Drug Accumulation In Tumors Research Articles

Human Growth Hormone Fragment 176–191 Peptide Enhances the Toxicity of Doxorubicin-Loaded Chitosan Nanoparticles Against MCF-7 Breast Cancer Cells

IntroductionNumerous drugs with potent toxicity against cancer cells are available for treating malignancies, but therapeutic efficacies are limited due to their inefficient tumor targeting and deleterious effects on non-cancerous tissue. Therefore, two improvements are mandatory for improved chemotherapy 1) novel delivery techniques that can target cancer cells to deliver anticancer drugs and 2) methods to specifically enhance drug efficacy within tumors. The loading of inert drug carriers with anticancer agents and peptides which are able to bind (target) tumor-related proteins to enhance tumor drug accumulation and local cytotoxicity is a most promising approach.ObjectiveTo evaluate the anticancer efficacy of Chitosan nanoparticles loaded with human growth hormone hGH fragment 176–191 peptide plus the clinical chemotherapeutic doxorubicin in comparison with Chitosan loaded with doxorubicin alone.MethodsTwo sets of in silico experiments were performed using molecular docking simulations to determine the influence of hGH fragment 176–191 peptide on the anticancer efficacy of doxorubicin 1) the binding affinities of hGH fragment 176–191 peptide to the breast cancer receptors, 2) the effects of hGH fragment 176–191 peptide binding on doxorubicin binding to these same receptors. Further, the influence of hGH fragment 176–191 peptide on the anticancer efficacy of doxorubicin was validated using viability assay in Human MCF-7 breast cancer cells.ResultsIn silico analysis suggested that addition of the hGH fragment to doxorubicin-loaded Chitosan nanoparticles can enhance doxorubicin binding to multiple breast cancer protein targets, while photon correlation spectroscopy revealed that the synthesized dual-loaded Chitosan nanoparticles possess clinically favorable particle size, polydispersity index, as well as zeta potential.ConclusionThese dual-loaded Chitosan nanoparticles demonstrated greater anti-proliferative activity against a breast cancer cell line (MCF-7) than doxorubicin-loaded Chitosan. This dual-loading strategy may enhance the anticancer potency of doxorubicin and reduce the clinical side effects associated with non-target tissue exposure.

Pancreatic Cancer: Nucleic Acid Drug Discovery and Targeted Therapy.

Pancreatic cancer (PC) is one of the most lethal cancers with an almost 10% 5-year survival rate. Because PC is implicated in high heterogeneity, desmoplastic tumor-microenvironment, and inefficient drug-penetration, the chemotherapeutic strategy currently recommended for the treatment of PC has limited clinical benefit. Nucleic acid-based targeting therapies have become strong competitors in the realm of drug discovery and targeted therapy. A vast evidence has demonstrated that antibody-based or alternatively aptamer-based strategy largely contributed to the elevated drug accumulation in tumors with reduced systematic cytotoxicity. This review describes the advanced progress of antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNA (mRNAs), and aptamer-drug conjugates (ApDCs) in the treatment of PC, revealing the bright application and development direction in PC therapy.

H2S‐Responsive Small‐Molecule Nanocarriers for Drug Delivery to Colorectal Tumors

AbstractHydrogen sulfide (H2S), a gaseous signaling molecule, is excessively produced in disease lesions like lung tumors and colorectal tumors. H2S is used as a trigger for stimuli‐responsive drug delivery in cancer therapies, which enables controlled release of chemotherapeutics and improves their biocompatibility and efficacy. Herein, a H2S‐responsive small‐molecule nanocarrier is developed based on the self‐assembly of a trigonal molecule, tris(azido benzyl)‐tri(2‐aminoethyl) amine (ATAEA). ATAEA with three H2S‐responsive azido benzyl groups can self‐assemble into nanocarriers (ATNPs) and encapsulate hydrophobic doxorubicin (DOX) to form drug‐loaded nanoparticles (DOX/ATNPs). H2S induces the reduction of azido benzyl group and 1,6‐elimination, which results in the dissociation of the ATAEA molecules and the nanoparticles. In HCT116 colon cancer cells, efficient H2S‐responsive DOX release from DOX/ATNPs is observed. In vivo administration of DOX/ATNPs in colon tumor‐bearing mice leads to higher drug accumulation in tumors and evident tumor growth inhibition, in comparison with non‐responsive nanoparticles. This work provides a new strategy to develop H2S‐responsive drug delivery systems for precise drug delivery to H2S‐enriched disease lesions.

