Colon-targeted piperine-glycyrrhizic acid nanocrystals for ulcerative colitis synergetic therapy via macrophage polarization.

Ulcerative colitis (UC) is a chronic inflammatory disease that affects the gastrointestinal tract and is characterized by immune dysregulation. Oral administration of nanoformulations containing immunomodulators is a desirable approach to treating UC. However, low drug-loading (<10%, typically), premature drug release, and systemic absorption of these nanoformulations continue to be significant challenges restricting clinical applications. Herein, we developed colon-targeted piperine-glycyrrhizic acid nanocrystals (ES100-PIP/GA NCs) to treat UC through the regulation of macrophages. The ES100-PIP/GA NCs exhibited ultra-high drug loading and colon-specific drug release. In vitro studies demonstrated that the ES100-PIP/GA NCs could effectively be internalized by lipopolysaccharide (LPS)-induced RAW 264.7 and Caco-2 cells. More importantly, the ES100-PIP/GA NCs could downregulate pro-inflammatory factors (IL-1ß, IL-17A), upregulate anti-inflammatory factors (TGF-ß1), and repair the intestinal mucosal barrier. In a murine model of acute colitis induced by dextran sodium sulfate (DSS), ES100-PIP/GA NCs could protect PIP and GA from gastric acid destruction, reach the colon, and significantly inhibit colitis. Surprisingly, ES100-PIP/GA NCs enhance M2 macrophages by increasing the mammalian target of rapamycin (mTOR), and inhibit M1 macrophages by reducing hypoxia-inducible factor-1α (HIF-1α). Overall, this study shows that ES100-PIP/GA NCs have synergistic immunotherapy capabilities with macrophage regulation, which offers a promising blueprint for the oral delivery of multicomponent drugs in UC therapy.

Immunotherapeutic treatment of lung cancer and bone metastasis with a mPLA/mRNA tumor vaccine.

Malignant expansion and rapid metastasis are the main limiting factors to successful treatment of lung cancer. Messenger RNA (mRNA) tumor vaccines are a promising immunotherapeutic treatment for lung cancer as well as other metastatic cancers. Herein, we developed a mPLA/mRNA tumor vaccine (mLPR) to escort mRNA into the cytoplasm and improve immune response with the help of TLR4 agonist mPLA. After nasal administration, the mLPR vaccine stimulated the maturation of dendritic cells, reprogramed M2 macrophages into M1 macrophages, as well cross-activated innate and adaptive immune responses. The mLPR vaccine inhibited the development of lung cancer and reduced bone metastasis by means of immune cell activation, IFN-γ/IL-12 cytokine secretion, and natural killer cell-mediated antibody dependent cellular cytotoxicity. The mPLA/mRNA tumor vaccine will provide ideas and application prospects for the use of mRNA tumor vaccine in the treatment of lung cancer. STATEMENT OF SIGNIFICANCE: Lung cancer and bone metastasis seriously affect patient survival, and traditional treatment methods are inefficient and have many side effects. We have constructed an mRNA vaccine that simultaneously activates the innate immune and adaptive responses of the body, in order to achieve better immunotherapeutic effects. To sum up, we confirmed through vaccine design and in vitro and in vivo immunological studies that the mLPR vaccine stimulated the maturation of dendritic cells, reprogrammed M2 macrophages into M1 macrophages, as well cross activated in vivo and adaptive immune responses.

pH-responsive bufadienolides nanocrystals decorated by chitosan quaternary ammonium salt for treating colon cancer.

Due to its poor prognosis and propensity for metastasizing, colon cancer, a frequent cancer of the gastrointestinal system, has a high morbidity and mortality rate. However, the harsh physiological conditions of the gastrointestinal tract can cause the anti-cancer medicine bufadienolides (BU) to lose some of its structure, impairing its ability to fight cancer. In this study, pH-responsive bufadienolides nanocrystals decorated by chitosan quaternary ammonium salt (HE BU NCs) were successfully constructed by a solvent evaporation method to improve the bioavailability, release characteristics and intestinal transport ability of BU. In vitro, studies have shown that HE BU NCs could improve BU internalization, significantly induce apoptosis, decrease mitochondrial membrane potential, and increase ROS levels in tumour cells. In vivo, experiments showed that HE BU NCs effectively targeted intestinal sites, increased their retention time, and exerted antitumor activity through Caspase-3 and Bax/Bcl-2 ratio pathways. In conclusion, pH-responsive bufadienolides nanocrystals decorated by chitosan quaternary ammonium salt could protect bufadienolides from the destruction of an acidic environment, achieve synergistic release in the intestinal site, improve oral bioavailability, and ultimately exert anti-colon cancer effects, which is a promising strategy for the treatment of colon cancer.

