Low Drug Delivery Efficiency Research Articles

Tumor Microenvironment-Responsive Biodegradable Nanomedicine for Self-Enhanced Synergistic Chemo-, Photothermal, and Chemodynamic Therapy.

The nanoscale multidrug codelivery system for synergistic therapy is an effective strategy for tumor treatment. However, the low drug delivery efficiency and poor therapeutic effects limit its application. Here, based on the coordination effect of Artemisinin (Art), quercetin (Qc), and Fe3+, we had constructed a safe and efficient carrier-free hyaluronic acid (HA)-modified Art-Fe-Qc nanoparticles (AFQ@HA NPs) for enhanced chemotherapy/photothermal therapy (PTT)-chemodynamic therapy (CDT) synergistic therapy, which achieved an ultrahigh drug loading efficiency and a multifunction anticancer strategy. The results showed that high drug loading was achieved based on drug coordination self-assembly, with Art and Qc contents of 38.6 and 42.7%, respectively. At the same time, based on the Qc-Fe coordination molecular network, the system had excellent photothermal conversion performance with an efficiency of 57.3% and could effectively inhibit the expression of HSP70, achieving enhanced PTT. Further, under the stimulation of excessive H2O2 and glutathione (GSH) in the tumor microenvironment, the AFQ@HA NPs were continuously degraded, while releasing Art and Fe3+/Fe2+ to achieve iron ion-enhanced CDT. The results of in vitro and in vivo experiments showed that AFQ@HA NPs could achieve chemotherapy-PTT-CDT synergistic therapy in response to tumor microenvironment by passively targeting and actively targeting tumor cells with CD44, demonstrating its excellent targeted antitumor effects.

Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis.

Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro. Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 μM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

Photothermal and Antibacterial PDA@Ag/SerMA Microneedles for Promoting Diabetic Wound Repair.

Diabetic foot ulcer (DFU) is a common and severe complication of diabetes characterized by wound neuropathy, ischemia, and susceptibility to infection, making its treatment difficult. Dressings are commonly used in treating diabetic wounds; however, they have disadvantages, including lack of flexibility and mechanical strength, lack of coagulation activity, resistance to biodegradation, and low drug delivery efficiency. Developing more effective strategies for diabetic wound treatment has become a new focus. Microneedles (MN) can be used as a drug delivery platform for DFU wounds, allowing safe, effective, painless and minimally invasive medication administration through the skin. Herein, PDA@Ag/SerMA microneedles were prepared by combining the photothermal properties of polydopamine (PDA), the antimicrobial properties of argentum (Ag), and the ability of sericin methacryloyl (SerMA) to promote cell mitosis to accelerate wound healing and treat diabetic ulcer wounds. The results revealed that PDA@Ag/SerMA microneedles exhibited approximately 100% antimicrobial efficacy against Staphylococcus aureus and Escherichia coli under 808 nm near-infrared (NIR) irradiation. Furthermore, the wound healing rate of mice reached 95% within 12 days, which demonstrated the excellent antibacterial properties and wound healing efficacy of PDA@Ag/SerMA microneedles at cellular and animal levels, providing a potential solution for treating DFU.

Thrombin and NIR dual-responsive system driven by heat-gas for thrombus targeted therapy

Drug thrombolysis is the main means of clinical treatment for thrombotic-related diseases. However, serious bleeding complications caused by low drug delivery efficiency and secondary vascular embolism usually lead to unsatisfactory therapeutic effects. Herein, we constructed a thrombin and near-infrared (NIR) dual-responsive drug-loaded intelligent system to solve the above problems. The CREKA-modified polydopamine (PDA) nanoparticles (NPs) were crosslinked by thrombin-responsive peptide (Pep), to obtain Pep-PPC nanocarriers with special mesoporous nanostructures. Subsequently, NO donor BNN6 and thrombolytic drug UK were loaded on the surface and into the mesoporous of Pep-PPC, to get the multifunctional Pep-NO@PPC/UK. In vitro and in vivo results proved that Pep-NO@PPC/UK could effectively recognize and aggregate at the thrombus site via CREKA-mediated active targeting. Then local abundant thrombin cleaved the nanoplatform to release UK. Meanwhile, PDA converted NIR light into heat and synchronously triggered NO release. This transformed the DDS into a “heat-gas” dual propulsion nanomotor in situ, driving deep penetration of UK in thrombus tissue. Under the combined action of UK and PTT, arterial thrombosis rapidly dissolved with relatively low bleeding risk. More importantly, NO generated in situ could prevent re-embolism of blood vessels at the thrombolytic site by inhibiting activated platelet aggregation, ultimately improving vascular reperfusion rate through a combination of attack and defense mode.