Targeted delivery of doxorubicin by Thermo/pH-responsive magnetic nanoparticles in a rat model of breast cancer

The novel folate conjugated Thermo/pH-responsive magnetic nanoparticles (folate-poly-MNPs) have been developed as a potential nanocarrier for improving site-specific drug delivery, tumor drug accumulation, and therapeutic effects while reducing the adverse effects of conventional drug delivery systems. To evaluate the anticancer efficacy of developed tumor-targeted drug delivery system, forty rat models of breast cancer received saline as control, DOX, DOX-poly-MNPs, and DOX-folate-poly-MNPs at a dose of 2 mg/kg/48 h. The DOX-folate-poly-MNPs showed a significant increase in protein expression of BAX and C-caspase-3 with concomitant downregulation of Bcl-2 expression and ki67 proliferation index compared to the DOX group. The synergistic antitumor efficacy of passive and active drug targeting led to enhanced drug uptake, increased tumor cell apoptosis, decreased tumor volume, and a prolonged survival rate in animals, suggesting that DOX-folate-poly-MNPs may prove to be a promising nanomedicine for the smart treatment of breast cancer in the future.

ATP-Triggered Drug Release of Self-Assembled 3D DNA Nanostructures for Fluorescence Imaging and Tumor Therapy.

Stimulus-responsive materials are ideal carriers for precisely controlled drug delivery due to their high selectivity. However, the complex physiological environment hinders its development in clinical medicine. Here, we aim to design a self-assembled three-dimensional (3D) DNA nanostructure drug delivery system with adenosine-5'-triphosphate (ATP)-triggered drug release for tumor fluorescence imaging analysis and targeted drug delivery. Dox@3D DNA nanostructures are self-assembled by a simple one-pot annealing reaction and embedded with drugs, which are structurally stable but can be induced using high concentrations of ATP in tumor cells to cleave and release drugs rapidly, facilitating the rapid accumulation of drugs in tumors and exerting therapeutic effects, thus effectively avoiding damage to normal tissues. This work demonstrates that 3D DNA nanostructures can be used as efficient drug nanocarriers with promising applications in tumor therapy.

Iodine Conjugated Pt(IV) Nanoparticles for Precise Chemotherapy with Iodine-Pt Guided Computed Tomography Imaging and Biotin-Mediated Tumor-Targeting.

Theranostics of platinum (Pt)-based chemotherapy are able to self-track the biodistribution and pharmacokinetics while performing therapeutic effects. Pt-based CT imaging is expected to visualize and monitor the tumor throughout the entire tumor inhibition stage. However, a sufficient Pt concentration is necessary for CT imaging, which may bring about severe nephrotoxicity. A Bio-Pt-I compound is designed and synthesized by conjugation of iodine and biotin to the structure of Pt and further self-assembles into nanoparticles. The introduction of iodine not only enhances the CT imaging signal with a much lower dose of Pt but also overcomes the resistance of tumor cells to Pt-containing nanomedicine by inhibiting the expression of Bcl-2. Furthermore, biotin-mediated tumor targeting increases drug accumulation in tumors. This work combines CT imaging based self-track with efficient cisplatin-resistance reversion ability, which may promote the clinical transformation of Pt-containing nanomedicine.

Wirelessly Activated Nanotherapeutics for In Vivo Programmable Photodynamic-Chemotherapy of Orthotopic Bladder Cancer.