Carbonic anhydrase IX-targeted nanovesicles potentiated ferroptosis by remodeling the intracellular environment for synergetic cancer therapy.

Ferroptosis is one critical kind of regulated cell death for tumor suppression, yet it still presents challenges of low efficiency due to the intracellular alkaline pH and aberrant redox status. Herein, we reported a carbonic anhydrase IX (CA IX)-targeted nanovesicle (PAHC NV) to potentiate ferroptosis by remodeling the intracellular environment. CA IX inhibitor 4-(2-aminoethyl) benzene sulfonamide (AEBS) was anchored onto nanovesicles loaded with hemoglobin (Hb) and chlorin e6 (Ce6). Upon reaching tumor regions, PAHC could be internalized by cancer cells specifically by means of CA IX targeting and intervention. Afterwards, the binding of AEBS could elicit intracellular acidification and alter redox homeostasis to boost the lipid peroxidation (LPO) level, thus aggravating the ferroptosis process. Meanwhile, Hb served as an iron reservoir that could efficiently evoke ferroptosis and release O2 to ameliorate tumor hypoxia. With the help of self-supplied O2, Ce6 produced a plethora of 1O2 for enhanced photodynamic therapy, which in turn favored LPO accumulation to synergize ferroptosis. This study presents a promising paradigm for designing nanomedicines to heighten ferroptosis-based synergetic therapeutics through remodeling the intracellular environment.

Zinc-doped Prussian blue nanoparticles for mutp53-carrying tumor ion interference and photothermal therapy.

Quite a great proportion of known tumor cells carry mutation in TP53 gene, expressing mutant p53 proteins (mutp53) missing not only original genome protective activities but also acquiring gain-of-functions that favor tumor progression and impede treatment of cancers. Zinc ions were reported as agents cytocidal to mutp53-carrying cells by recovering p53 normal functions and abrogating mutp53. Meanwhile in a hyperthermia scenario, the function of wild type p53 is required to ablate tumors upon heat treatment hence the effects might be hindered in a mutp53 background. We herein synthesized zinc-doped Prussian blue (ZP) nanoparticles (NPs) to combine Zn2+ based and photothermal therapeutic effects. An efficient release of Zn2+ in a glutathione-enriched tumor intracellular microenvironment and a prominent photothermal conversion manifested ZP NPs as zinc ion carriers and photothermal agents. Apoptotic death and autophagic mutp53 elimination were found to be induced by ZP NPs in R280K mutp53-containing MDA-MB-231 cells and hyperthermia was rendered to ameliorate the treatment in vitro through further mutp53 elimination and increased cell death. The combinatorial therapeutic effect was also confirmed in vivo in a mouse model. This study might expand zinc delivery carriers and shed a light on potential interplay of hyperthermia and mutp53 degradation in cancer treatment.

pH/Thermal-Sensitive Nanoplatform Capable of On-Demand Specific Release to Potentiate Drug Delivery and Combinational Hyperthermia/Chemo/Chemodynamic Therapy.

Therapeutic platforms with spatiotemporal control were recently of considerable interest. However, the site-specific regulation of chemotherapeutics release remains an enormous challenge. Herein, a versatile nanoplatform capable of tumor-specific delivery and controlled drug release, coined as PDDFe, was constructed for elevating cancer theranostics. Iron-oxide nanoparticles (IONPs) and doxorubicin (Dox) were encapsulated in pH/thermal-sensitive micelles composed of poly(ethylene)glycol-poly(ß-amino esters) and dipalmitoyl phosphatidylcholine to obtain tumor-targeted dual-responsive nanoplatforms. With remarkable magnetic targeting effects, PDDFe specifically accumulated at tumor locations. After internalization by cancer cells, the acidic environment and localized heat generated by hyperthermia therapy would spur PDDFe to become loose and collapse to liberate its payload. In addition to boosting the release, the increased temperature also resulted in direct tumor damage. Meanwhile, the released Dox and IONPs, respectively, stimulated chemotherapy and chemodynamic therapy to jointly destroy cancer, thus leading to a pronounced therapeutic effect. In vivo magnetic resonance/fluorescence/photoacoustic imaging experiments validated that the dual-sensitive nanoplatforms were able to accumulate at the tumor sites. Treatment with PDDFe followed by alternating magnetic field and laser irradiation could prime hyperthermia/chemo/chemodynamic therapy to effectively retard tumor growth. This work presents a nanoplatform with a site-specific controlled release characteristic, showing great promises in potentiating drug delivery and advancing combinational cancer therapy.

