exendin-4 injection. Efficacy study in a T2D mouse model showed that the optimized formulation achieved a rapid reduction of the blood glucose level to the normal range within <12 h and maintained the same level for 72 h following a single intraperitoneal dose. The blood glucose level was maintained to below the therapeutic level (< 15 mmol/L) for 6 days, and the treatment led to reduced body weight with pathological and functional improvements in the kidney and liver. This tannic acid/exendin-4/Fe3+ ternary nanoparticle system holds translational potential in treating T2D, due to its improved treatment outcomes in terms of extended release of exendin-4, prolonged control of blood glucose level, reduced dosing frequency, and improved pathological indicators.

Size-controlled lipid nanoparticle production using turbulent mixing to enhance oral DNA delivery.

Lipid-based nanoparticles (LNPs) have been developed to address the transport and uptake barriers to enhance the delivery efficiency of plasmid DNA therapeutics. In these systems, plasmid DNA can be encapsulated through condensation by a cationic lipid to form lipo-complexes, or polycation following complexation into cationic liposomes to form lipo-polyplexes. Conventional methods for achieving these two DNA-delivering LNP vehicles suffer from significant batch-to-batch variation, poor scalability and complicated multi-step preparation procedures. Resultant nanoparticles often have uncontrollable size and surface charge with wide distribution, and poor stability when exposed to physiological media. Here we report a single-step flash nanocomplexation (FNC) process using turbulent mixing to prepare uniform lipo-complex or lipo-polyplex LNPs in a scalable manner, demonstrating excellent control over the nanoparticle size (from 40 to several hundred nm) and surface charge, with narrow size distribution. The FNC-produced LNPs could be purified and concentrated using a tangential flow filtration (TFF) process in a scalable manner. An optimized formulation of purified lipo-complex LNPs (DOTAP/Chol/DNA, 45 nm) showed significantly higher (5-fold in the lungs and 4-fold in the liver) transgene expression activity upon oral dosage than lipo-polyplex LNPs (DPPC/Chol/lPEI/DNA, 75 nm) or lPEI/DNA nanoparticles (43 nm). Repeated dosing (4 days, 150 µg/day) of the lipo-complex LNPs sustained the transgene activity over a period of one week without detectable toxicity in major organs, suggesting its potential for clinical translation. STATEMENT OF SIGNIFICANCE: We report a new method to prepare uniform size-controlled lipid-based DNA-loaded nanoparticles by turbulent mixing delivered by a multi-inlet vortex mixer. Two distinct compositions were successfully prepared: (1) lipo-complexes, through condensation of the plasmid DNA by cationic lipids; (2) lipo-polyplexes, by encapsulation of DNA/PEI together with neutral lipids. Comparing with conventional methods, which use multi-step processes with high batch-to-batch variations and poor control over nanoparticle characteristics, this method offers a single-step, continuous and reproducible assembly methodology that would promote the translation of such gene medicine products. Effective purification and concentration of nanoparticles were achieved by adopted tangential flow filtration method. Following oral gavage in mice, the lipo-complex nanoparticles showed the highest level of transgene expression in the lung and liver.

Molecular bottlebrush as a unimolecular vehicle with tunable shape for photothermal cancer therapy.

Morphology of delivery nanovehicle plays a significant role in bioavailability of drug. Molecular bottlebrush (MBB)-based unimolecular micelle, with tunable morphologies including sphere, rod, and worm, offers a new aspect to uncover the relationship between morphology and bio-behaviors. In this study, a series of MBB as unimolecular micelle with core-shell structures were tailor-made through controlled/living polymerization and click chemistry, and served as carriers of IR780 photothermal agent. With an excellent IR780 loading content of up to ca. 25%, these molecular nanovehicles still maintained their molecular morphologies and did not aggregate in cell culture medium. Among three MBB, the rodlike one exhibited best performance in cell uptake in the 2D and also in spheroid penetration in 3D cell culture. Furthermore, this rodlike system had preferential accumulation in tumor in vivo and excellent effect on photothermal cancer therapy which effectively inhibited tumor growth. These results demonstrated an important role of nanoparticle shape on bio-behaviors and the unimolecular micelle could be a promising nanovehicle with precisely defined structure for biomedicine applications.

Facile synthesis of highly uniform selenium nanoparticles using glucose as the reductant and surface decorator to induce cancer cell apoptosis.

Selenium nanoparticles (SeNPs) have attracted increasing attention due to their potential application as an effective drug delivery system. However, the conventional synthetic methods are mostly confined to solution-based synthesis that are time consuming and with low efficiency. Herein, we demonstrate the facile synthesis of highly uniform SeNPs using glucose as the reductant and surface decorator (Glu-SeNPs) that could induce cancer cell apoptosis. Glucose was used as the reducing agent to reduce sodium selenite (Na2SeO3) at high temperature (115 °C), which also acted as the surface decorator of SeNPs to prevent aggregation in an aqueous solution, thus enhancing its stability under physiological conditions. The functionalized nanoparticles demonstrated high hemocompatibility and showed selective cytotoxicity towards various human cancer cells, but not normal cells, through induction of apoptosis by initiating both intrinsic and extrinsic pathways. Furthermore, studies on the action mechanisms revealed that internalized Glu-SeNPs significantly and rapidly triggered intracellular ROS overproduction and mitochondria dysfunction to regulate the cell fate. Taken together, this study provides a new and effective method for facile synthesis of SeNPs possessing potent anticancer efficacy.