Aggregable Nanoparticles-Enabled Chemotherapy and Autophagy Inhibition Combined with Anti-PD-L1 Antibody for Improved Glioma Treatment.

Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition, and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could passively target the glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at the glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus resensitize glioma cells to DOX. Parallelly, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising antiglioma effect. Moreover, cotreatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash antiglioma immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance antiglioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients.

Normalizing Tumor Vessels To Increase the Enzyme-Induced Retention and Targeting of Gold Nanoparticle for Breast Cancer Imaging and Treatment.

Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressure, and improve drug delivery. Herein, a novel strategy combining cediranib, a tumor vessel normalizing agent, with an enzyme responsive size-changeable gold nanoparticle (AuNPs-A&C) was developed. In vivo photoacoustic and fluorescence imaging showed that oral pretreatment with 6 mg/kg/day of cediranib for two consecutive days significantly enhanced the retention of AuNPs-A&C in 4T1 tumor. In vivo photoacoustic imaging for hemoglobin (Hb) and oxyhemoglobin (HbO2), Evans blue assay, and immunofluorescence assay showed that cediranib pretreatment markedly increased tumor vascular permeability and tumor oxygenation, while distinctly decreased the tumor microvessel density, demonstrating normalized tumor vessels and favorably altered microenvironment. Additionally, the combination strategy considerably elevated the tumor targeting capacity of different nanoparticle formulations (AuNPs-PEG, AuNPs-A&C), while coadministration of cediranib and AuNPs-A&C achieved prevailing tumor targeting and antitumor efficacy in 4T1 tumor bearing mouse model. In conclusion, we report a novel combined administration strategy to further improve tumor diagnosis and treatment.

Fluorescent carbonaceous nanodots for noninvasive glioma imaging after angiopep-2 decoration.

Fluorescent carbonaceous nanodots (CDs) have attracted much attention due to their unique properties. However, their application in noninvasive imaging of diseased tissues was restricted by the short excitation/emission wavelengths and the low diseased tissue accumulation efficiency. In this study, CDs were prepared from glucose and glutamic acid with a particle size of 4 nm. Obvious emission could be observed at 600 to 700 nm when CDs were excited at around 500 nm. This property enabled CDs with capacity for deep tissue imaging with low background adsorption. Angiopep-2, a ligand which could target glioma cells, was anchored onto CDs after PEGylation. The product, An-PEG-CDs, could target C6 glioma cells with higher intensity than PEGylated CDs (PEG-CDs), and endosomes were involved in the uptake process. In vivo, An-PEG-CDs could accumulate in the glioma site at higher intensity, as the glioma/normal brain ratio for An-PEG-CDs was 1.73. The targeting effect of An-PEG-CDs was further demonstrated by receptor staining, which showed An-PEG-CDs colocalized well with the receptors expressed in glioma. In conclusion, An-PEG-CDs could be successfully used for noninvasive glioma imaging.

PEGylated fluorescent carbon nanoparticles for noninvasive heart imaging.

Fluorescent carbon nanoparticles (CNP) have gained much attention due to their unique fluorescent properties and safety. In this study, we evaluated the potential application of CNP and PEGylated CNP (PEG-CNP) in noninvasive heart imaging. CNP was prepared by hydrothermal treatment of silk. The particle size and zeta potential of CNP were 121.8 nm and -3.7 mV, respectively, which did not change significantly after PEGylation with a PEG density of 4.43 ± 0.02 µg/mg CNP. FTIR and XPS showed that CNP possessed several functional groups, such as -COOH, -OH, and NH2, which could be utilized for PEGylation and other modifications. CNP displayed strong blue fluorescence after excitation at the wavelength of 375 nm. PEG-CNP displayed better serum stability compared to CNP. The hemolysis rate of PEG-CNP was lower than that of CNP, suggesting PEGylation could enhance the hemocompatibility of CNP. Both CNP and PEG-CNP showed higher uptake capacity by H9c2 cells (a heart cell line) than that by human umbilical vein endothelial cells (HUVEC), suggesting the particles tend to be selectively taken up by heart cells. Both CNP and PEG-CNP were proven to be taken up through endosome-mediated pathway, and the colocalization of nanoparticles with mitochondria was also observed. In vivo results demonstrated that CNP could target heart with much higher fluorescent intensity than liver and spleen. Although PEGylation could decrease the distribution in heart, it remained high for PEG-CNP. In conclusion, CNP could be used for heart imaging, and moreover, PEGylation could improve the stability and biocompatibility of CNP.