Copper-based theranostic nanocatalysts for synergetic photothermal-chemodynamic therapy.

Chemodynamic therapy (CDT) has aroused extensive attention as a potent therapeutic modality. However, its practical application is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within metastatic breast cancer. Herein, a copper-based single-site nanocatalyst functionalized with carbonic anhydrase inhibitor (CAI) was constructed for magnetic resonance/photoacoustic imaging (MRI/PA)-guided synergetic photothermal therapy (PTT) and CDT. Once reaching tumor sites, the nanocatalyst can be recognized by tumor cell membranes-overexpressed carbonic anhydrase IX (CA IX). Subsequently, the single-site CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant defense system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thereby continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst can generate local heat, which not only permits PTT but also enhances the nanocatalyst-mediated CDT. Moreover, the suppression of CA IX can hinder the tumor extracellular matrix degradation to prevent tumor metastasis. Overall, this work highlighted the great application prospect in enhancing CDT via tumor acidic/redox microenvironment remodeling, and provides an insightful paradigm for inhibiting breast cancer metastasis. STATEMENT OF SIGNIFICANCE: The practical application of chemodynamic therapy (CDT) is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within cancer. Herein, we developed a carbonic anhydrase inhibitor (CAI)-functionalized Cu-based nanocatalyst. Once reaching tumor sites, the CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thus continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst not only permits PTT but also enhances the CDT.

Macrophage-Mimic Hollow Mesoporous Fe-Based Nanocatalysts for Self-Amplified Chemodynamic Therapy and Metastasis Inhibition via Tumor Microenvironment Remodeling.

Fe-based nanomaterials with Fenton reaction activity are promising for tumor-specific chemodynamic therapy (CDT). However, most of the nanomaterials suffer from low catalytic efficiency due to its insufficient active site exposure and the relatively high tumor intracellular pH, which greatly impede its clinical application. Herein, macrophage membrane-camouflaged carbonic anhydrase IX inhibitor (CAI)-loaded hollow mesoporous ferric oxide (HMFe) nanocatalysts are designed to remodel the tumor microenvironment with decreased intracellular pH for self-amplified CDT. The HMFe not only serves as a Fenton agent with high active-atom exposure to enhance CDT but also provides hollow cavity for CAI loading. Meanwhile, the macrophage membrane-camouflaging endows the nanocatalysts with immune evading capability and improves tumoritropic accumulation by recognizing tumor endothelium and cancer cells through α4/VCAM-1 interaction. Once internalized by tumor cells, the CAI could be specifically released, which can not only inhibit CA IX to induce intracellular H+ accumulation for accelerating the Fenton reaction but also could prevent tumor metastasis because of the insufficient H+ formation outside cells for tumor extracellular matrix degradation. In addition, the HMFe can be employed to highly efficient magnetic resonance imaging to real-time monitor the agents' bio-distribution and treatment progress. Both in vitro and in vivo results well demonstrated that the nanocatalysts could realize self-amplified CDT and breast cancer metastasis inhibition via tumor microenvironment remodeling, which also provides a promising paradigm for improving CDT and antimetastatic treatment.

Trojan-Horse Diameter-Reducible Nanotheranostics for Macroscopic/Microscopic Imaging-Monitored Chemo-Antiangiogenic Therapy.