Macrophages-mediated delivery of protoporphyrin for sonodynamic therapy of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by infiltration of inflammatory cells, hyperplasia of synovium, and destruction of the joint cartilage. Owing to the low drug delivery efficiency and limited immunosuppression effect, complete cure for RA remains a formidable challenge. Here, we show that live macrophages (Mφs) carrying protoporphyrin-loaded Fe3O4 nanoparticles can migrate to the RA tissues and inhibit the inflammation by sonodynamic therapy. The inflammation of RA leads to the release of cytokines, which guides the migration of the Mφs into the RA tissues, realizing precise delivery of therapeutics. The following sonodynamic therapy induced by ultrasound and protoporphyrin destructs the proliferating synovial cells and also infiltrated inflammatory cells, demonstrating significant therapeutic effect for RA. Meanwhile, the cytokines and relapse of RA can be remarkably suppressed because of the efficient damage to the resident inflammatory cells.

Novel nanocomposites improve functional recovery of spinal cord injury by regulating NF-κB mediated microglia polarization

Secondary neuroinflammation caused by proinflammatory microglia exacerbates the disability of patients with spinal cord injury (SCI), while low drug delivery efficiency reduces the therapeutic effect of conventional drugs on promoting functional recovery. Nowadays, resorting to nanocomposites has been regarded as a promising approach to overcome such an obstacle. Herein, neutrophil membrane-coated quercetin-loaded nanoparticles (denoted NQNPs) were developed to improve drug delivery efficiency and repolarize microglia thereby inhibiting secondary neuroinflammation in SCI. Quercetin-loaded nanoparticles (QNPs), which have the capacity to reprogram proinflammatory microglia toward anti-inflammatory microglia, act as the inner core of NQNPs. The neutrophil membrane was further coated onto the inner core for targeted drug delivery and co-neutralizing inflammatory factors. In vitro and in vivo studies demonstrated that NQNPs could controllably release quercetin under the reactive oxygen species (ROS) abundant environment, reprogram microglia polarization toward M2 phenotype via nuclear factor kappa-B (NK-κB) pathway, thereby inhibiting excessive neuroinflammation, increasing the density and functional status of neurons, and finally promoting motor recovery of SCI with outstanding biocompatibility. We believe that the current research brings a novel strategy and sheds new light on the treatment of SCI.

Simple and versatile in situ thermo-sensitive hydrogel for rectal administration of SZ-A to alleviate inflammation and repair mucosal barrier in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal function. Ramulus mori (Sangzhi) alkaloids (SZ-A), derived from twigs of mulberry, were approved by the National Medical Products Administration in 2020 for treating type 2 diabetes mellitus. Accumulated evidence has confirmed that SZ-A also alleviates non-alcoholic fatty liver disease and ameliorates inflammation, indicating its potential to address inflammation in UC. However, the treatment of UC faces challenges due to low drug delivery efficiency and short retention time. To overcome these challenges, an injectable and adherent in-situ thermo-sensitive hydrogel containing SZ-A was developed for rectal drug delivery, utilizing the thermo-sensitive polymers Poloxamer 407 and 188. The thermo-sensitive hydrogel system was designed with a moderate gelation temperature of 32 ± 0.5 °C, a short gelation time of 64 s, a pH range of 7–10, high moisturizing capability exceeding 90%, and moderate mechanical strength of 4–5 s. In a rat model with UC, the in situ thermo-sensitive hydrogel significantly extended the retention time at the colonic site and enabled sustained release after rectal administration. Symptoms of UC were markedly reduced following rectal administration of SZ-A thermo-sensitive hydrogel. Furthermore, the release of inflammatory factors, such as interleukin-1β (IL-1β), IL-6, IL-18, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1), significantly decreased in the SZ-A thermo-sensitive hydrogel group. The integrity of the colonic mucosal barrier was significantly enhanced following the application of SZ-A thermo-sensitive hydrogel. In conclusion, rectal administration of SZ-A in situ thermo-sensitive hydrogel effectively alleviated UC symptoms, inhibited the secretion of inflammatory factors, and promoted the repair of the colonic mucosal barrier. This approach holds promise as a potential treatment for UC.