Photochemical internalization (PCI) is a promising intervention using photodynamic therapy (PDT) to enhance the activity of chemotherapeutic drugs. However, current bladder cancer treatments involve high‐dose chemotherapy and high‐irradiance PDT which cause debilitating side effects. Moreover, low penetration of light and drugs in target tissues and cumbersome light delivery procedures hinder the clinical utility of PDT and chemotherapy combination for PCI. To circumvent these challenges, a photodynamic‐chemotherapy approach is developed comprising tumor‐targeting glycosylated nanocarriers, coloaded with chlorin e6 (Ce6) and gemcitabine elaidate (GemE), and a miniaturized implantable wirelessly powered light‐emitting diode (LED) as a light source. The device successfully delivers four weekly light doses to the bladder while the nanocarrier promoted the specific accumulation of drugs in tumors. This approach facilitates the combination of low‐irradiance PDT (1 mW cm−2) and low‐dose chemotherapy (≈1500× lower than clinical dose) which significantly cures and controls orthotopic disease burden (90% treated vs control, 35%) in mice, demonstrating a potential new bladder cancer treatment option.

Boosting ferroptosis via abplatin(iv) for treatment of platinum-resistant recurrent ovarian cancer

Platinum resistance represents a huge difficulty in ovarian cancer treatment, resulting in disease recurrence and deaths in patients. However, platinum-resistant, recurrent diseases still lack fundamentally effective treatment. Herein, four platinum(IV) (Pt(IV)) prodrugs were developed from the most widely used cisplatin (CisPt) and oxaliplatin (OxaPt), which were subsequently loaded with human serum albumin (HSA) to form nanoparticles (NP1-NP4). We found that NP1, also named Abplatin(iv), showed the best anticancer activity in six ovarian cancer cell lines of various pathological types. Hence, Abplatin(iv) was further evaluated in terms of translational potential. We established patient-derived cells (PDCs) and patient-derived organoids (PDOs) and observed enhanced antitumor effects of Abplatin(iv) in these ex vivo models. Furthermore, in mice bearing orthotopic ovarian cancer, intraperitoneal administration of Abplatin(iv) resulted in targeted drug accumulation in tumors and decreased tumor burden more effectively than CisPt, without causing any detectable side effects. In addition, by analyzing single-cell transcriptome sequencing results, we found a phenotypic shift toward stem-like cells in ovarian cancers undergoing chemotherapy. Therefore, cancer stem cells (SKOV3–3rd) mimicking such persistent tumor cells in postchemotherapeutic residual lesions were established. Abplatin(iv) exhibited a significantly improved antitumor effect on SKOV3–3rd cells both in vitro and in vivo. Finally, RNA sequencing revealed that Abplatin(iv) worked by boosting cell ferroptosis compared with CisPt. Taken together, Abplatin(iv) exhibits low systemic toxicity and high anticancer activity. In particular, it shows robust efficacy against platinum-resistant ovarian cancer derived from patients, indicating its great clinical translation potential.

Enhanced tumor accumulation and therapeutic efficacy of liposomal drugs through over-threshold dosing