Although nanotheranostics have displayed striking potential toward precise nanomedicine, their targeting delivery and tumor penetration capacities are still impeded by several biological barriers. Besides, the current antitumor strategies mainly focus on killing tumor cells rather than antiangiogenesis. Enlightened by the fact that the smart transformable self-targeting nanotheranostics can enhance their targeting efficiency, tumor penetration, and cellular uptake, we herein report carrier-free Trojan-horse diameter-reducible metal-organic nanotheranostics by the coordination-driven supramolecular sequential co-assembly of the chemo-drug pemetrexed (PEM), transition-metal ions (FeIII), and antiangiogenesis pseudolaric acid B. Such nanotheranostics with both a high dual-drug payload efficiency and outstanding physiological stability are responsively decomposed into numerous ultra-small-diameter nanotheranostics under stimuli of the moderate acidic tumor microenvironment and then internalized into tumor cells through tumor-receptor-mediated self-targeting, synergistically enhancing tumor penetration and cellular uptake. Besides, such nanotheranostics enable visualization of self-targeting capacity under the macroscopic monitor of computed tomography/magnetic resonance imaging, thereby realizing efficient oncotherapy. Moreover, tumor microvessels are precisely monitored by optical coherence tomography angiography/laser speckle imaging during chemo-antiangiogenic therapy in vivo, visually verifying that such nanotheranostics possess an excellent antiangiogenic effect. Our work will provide a promising strategy for further tumor diagnosis and targeted therapy.

H2O2 Self-Supplying and GSH-Depleting Nanoplatform for Chemodynamic Therapy Synergetic Photothermal/Chemotherapy.

Chemodynamic therapy (CDT) that utilizes Fenton-type reactions to convert endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (•OH) is a promising strategy in anticancer treatment, but the overexpression of glutathione (GSH) and limited endogenous H2O2 make the efficiency of CDT unsatisfactory. Here, an intelligent nanoplatform CuO2@mPDA/DOX-HA (CPPDH), which induced the depletion of GSH and the self-supply of H2O2, was proposed. When CPPDH entered tumor cells through the targeting effect of hyaluronic acid (HA), a release of Cu2+ and produced H2O2 were triggered by the acidic environment of lysosomes. Then, the Cu2+ was reduced by GSH to Cu+, and the Cu+ catalyzed H2O2 to produce •OH. The generation of •OH could be distinctly enhanced by the GSH depletion and H2O2 self-sufficiency. Besides, an outstanding photothermal therapy (PTT) effect could be stimulated by NIR irradiation on mesoporous polydopamine (mPDA). Meanwhile, mPDA was an excellent photoacoustic reagent, which could monitor the delivery of nanocomposite materials through photoacoustic (PA) imaging. Moreover, the successful delivery of doxorubicin (DOX) realized the integration of chemotherapy, PTT, and CDT. This strategy could solve the problem of insufficient CDT efficacy caused by the limited H2O2 and overexpression of GSH. This multifunctional nanoplatform may open a broad path for self-boosting CDT and synergistic therapy.

Mn(II)-directed dual-photosensitizers co-assemblies for multimodal imaging-guided self-enhanced phototherapy.

Phototherapy has attracted increasing attention in cancer therapy owing to its non-invasive nature, high spatiotemporal selectivity, and negligible side effects. However, a single photosensitizer often exhibits poor photothermal conversion efficiency or insufficient reactive oxygen species (ROS) productivity. Even worse, the ROS can be consumed by tumor overexpressed reductive glutathione, resulting in severely compromised phototherapy. In this paper, we prepared a MnII-coordination driven dual-photosensitizers co-assemblies (IMCP) for imaging-guided self-enhanced PDT/PTT. Specifically, a photothermal agent indocyanine green (ICG), a photodynamic agent chlorin e6 (Ce6), and a transition metal ion (MnII/III) were chosen to synthesize the nanodrug via coordination-driven co-assembly. The as-prepared IMCP exhibited extremely high photosensitizer payload (96 wt%), excellent physiological stability, and outstanding tumor accumulation. Moreover, the existence of MnII not only assists the nanostructure formation but also could competitively coordinate with GSH to minimize the unnecessary ROS consumption, thus improving PDT efficiency. Meanwhile, benefiting from the intrinsic fluorescence, photoacoustic imaging ability of photosensitizers, and the MRI contrast potential of MnII/III, IMCP exhibited superior imaging potential for guiding tumor phototherapy. By changing the excitation wavelength suitably, IMCP could realize the switch between PTT and PDT. In short, the dual-PSs co-assembled nanotheranostic has great potential for multi-modal imaging guided phototherapy.