Ionic Liquids in Pharmaceutical and Biomedical Applications: A Review.

The unique properties of ionic liquids (ILs), such as structural tunability, good solubility, chemical/thermal stability, favorable biocompatibility, and simplicity of preparation, have led to a wide range of applications in the pharmaceutical and biomedical fields. ILs can not only speed up the chemical reaction process, improve the yield, and reduce environmental pollution but also improve many problems in the field of medicine, such as the poor drug solubility, product crystal instability, poor biological activity, and low drug delivery efficiency. This paper presents a systematic and concise analysis of the recent advancements and further applications of ILs in the pharmaceutical field from the aspects of drug synthesis, drug analysis, drug solubilization, and drug crystal engineering. Additionally, it explores the biomedical field, covering aspects such as drug carriers, stabilization of proteins, antimicrobials, and bioactive ionic liquids.

An Adjuvant Micelle-Based Multifunctional Nanosystem for Tumor Immunotherapy by Remodeling Three Types of Immunosuppressive Cells.

Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.

Membrane-immobilized gemcitabine for cancer-targetable NK cell surface engineering.

Although natural killer (NK) cell-based adoptive cell transfer (ACT) has shown promise in cancer immunotherapy, its efficacy against solid tumors is limited in the immunosuppressive tumor microenvironment (TME). Combinatorial therapies involving chemotherapeutic drugs such as gemcitabine (Gem) and NK cells have been developed to modulate the TME; however, their clinical application is constrained by low drug delivery efficiency and significant off-target toxicity. In this study, we developed cell membrane-immobilized Gem conjugates (i.e., lipid-Gem conjugates), designed to anchor seamlessly onto NK cell surfaces. Our modular-designed ex vivo cell surface engineeringmaterials comprise a lipid anchor for membrane immobilization, poly(ethylene glycol) to inhibit endocytosis, a disulfide bond as cleavable linker by glutathione (GSH) released during cancer cell lysis, and Gem for targeted sensitization. We demonstrated that the intrinsic properties of NK cells, such as proliferation and surface ligand availability, were preserved despite coating with lipid-Gem conjugates. Moreover, delivery of Gem prodrugs by lipid-Gem coated NK (GCNK) cells was shown to enhance antitumor efficacy against pancreatic cancer cells (PANC-1) through the following mechanisms: (1) NK cells recognized and attacked cancer cells, (2) intracellular GSH was leaked out from the lysed cancer cells, enabling cleavage of disulfide bond, (3) released Gem from the GCNK cells delivered to the target cells, (4) Gem upregulated MHC class I-related chain A and B on cancer cells, and (5) thereby activating NK cells led to enhance antitumor efficacy. The simultaneous co-delivery of membrane-immobilized Gem with NK cells could potentially facilitate both immune synapse-mediated cancer recognition and chemotherapeutic effects, offering a promising approach to enhance the anticancer efficacy of conventional ACTs.

Organic-Solvent-Free "Lego-Like" Modular Preparation of Fab-Nondestructive Antibody-Drug Conjugates with Ultrahigh Drug-to-Antibody Ratio.