BackgroundMost intravenously administered drug-loaded nanoparticles are taken up by liver Kupffer cells, and only a small portion can accumulate at the tumor, resulting in an unsatisfactory therapeutic efficacy and side effects for chemotherapeutic agents. Tumor-targeted drug delivery proves to be the best way to solve this problem; however, the complex synthesis, or surface modification process, together with the astonishing high cost make its clinical translation nearly impossible.MethodsReferring to Ouyang’s work and over-threshold dosing theory in general, blank PEGylated liposomes (PEG-Lipo) were prepared and used as tumor delivery enhancers to determine whether they could significantly enhance the tumor accumulation and in vivo antitumor efficacy of co-injected liposomal ACGs (PEG-ACGs-Lipo), a naturally resourced chemotherapeutic. Here, the phospholipid dose was used as an indicator of the number of liposomes particles with similar particle sizes, and the liposomes was labelled with DiR, a near-red fluorescent probe, to trace their in vivo biodistribution. Two mouse models, 4T1-bearing and U87-bearing, were employed for in vivo examination.ResultsPEG-Lipo and PEG-ACGs-Lipo had similar diameters. At a low-threshold dose (12 mg/kg equivalent phospholipids), PEG-Lipo was mainly distributed in the liver rather than in the tumor, with the relative tumor targeting index (RTTI) being ~ 0.38 at 72 h after administration. When over-threshold was administered (50 mg/kg or 80 mg/kg of equivalent phospholipids), a much higher and quicker drug accumulation in tumors and a much lower drug accumulation in the liver were observed, with the RTTI increasing to ~ 0.9. The in vivo antitumor study in 4T1 tumor-bearing mice showed that, compared to PEG-ACGs-Lipo alone (2.25 mg/kg phospholipids), the co-injection of a large dose of blank PEG-Lipo (50 mg/kg of phospholipids) significantly reduced the tumor volume of the mice by 22.6% (P < 0.05) and enhanced the RTTI from 0.41 to 1.34. The intravenous injection of a low drug loading content (LDLC) of liposomal ACGs (the same dose of ACGs at 50 mg/kg of equivalent phospholipids) achieved a similar tumor inhibition rate (TIR) to that of co-injection. In the U87 MG tumor-bearing mouse model, co-injection of the enhancer also significantly promoted the TIR (83.32% vs. 66.80%, P < 0.05) and survival time of PEG-ACGs-Lipo.ConclusionAn over-threshold dosing strategy proved to be a simple and feasible way to enhance the tumor delivery and antitumor efficacy of nanomedicines and was benefited to benefit their clinical result, especially for liposomal drugs.Graphical

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe.

The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety—alpha-fetoprotein receptor-binding peptide—enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.

Pharmacodynamics and pharmacokinetics of PLGA-based doxorubicin-loaded implants for tumor therapy

The traditional systemic chemotherapy through intravenous infusion of doxorubicin (DOX) has many side effects. The aim of this study was to develop a PLGA-based DOX-loaded implant and to evaluate the efficacy and drug metabolism distribution of the implant in intratumoral chemotherapy for osteosarcoma (OS). In this study, implants containing DOX, poly(d,l-lactide-co-glycolide), and polyethylene glycol 4000 were prepared by melt-molding method. Then, the antitumor activity and systemic drug distribution of the implants were tested in a K7M2 OS bearing mouse model. The scanning electron microscope images showed that DOX was uniformly dispersed in the polymer matrix. Both the in vitro and in vivo release profiles of implants are characterized by three-phase release. Implantation of DOX-loaded implants into tumors can inhibit tumor growth in a dose-dependent manner. The pharmacokinetic behavior shows that intratumor chemotherapy through implants has a much higher drug concentration in tumors than in normal tissues, which may be the reason for improving antitumor activity and reducing systemic side effects. In summary, the drug release of the implants prepared in this study is sustained and stable, which promotes long-term local accumulation of drugs in tumors, improves the efficacy of chemotherapy and has low toxicity to normal tissues.

Intracellular Self-Immolative Polyprodrug with Near-Infrared Light Guided Accumulation and in Vivo Visualization of Drug Release.

The selective accumulation and real-time monitoring of drug release at tumor site are the key bottlenecks to the clinical translation of polyprodrug. Herein, an intracellular self-immolative polyprodrug (PMTO) is exploited, which not only shows the enhanced cellular internalization and selective accumulation in tumor site under the mild hyperthermia triggered by laser irradiation, but also possesses the self-monitoring drug release ability in vivo. The polyprodrug amphiphiles are synthesized by sequential esterification reaction, and hydrophilic poly(ethylene glycol) serves as blocking agent. On account of the mild hyperthermia produced by PMTO under the laser irradiation at tumor site, the cell membranous permeability increases, resulting in the enhanced cellular internalization and drug accumulation in tumor. After internalized by cells, the self-immolative PMTO nanoparticles can release free mitoxantrone (MTO) in intracellular reductive environment, and ratiometric photoacoustic imaging based on distinct signals between MTO and PMTO is presented to trace the drug release in vivo. Finally, this self-monitoring polyprodrug presents significant tumor suppression efficacy, which exhibits great potential for guiding the clinical medication in cancer treatment.

Liposomal 5-Fluorouracil Polymer Complexes Facilitate Tumor-Specific Delivery: Pharmaco-Distribution Kinetics Using Microdialysis.