A carrier-free metal-coordinated dual-photosensitizers nanotheranostic with glutathione-depletion for fluorescence/photoacoustic imaging-guided tumor phototherapy.

As a promising noninvasive tumor treatment modality, dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has drawn extensive research interest in imaging-guided synergistic antitumor treatment. However, developing a high-efficient phototherapeutic agent is still a huge challenge, since single photosensitizer often suffers from the insufficient photothermal conversion efficiency (PCE) or low reactive oxygen species (ROS) productivity. Moreover, the overexpression of reductive glutathione (GSH) in tumor cells also severely compromises PDT efficiency. Here, inspired by the glutathione oxidase activity of high-valent transition metal ions, we designed a copper-coordinated nanotheranostic (PhA@NanoICG) by the coordination-driven co-assembly of photothermal-agent indocyanine green (ICG) and photodynamic-agent pheophorbide A (PhA), in which Cu2+ acted as a bridge to tightly associate ICG with PhA. Such carrier-free metal-coordinated nanotheranostics exhibited ultra-high dual-photosensitizers co-loading (~96.74 wt%) and excellent structural stability. Notably, NanoICG significantly increase the PCE of ICG via J-aggregation induced UV-vis absorption red-shift. Once PhA@NanoICG accumulated in tumor sites, they could be disassembled triggered by the weakly acidic and highly reducible tumor microenvironment. Moreover, the Cu2+ can deplete intracellular GSH and impair cellular antioxidant defense system, reducing the unnecessary ROS consumption caused by glutathione. Under fluorescence/photoacoustic imaging-guided laser irradiation, local hyperthermia and ROS were generated to induce tumor cells apoptosis. The in vitro and in vivo experiments consistently confirm that PhA@NanoICG could induce remarkable tumor inhibition through self-enhanced PTT and PDT, which may pave a new way for cancer therapy.

Self-Distinguishing and Stimulus-Responsive Carrier-Free Theranostic Nanoagents for Imaging-Guided Chemo-Photothermal Therapy in Small-Cell Lung Cancer.

Lack of tumor targeting and low drug payload severely impedes various nanoagents further employed in small-cell lung cancer (SCLC). Therefore, how to develop a new targeting ligand and enhance drug payload has been an urgent need for SCLC therapy. Herein, we first sift and verify that capreomycin (Cm) has a high affinity toward CD56 receptors overexpressed on SCLC cells. Motivated by the concept of self-targeted drug delivery, Cm is selected as the specific targeting ligand toward CD56 receptors and chemodrug doxorubicin (Dox) is adopted to be covalently linked via the redox-responsive disulfide linkage. The synthesized self-distinguishing prodrug (Dox-ss-Cm) and FDA-approved photosensitizer indocyanine green (ICG) as structural motifs can be self-assembled into theranostic nanoagents (ICG@Dox-ss-Cm NPs) within an aqueous solution. Such carrier-free nanoagents with high drug payload can exert targeted on-demand drug release under multiple stimuli of intracellular lysosomal acidity, glutathione (GSH), and an external near-infrared (NIR) laser. Besides, our nanoagents can be specifically self-targeted to SCLC sites in vivo and self-distinguishing via SCLC cells in vitro; thus, they decrease the undesirable effects on normal tissues and organs. Further in vitro and in vivo studies uniformly confirm that such nanoagents show highly synergistic effects for SCLC chemo-photothermal therapy (PTT) under the precise guidance of NIR fluorescence (NIRF)/photoacoustic (PA) imaging. Taken together, our work can provide a novel and promising strategy for the targeted treatment of SCLC.

Design of light/ROS cascade-responsive tumor-recognizing nanotheranostics for spatiotemporally controlled drug release in locoregional photo-chemotherapy.