Antibody-drug conjugates (ADCs) have exciting possibilities in targeted tumor therapy. However, in the existing ADC preparation processes, the random attachment of the payloads to the antigen-binding fragments (Fab) greatly increases the risk of disrupting its antigen recognition ability, while the drug-antibody ratio(DAR) is low, leading to a cumbersome preparation process and low drug delivery efficiency. Herein, poly(glutamic acid) is used to expand the number of drug binding sites, based on the "click chemistry" of azide and DBCO, and the high affinity of Fc-III-4C peptide to the crystalline fragment (Fc) of the monoclonal antibodies. Various antibody-polymer-drug conjugates are obtained with ultrahigh DAR using this organic-solvent-free "Lego-like" modular construction. Among them, aHER2-P-MMAE with DAR of 41.6 achieves tumor growth inhibition (TGI) of 99.7% for both medium-sized and large SKOV-3 ovarian tumors, and aPDL1-P-MMAE (DAR = 40.7) achieves TGI of 98.5% for MC38 colon tumors. In summary, a universal platform is created to prepare Fab-nondestructive ADCs with ultrahigh DAR, which can be used to develop precision medicine for personalized anticancer therapy.

Zwitterionic Inhaler with Synergistic Therapeutics for Reprogramming of M2 Macrophage to Pro-Inflammatory Phenotype.

Myriad lung diseases are life threatening and macrophages play a key role in both physiological and pathological processes. Macrophages have each pro-/anti-inflammatory phenotype, and each lung disease can be aggravated by over-polarized macrophage. Therefore, development of a method capable of mediating the macrophage phenotype is one of the solutions for lung disease treatment. For mediating the phenotype of macrophages, the pulmonary delivery system (PDS) is widely used due to its advantages, such as high efficiency and accessibility of the lungs. However, it has a low drug delivery efficiency ironically because of the perfect lung defense system consisting of the mucus layer and airway macrophages. In this study, zwitterion-functionalized poly(lactide-co-glycolide) (PLGA) inhalable microparticles (ZwPG) are synthesized to increase the efficiency of the PDS. The thin layer of zwitterions formed on PLGA surface has high nebulizing stability and show high anti-mucus adhesion and evasion of macrophages. As a reprogramming agent for macrophages, ZwPG containing dexamethasone (Dex) and pirfenidone (Pir) are treated to over-polarized M2 macrophages. As a result, a synergistic effect of Dex/Pir induces reprogramming of M2 macrophage to pro-inflammatory phenotypes.

Water-responsive gel extends drug retention and facilitates skin penetration for curcumin topical delivery against psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by erythema, scaling, and skin thickening. Topical drug application is recommended as the first-line treatment. Many formulation strategies have been developed and explored for enhanced topical psoriasis treatment. However, these preparations usually have low viscosity and limited retention on the skin surface, resulting in low drug delivery efficiency and poor patient satisfaction. In this study, we developed the first water-responsive gel (WRG), which has a distinct water-triggered liquid-to-gel phase transition property. Specifically, WRG was kept in a solution state in the absence of water, and the addition of water induced an immediate phase transition and resulted in a high viscosity gel. Curcumin was used as a model drug to investigate the potential of WRG in topical drug delivery against psoriasis. In vitro and in vivo data showed that WRG formulation could not only extend skin retention but also facilitate the drug permeating across the skin. In a mouse model of psoriasis, curcumin loaded WRG (CUR-WRG) effectively ameliorated the symptoms of psoriasis and exerted a potent anti-psoriasis effect by extending drug retention and facilitating drug penetration. Further mechanism study demonstrated that the anti-hyperplasia, anti-inflammation, anti-angiogenesis, anti-oxidation, and immunomodulation properties of curcumin were amplified by enhanced topical drug delivery efficiency. Notably, neglectable local or systemic toxicity was observed for CUR-WRG application. This study suggests that WRG is a promising formulation for topically psoriasis treatment.