Liposomes are widely used as carriers for anticancer drugs due to their ability to prolong the retention of encapsulated drugs in blood plasma while directing their distribution increasingly into tumor tissue. We report on the development of stealth liposomal formulations for the common chemotherapy drug 5-fluorouracil, where pharmacokinetic studies were undertaken using a microdialysis probe to specifically quantify drug accumulation in tumor, which was contrasted to drug exposure to healthy tissue. Greater accumulation of the drug into the tumor than into healthy subcutaneous tissue was observed for neutral and cationic liposomal 5-fluorouracil polymer complexes in comparison to the conventional delivery by an injected solution. Increased drug accumulation in tumor also correlated to reduced tumor growth. This research has generated new mechanistic insight into liposomal-specific delivery to tumors with potential to improve the efficacy and reduce the toxicity of chemotherapy.

Combined Fluorescence and Optoacoustic Imaging for Monitoring Treatments against CT26 Tumors with Photoactivatable Liposomes.

Simple SummaryA new approach of combined optoacoustic (OA) and fluorescence (FL) imaging for in vivo real-time tracing photosensitizer (PS) kinetics and functional vascular effects in the treated area was developed. FL monitoring using a photoactivatable multi-inhibitor liposomal (PMILs) platform, demonstrates enhancement of PS accumulation in tumor, 24 h post-treatment. OA monitoring revealed the alterations of the tumor vasculature structure after treatment, which is in good agreement with the histological data that shows five times higher percentage of hemorrhages in PMIL treated mice compared to the untreated group.The newly developed multimodal imaging system combining raster-scan optoacoustic (OA) microscopy and fluorescence (FL) wide-field imaging was used for characterizing the tumor vascular structure with 38/50 μm axial/transverse resolution and assessment of photosensitizer fluorescence kinetics during treatment with novel theranostic agents. A multifunctional photoactivatable multi-inhibitor liposomal (PMILs) nano platform was engineered here, containing a clinically approved photosensitizer, Benzoporphyrin derivative (BPD) in the bilayer, and topoisomerase I inhibitor, Irinotecan (IRI) in its inner core, for a synergetic therapeutic impact. The optimized PMIL was anionic, with the hydrodynamic diameter of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01, and the zeta potential between −14.9 ± 1.04 to −16.9 ± 0.92 mV. In the in vivo studies on BALB/c mice with CT26 tumors were performed to evaluate PMILs’ therapeutic efficacy. PMILs demonstrated the best inhibitory effect of 97% on tumor growth compared to the treatment with BPD-PC containing liposomes (PALs), 81%, or IRI containing liposomes (L-[IRI]) alone, 50%. This confirms the release of IRI within the tumor cells upon PMILs triggering by NIR light, which is additionally illustrated by FL monitoring demonstrating enhancement of drug accumulation in tumor initiated by PDT in 24 h after the treatment. OA monitoring revealed the largest alterations of the tumor vascular structure in the PMILs treated mice as compared to BPD-PC or IRI treated mice. The results were further corroborated with histological data that also showed a 5-fold higher percentage of hemorrhages in PMIL treated mice compared to the control groups. Overall, these results suggest that multifunctional PMILs simultaneously delivering PDT and chemotherapy agents along with OA and FL multi-modal imaging offers an efficient and personalized image-guided platform to improve cancer treatment outcomes.

Biodegradable and self-fluorescent ditelluride-bridged mesoporous organosilica/polyethylene glycol-curcumin nanocomposite for dual-responsive drug delivery and enhanced therapy efficiency