Carrier-free nanotheranostics with high drug loading and no carrier-related toxicity are highly promising cancer therapy agents. However, the limited tumor accumulation and poorly controlled drug release of these nanotheranostics continue to be major challenges that restrict clinical applications. In this study, we develop a tumor-recognizing carrier-free nanotheranostic with light/reactive oxygen species (ROS) cascade-responsiveness for spatiotemporally selective photo-chemotherapy. The nanotheranostic is constructed by co-assembly of the indocyanine green (ICG) photosensitizer and the mannose-thioketal-doxorubicin conjugate (MAN-TK-DOX) (abbreviated as IMTD), efficiently preventing premature DOX leakage during blood circulation while reducing nonspecific damage to normal tissues/cells. Once accumulated in tumor tissues, IMTD rapidly diffuses into cancer cells via lectin receptors-mediated endocytosis. Photoacoustic/fluorescence-imaging-guided laser irradiation induces local hyperthermia and ROS generation in tumor cells, thereby promoting apoptosis. Together, the ICG-generated ROS and the endogenous ROS in cancer cells synergistically enhance DOX release, resulting in more efficient chemotherapeutic effects. The in vitro and in vivo results consistently demonstrate that IMTD achieves superior tumor accumulation, highly controllable drug release, and synergetic photo-chemotherapy. Therefore, the co-assembly of an ROS-sensitive targeting ligand-chemodrug conjugate and a photosensitizer could be used to develop spatiotemporally light-activatable nanotheranostics for precision cancer therapy. STATEMENT OF SIGNIFICANCE: Synergistic phototherapy and chemotherapy have been considered as a promising cancer treatment modality to maximize the therapeutic efficacy. Unfortunately, most nanodrugs consisting of chemotherapeutic drug and photosensitizer suffer from suboptimal tumor accumulation and poorly controlled drug release, which results in reduced therapeutic outcome. In this study, Mannose (MAN) was conjugated to the anticancer drug doxorubicin (DOX) by a ROS-sensitive thioketal linker (TK), the obtained amphiphilic MAN-TK-DOX could serve as an ideal self-carrier material to deliver photosensitizer, thus to achieve high-efficient tumor-targeting, spatiotemporal controlled drug release, and superior antitumor effect. We believe that the ROS-sensitive amphiphilic targeting ligand-chemodrug conjugate could be developed as a universal approach for designing tumor-targeted nanodrugs with precisely controlled drug release.

Novel, Self-Distinguished, Dual Stimulus-Responsive Therapeutic Nanoplatform for Intracellular On-Demand Drug Release.

On-demand drug release nanoplatforms are promising alternative strategies for enhancing the therapeutic effect of cancer chemotherapy. However, these nanoplatforms still have many drawbacks including rapid blood clearance, nontargeted specificity, and a lack of immune escape function. Even worse, they are also hindered via the dosage-limiting toxicity of traditional chemotherapeutic drugs. Herein, both dual-functional mannose (enhances the antitumor activity of chemotherapeutic drugs and exhibits an innate affinity against the lectin receptor) and amphiphilic d-α-tocopheryl polyethylene glycol 1000 succinate were selected to be covalently linked via a redox-responsive monothioether linkage. The synthesized self-distinguished polymer (TSM), as a structural motif, can be self-assembled into nanoparticles (TSM NPs) in an aqueous solution, in which doxorubicin (DOX) is loaded by weak interactions (TSM-DOX NPs). These TSM-DOX NPs can provide targeted, on-demand drug release under dual stimuli from lysosomal acidity and glutathione (GSH). In addition, TSM-DOX NPs can be self-distinguished via tumor cells in vitro and specifically self-distinguished from the tumor site in vivo. Further in vitro and in vivo research consistently demonstrated that TSM-DOX NPs display highly synergistic chemotherapeutic effects. Taken together, the data show that the self-distinguished GSH-responsive polymer TSM has the potential to load various therapeutic agents.

Dual-self-recognizing, stimulus-responsive and carrier-free methotrexate-mannose conjugate nanoparticles with highly synergistic chemotherapeutic effects.