Redox-responsive engineered hybrid nanomedicine for gallbladder cancer therapy via hyaluronic acid depletion

Gallbladder cancer (GBC) is a highly fatal and most common biliary tract cancer for which there is no uniform chemotherapy regimen at present. Although several chemotherapy regimens are currently being examined in clinical trials, they are limited by the high systemic toxicity and low drug delivery efficiency. Based on the characteristics of the tumor microenvironment of GBC tumors that it is rich in hyaluronic acid (HA), herein, we design a paclitaxel (PTX)-loaded organosilica hybrid nanocarrier (named as PTX@PDHNs-HAase) modified with hyaluronidase (HAase), aiming to enhance the delivery and therapeutic efficiency of PTX in GBC tumors. Once the nanocarrier reaches the tumor site through the enhanced permeability and retention effect, HAase loaded onto the nanocarrier will degrade the excess HA presented at the GBC tumor site to cause its depletion, thereby softening the hard extracellular matrix (ECM) and facilitating further penetration of nanomedicine into the GBC tumor cells and releasing PTX under glutathione (GSH) stimulation to accomplish the chemotherapeutic effect. More importantly, PTX@PDHNs-HAase not only presents excellent therapeutic effect in vivo (tumor inhibition rate: 88.6%), but also reduces the systemic toxicity of PTX. To the best of our knowledge, this is the first exploration of the strategy to enhance the efficacy of chemotherapeutic agent for GBC tumor therapy by degrading HA to dismantle ECM for enhanced nanomedicine delivery, thus providing a promising paradigm for GBC treatment.

Bio‐Inspired Coordination‐Assembled Nanoparticles for Enhanced Drug Delivery of Tumor Chemotherapeutics

AbstractOwing to low drug delivery efficiency (<1%), nanoparticle‐based drug delivery system remains great challenge for efficient tumor chemotherapeutics. In this study, bioinspired coordination‐assembled nanoparticles (CuET@HR‐Pro) are fabricated by programming the assembly of three types of functional biomolecules (heparin, cRGD, and protamine) and the anti‐cancer drug (CuET). The nanoparticles enhanced the drug delivery efficiency of an intravenous injective dose to up to 6.9%, and thereby significantly improving the anti‐tumor efficacy of the drug. The CuET@HR‐Pro is fabricated by patching coordination‐assembled CuET@heparin‐cRGD (CuET@HR) nanoparticles onto the surface of protamine (Pro) nanoparticles in 10% fetal bovine serum. The enhanced drug delivery capacity of the obtained CuET@HR‐Pro nanoparticles is due to their improved stability (anti‐complement activation, anti‐protein adhesion), targeting capacity, and cell penetration ability. As expected, CuET@HR‐Pro exhibited a superior inhibitory effect on orthotopic ovarian cancer in nude mice. The proposed strategy provides an alternative for achieving highly efficient drug delivery and tumor therapy.

Tumor-targeted dual-starvation therapy based on redox-responsive micelle nanosystem with co-loaded LND and BPTES.

The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, HPPPH@L@B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.

Self-Assembly of Podophyllotoxin-Loaded Lipid Bilayer Nanoparticles for Highly Effective Chemotherapy and Immunotherapy via Downregulation of Programmed Cell Death Ligand 1 Production.

Low drug delivery efficiency elevates the cost of medication, lowers the therapeutic efficacy, and appears as a leading reason for unmet needs in anticancer therapies. Herein, we report the development of self-assembled podophyllotoxin-loaded lipid bilayer nanoparticles that inhibit the production of programmed cell death ligand 1 in lung cancer cells and promote tumor-specific immune responses, thus offering a strategy for regulating the immunosuppressive microenvironment of tumors. In addition, encapsulation of podophyllotoxin in the nanoparticles reduced its systemic toxicity, enhanced its penetration into tumors, and increased its antitumor efficacy. Systemic injection of the nanoparticles into tumor-bearing mice not only prevented tumor immune escape but also significantly inhibited tumor growth and extended survival. In general, the podophyllotoxin-loaded nanoparticles exhibited both immunological effects and antitumor effects in addition to having better targeting activity and fewer side effects than free podophyllotoxin. We expect our findings to facilitate the development of therapies for lung cancer.

A ROS-responsive biomimetic nano-platform for enhanced chemo-photodynamic-immunotherapy efficacy.