Mesoporous organosilica as drug delivery carriers capable of achieving improved cargo release, enhanced biodegradation, and direct imaging with prolonged circulation time and tracking cargo distribution is highly in demand for biomedical applications. Herein, we report a ditelluride-bridged mesoporous organosilica nanoparticle (DTeMSN)/polyethylene glycol-curcumin (PEG-CCM) nanocomposite through coassembly with oxidative/redox and self-fluorescent response. Tellurium is introduced into the silica framework for the first time as a drug delivery vehicle. In this case, the DTeMSNs as an inner core enable disassembly under oxidative and redox conditions via the cleavage of ditelluride bond, facilitating the drug release of doxorubicin (DOX) in a matrix degradation controlled manner. Through the systematical comparison of diselenide-bridged MSNs and DTeMSNs, DTeMSNs exhibit remarkable advantages in loading capacity, drug release, and degradation behavior, thereby significantly affecting the cytotoxicity and antitumor efficacy. The self-fluorescent response of PEG-CCM shell coated on the surface of DTeMSNs can real-timely track the cellular uptake, DOX release, and biodistribution owing to the intrinsic and stable fluorescence of CCM. Moreover, PEG-CCM could prolong circulation time, provide preferable drug accumulation in tumors, and increase antitumor efficacy of DOX-loaded DTeMSNs. Our findings are likely to enrich the family of organosilica that served as fluorescence-guided drug delivery carriers.

Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer

Combination chemotherapy is a promising strategy for cancer treatment in clinics especially when multidrug-resistant cancer is emerging. One significant challenge remains in achieving sufficient multi-drug delivery into tumor cells to maximize the synergetic therapeutic effect, as it is hard to concentrate drugs in drug-resistant cancer. Therefore herein, metal–organic framework (MOF)-based polymer-coated hybrid nanoparticles (NPs) were devised and constructed for the co-delivery of doxorubicin and cisplatin to enhance combination therapy of multidrug-resistant cancer. The MOF@polymer nanocarrier combined the merits of high multi-drug loading capacity, physiological stability, and tumor microenvironment pH-responsiveness, facilitating simultaneous delivery of drugs into cancer cells and making the most of synergistic antitumor effect. Remarkably, this hybrid nanocarrier maintains a negative surface charge during circulation to guarantee a stable and prolonged process in vivo, and then exposes inner positive MOF after degradation of the outer polymer in the acidic tumor microenvironment to promote multi-drug release, cellular internalization, nuclear localization, and tumor penetration. In vitro and in vivo studies with drug-resistant MCF-7/ADR cancer suggested that the nanocarrier could achieve increased accumulation of drugs in solid tumors, remarkable tumor elimination results as well as minimized side effects, indicating an improved efficacy and safety of combination chemotherapy. MOF@polymer hybrid nanocarriers provide new insights into the development of stimuli-responsive co-delivery systems of multiple drugs.

Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma

Cutaneous melanoma is one of the most common malignant skin cancer with high lethality. Chemotherapy and photothermal therapy are important and extensively studied treatment modalities for melanoma. However, these therapies still face some challenges, which severely restrict their further applications, such as unsatisfactory efficacy of monotherapy, nonspecific uptake and release during drug delivery, and unexpected adverse effects from system administration. Recently, the strategies of collaboration, functional modification, stimuli-responsive design, and topical administration all show great prospect for solving above problems. In this research, a multifunctional nanoparticle-integrated dissolving microneedle drug delivery system was constructed, in which the nanoparticles were prepared based on the framework with the incorporation of photothermal agent (CuS) into Zeolitic imidazolate framework-8 and functionalized by hyaluronic acid. This system can co-load multi-modal drugs, improve specific uptake and distribution of targeted tumor, deliver drug locally, and release drug intelligently and spatiotemporally, thereby promising a low-dose administration with high efficiency. The high inhibiting tumor performance and excellent systematic safety were verified both in vitro and in vivo. Together, this smart design overcame the drawbacks of monotherapy and conventional system administration. We believe the nanoparticle-integrated dissolving microneedles will be in prospect of clinical application for more superficial tumors with further delicate optimization. Statement of significanceMelanoma is one of the most common skin cancers with high lethality. Extensively studied chemotherapy and photothermal therapy still face some challenges, such as the limited therapeutic efficacy and the severe system adverse effects. In order to overcome these drawbacks, the multifunctional nanoparticle-integrated dissolving microneedles (DMNs) were designed. Especially, the nanoparticles could co-load multi-modal drugs, improve specific uptake, and release drug intelligently and spatiotemporally. The microneedles could increase the drug accumulation in tumor, thus achieving excellent therapeutic efficacy and reducing side effects. This system paved the way to a less invasive, more focused and efficient therapeutic strategy for melanoma therapy.