Carrier-free nanoparticles (NPs) via chemotherapeutic drug-drug conjugate assembly are a promising alternative for tumor chemotherapy. However, these NPs are still hindered via their nonspecific internalization into certain healthy cells and tissues. Herein, dual-acting methotrexate (MTX) and mannose (MAN) were conjugated via a hydrolyzable ester bond to synthesize a MTX-MAN conjugate as one molecule, which could be directly self-assembled into stimulus-responsive carrier-free NPs (MTX-MAN NPs) in aqueous solution. Such carrier-free MTX-MAN NPs with an accurate drug to sugar ratio could achieve on-demand drug release by dual stimuli of lysosomal acidity and esterase. Besides, MTX-MAN NPs could be dual-recognized by tumor cells in vitro and specifically by tumors in vivo. Moreover, the large proportion of MAN located on the NPs' surface could exert a shielding effect to avoid phagocytosis of macrophages, leading to long blood circulation. Therefore, the MTX-MAN NPs sharply reduced the drug dosage and decreased the toxicity to normal cells and tissues. Further in vitro and in vivo studies consistently confirmed that the MTX-MAN NPs exhibited superior tumor accumulation and highly synergistic chemotherapeutic effects. Furthermore, we found for the first time that MAN could enhance the antitumor activity of MTX. Considering that bi-functional MTX and MAN are approved via the FDA, and MAN is highly biosafe, the dual-self-recognizing, stimulus-responsive, and carrier-free MTX-MAN NPs might be a simple, selective, and safe chemotherapeutic strategy.

Synchronized release of bufadienolides in a stable Lutrol F127 based solid dispersion prepared with spray congealing.

OBJECTIVE: The objective of this study was to design and prepare a novel solid dispersion using spray congealing to achieve fast and synchronous dissolution of bufalin, cinobufagin, and resibufogenin, three therapeutically complementary drugs. METHODS: The solid dispersion was characterized with dissolution, X-ray diffractometry, and fourier transform infrared spectroscopy after preparation and storage for four weeks at different temperatures and relative humidity. RESULTS: It was found that all drugs were molecularly dispersed within matrix and had a significant enhancement (∼4-fold higher) of dissolution rate. Furthermore, synchronized release of different drugs from a single carrier was achieved due to the highly molecular dispersibility and the excellent solubilization properties of F127. In addition, the solid dispersion was physically stable for at least four weeks at controlled conditions. But for samples under stress conditions, the results showed that drug-rich phase was formed and storage temperature was the dominant factor in determining stability of the solid dispersion (SD). CONCLUSIONS: These findings highlight the fitness of spray congealing to co-deliver multiple drugs, which open new perspectives for the development of more advanced combination of multiple therapeutic agents, presumably improving the bioavailability and therapeutic efficacy.

Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability.

Multicomponent formulations have attracted increasing attention because of their favourable patient compliance and greater therapeutic effect. The aim of this study was to develop a multicomponent nanosuspension formulation of bufadienolides, the antitumor components of a traditional Chinese medicine, toad venom, using a wet-milling technique to improve its dissolution behaviour. Croscarmellose sodium (CCS) and sodium lauryl sulfate (SLS) were chosen as the combined stabilizers of the nanosuspension. A Taguchi orthogonal array design was used for this study to optimize the formulation and process parameters. The optimized nanosuspension was characterized by its particle size distribution, zeta potential, morphology, crystallinity, molecular interactions, stability and dissolution. The results showed that the nanosuspension was a homogeneous amorphous system with average particle sizes of <100 nm and significantly improved dissolution behaviour. It was also physically stable for at least 2 months; steric and kinetic stabilization were its main stability mechanisms. These findings suggested that the use of wet milling to fabricate nanosuspensions is a promising method for achieving the fast and synchronized dissolution of multicomponent formulations, presumably increasing the bioavailability of poorly water-soluble drugs.

Design of multifunctional liposome-quantum dot hybrid nanocarriers and their biomedical application.

Luminescent semiconductor nanocrystals, also known as quantum dots (QDs), have rich surface chemistry and unique optical properties that make them useful as probes or carriers for molecular diagnostics and therapeutics. However, their potential toxicity and instability in biological environments have puzzled scientific researchers. Much research effort has been devoted to encapsulation of QDs with liposomal hybrids to make them versatile nanocarriers for simultaneous therapeutics and diagnostics (theranostics) and considerable progress has been made over recent years. We provide an overview of the use of QD-liposome complexes (QLCs) for imaging applications, in particular applications in theranostics. More specifically, the design considerations, intracellular uptake and tissue-specific targeting of QLCs are highlighted. Current findings of QLCs for theranostics are discussed. We also discuss the challenges and highlight future directions for applications of liposome-QD hybrid nanocarriers in the biomedical arena.