Due to the complex bloodstream components, tumor microenvironment and tumor heterogeneity, traditional nanoparticles have a limited effect (low drug delivery efficiency and poor penetration to the deeper tumor) on eradicating tumors. To solve these challenges, novel platelet membrane-coated nanoparticles (PCDD NPs) were constructed for combined chemo-photodynamic- and immunotherapy of melanoma. The platelet membrane imparted the PCDD nanoparticles with an excellent long circulation effect and tumor targeting ability, which solved the issues of low drug delivery efficiency. After reaching the tumor cells, it releases the drug-loaded CDD micelles, becoming positively charged and facilitating the deep penetration of tumors. Cytotoxic and apoptosis experiments showed that PCDD nanoparticles have the strongest tumor cell killing ability. Based on the excellent results in vitro, PCDD was used to assess anti-tumor and distal tumor inhibition in rat models. The results revealed that the PCDD combined PDT, immunotherapy and chemotherapy could not only inhibit the primary tumor growth (inhibition rate: 92.0%) but also suppress the distant tumor growth (inhibition rate: 90.7%) and lung metastasis, which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, leading to excellent results in tumor suppression and lung metastasis. In conclusion, this novel multifunctional PCDD nanoparticle is a promising platform for tumor combined chemotherapy, photodynamic therapy (PDT) and immunotherapy.

All‐in‐One Photoacoustic Theranostics Using Multi‐Functional Nanoparticles

AbstractBoth treatment and postoperative evaluation of cancer play vital roles in improving the survival rate of patients. However, existing cancer therapies face multiple challenges of low drug delivery efficiency, separation of treatment and evaluation, and lack of noninvasive, routine and cost‐efficient postoperative monitoring methods. To overcome these issues, an all‐in‐one anti‐cancer strategy is proposed by using the combination of the photoacoustic (PA) effect and polymer nanoparticles. This strategy shows enhanced nanoparticles delivery, significant tumor ablation, and the capability of non‐invasive and longitudinal postoperative evaluation. Near‐infrared (NIR) excited photoacoustic radiation force (PAF) based on the high optical absorption nanoparticles opens the vascular barrier, accumulates the nanoparticles inside the tumor, and enables visualization of real‐time nanoparticles distribution. Instead of conventional thermal therapy by using a continuous wave laser, the NIR pulsed laser coupled with PAF offers thermal therapy with further positive accumulation of nanoparticles, and significantly improves the treatment efficiency in return. In addition, the endogenous hemoglobin enables PA imaging to evaluate the efficacy of tumor therapy and monitor the progress of postoperative tumors in vivo through structural and functional parameters of the vascular network. This study presents a new opportunity for formulation of personalized and accurate tumor therapy, and timely feedback of therapeutic effect.

Polymeric microneedle-mediated transdermal delivery of melittin for rheumatoid arthritis treatment

Transdermal drug delivery systems for rheumatoid arthritis (RA) have been receiving increasing attention as they can potentially overcome drawbacks which exist in traditional oral or injection strategies, including low patient compliance and serious gastrointestinal side effects. However, transdermal delivery of RA drugs especially biological drugs suffers from low drug delivery efficiency due to the robust skin barrier. Herein, we fabricated melittin-loaded hyaluronic acid (HA) microneedles and investigated their capacity for inhibiting RA. We showed that melittin-loaded HA microneedles possessed high mechanical strength for successful delivery of melittin into the skin and effectively inhibited RA progression in adjuvant induced both rodent and murine models, as shown by results in histological, paw swelling and arthritis score. Furthermore, after modifying HA with cross-linkable groups, the fabricated microneedles with sustained release properties could further improve the therapeutic potency. Cytokine and T cell analysis in the paws and lymphatic organs indicated that the application of microneedles suppressed the levels of pro-inflammation cytokines including IL-17 and TNF-α, and increased the percentage of regulatory CD4 T cells. Our study revealed that polymeric microneedle-mediated transdermal delivery of melittin could serve as a new therapy with high compliance and good therapeutic efficacy for RA and other autoimmune diseases.