Synergistic effect of tumor chemo-immunotherapy induced by leukocyte-hitchhiking thermal-sensitive micelles

Some specific chemotherapeutic drugs are able to enhance tumor immunogenicity and facilitate antitumor immunity by inducing immunogenic cell death (ICD). However, tumor immunosuppression induced by the adenosine pathway hampers this effect. In this study, E-selectin-modified thermal-sensitive micelles are designed to co-deliver a chemotherapeutic drug (doxorubicin, DOX) and an A2A adenosine receptor antagonist (SCH 58261), which simultaneously exhibit chemo-immunotherapeutic effects when applied with microwave irradiation. After intravenous injection, the fabricated micelles effectively adhere to the surface of leukocytes in peripheral blood mediated by E-selectin, and thereby hitchhiking with leukocytes to achieve a higher accumulation at the tumor site. Further, local microwave irradiation is applied to induce hyperthermia and accelerates the release rate of drugs from micelles. Rapidly released DOX induces tumor ICD and elicits tumor-specific immunity, while SCH 58261 alleviates immunosuppression caused by the adenosine pathway, further enhancing DOX-induced antitumor immunity. In conclusion, this study presents a strategy to increase the tumor accumulation of drugs by hitchhiking with leukocytes, and the synergistic strategy of chemo-immunotherapy not only effectively arrested primary tumor growth, but also exhibited superior effects in terms of antimetastasis, antirecurrence and antirechallenge.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

Bacterial navigation for tumor targeting and photothermally-triggered bacterial ghost transformation for spatiotemporal drug release

Cancer chemotherapy is confronted with challenges regarding the effective delivery of chemotherapeutics into tumor cells after systemic administration. Herein, we propose a strategy to load drugs into probiotic E. coli Nissle 1917 (EcN) for self-guided navigation to tumor tissues and subsequently release the drugs with in situ transformation into bacterial ghosts (BGs). Chemotherapeutic agent 5-fluorouracil (FU) and macrophage phenotype regulator zoledronic acid (ZOL) are loaded into EcN through electroporation, followed by decoration of Au nanorods on the ECN surface to construct EcNZ/F@Au. High loading levels of 5FU (8.8%) and ZOL (10.5%) are achieved as well as high retention rates of bacterial viability (87%) and motion velocity (88%). Under near infrared (NIR) illumination the photothermal effect of Au nanorods elevates the local temperature to induce the transformation of live EcN into BGs. The created transmembrane channels initiate the gradual drug release from BGs, thus representing the first attempt to control the drug release via a biological evolution. An intermittent NIR illumination causes stepwise increases in the BG formation and drug release, which could implement an external on-off control and spatiotemporal drug release. Self-guided motion of EcN promotes efficient extravasation across blood vessels and preferential accumulation of drugs in tumors. In addition to the chemotherapeutic effect of FU, the local release of ZOL from EcNZ/F@Au enhances valid polarization of tumor-associated macrophages toward the M1 phenotype and an effective production of proinflammatory cytokines, leading to a synergistic efficacy on tumor growth inhibition. Thus, this study demonstrates a feasible strategy to integrate chemotherapy, immunotherapy, and photothermal effects in a concise manner for effective cancer treatment with few side effects. Statement of SignificanceBacteria are capable to trace and colonize in hypoxic tumor tissues. Bacterial drug carriers indicate limitations in efficient drug loading and effective release modulation. Herein, we propose a strategy to load drugs into bacteria for self-guided delivery and subsequently release the drugs in tumors with in situ transformation into bacterial ghost (BGs). Drugs are loaded into live bacteria through electroporation and Au nanorods are decorated on the bacterial surface, wherein the photothermal effect, chemotherapy, and immunotherapy are integrated in a concise manner. NIR illmumination of Au nanorods elevates the local temparature, induces the BG tranformation, and activates the spatiotemporal drug release, representing the first attempt of release modulation via a biological evolution.