Lapatinib-incorporated lipoprotein-like nanoparticles: preparation and a proposed breast cancer-targeting mechanism.

AIM: Lapatinib is a dual inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2), and used to treat advanced breast cancer. To overcome its poor water solubility, we constructed lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs), and evaluated the particle characteristics and possible anti-breast cancer mechanisms. METHODS: LTNPs (lapatinib bound to albumin as a core, and egg yolk lecithin forming a lipid corona) were prepared. The particle characteristics were investigated using transmission electron microscopy (TEM) and atomic force microscopy (AFM). The uptake and subcellular localization of LTNPs, as well as the effects of LTNPs on cell cycle were examined in BT-474 human breast cancer cells in vitro. Mice bearing BT-474 subcutaneous xenograft were intravenously injected with coumarin-6 loaded LTNPs (30 mg/kg) to study the targeting mechanisms in vivo. RESULTS: The LTNPs particles were generally spherical but flexible under TEM and AFM, and approximately 62.1 nm in size with a zeta potential of 22.80 mV. In BT-474 cells, uptake of LTNPs was mediated by endosomes through energy-dependent endocytosis involving clathrin-dependent pinocytosis and macropinocytosis, and they could effectively escape from endosomes to the cytoplasm. Treatment of BT-474 cells with LTNPs (20 µg/mL) induced a significant cell arrest at G0/G1 phase compared with the same concentration of lapatinib suspension. In mice bearing BT-474 xenograft, intravenously injected LTNPs was found to target and accumulate in tumors, and colocalized with HER2 and SPRAC (secreted protein, acidic and rich in cysteine). CONCLUSION: LTNPs can be taken up into breast cancer cells through specific pathways in vitro, and targeted to breast cancer xenograft in vivo via enhanced permeability and retention effect and SPARC.

Cathepsin B-Responsive Programmed Brain Targeted Delivery System for Chemo-Immunotherapy Combination Therapy of Glioblastoma.

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development of therapeutic resistance to conventional chemotherapy. TAM-targeted therapy combined with conventional chemotherapy has emerged as a promising strategy to combat GBM. However, the presence of the blood-brain barrier (BBB) severely limits the therapeutic efficacy. Meanwhile, the lack of ability to distinguish different targeted cells also poses a challenge for precise therapy. Herein, we propose a cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) for simultaneous TAM-targeted and GBM-targeted delivery. D&R-HM-MCA could cross the BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching the GBM site, the outer angiopep-2 modification could be detached from D&R-HM-MCA via cleavage of the CTSB-responsive peptide, which could circumvent abluminal LRP1-mediated efflux. The exposed p-aminophenyl-α-d-mannopyranoside (MAN) modification could further recognize glucose transporter-1 (GLUT1) on GBM and macrophage mannose receptor (MMR) on TAMs. D&R-HM-MCA could achieve chemotherapeutic killing of GBM and simultaneously induce TAM polarization from anti-inflammatory M2 phenotype to pro-inflammatory M1 phenotype, thus resensitizing the chemotherapeutic response and improving anti-GBM immune response. This CTSB-responsive brain-targeted delivery system not only can improve brain delivery efficiency, but also can enable the combination of chemo-immunotherapy against GBM. The effectiveness of this strategy may provide thinking for designing more functional brain-targeted delivery systems and more effective therapeutic regimens.

Targeted reprogramming of tumor-associated macrophages for overcoming glioblastoma resistance to chemotherapy and immunotherapy.

The resistance of glioblastoma multiforme (GBM) to standard chemotherapy is primarily attributed to the existence of tumor-associated macrophages (TAMs) in the GBM microenvironment, particularly the anti-inflammatory M2 phenotype. Targeted modulation of M2-TAMs is emerging as a promising strategy to enhance chemotherapeutic efficacy. However, combination TAM-targeted therapy with chemotherapy faces substantial challenges, notably in terms of delivery efficiency and targeting specificity. In this study, we designed a pH-responsive hierarchical brain-targeting micelleplex loaded with temozolomide (TMZ) and resiquimod (R848) for combination chemo-immunotherapy against GBM. This delivery system, termed PCPA&PPM@TR, features a primary Angiopep-2 decoration on the outer layer via a pH-cleavable linker and a secondary mannose analogue (MAN) on the middle layer. This pH-responsive hierarchical targeting strategy enables effective BBB permeability while simultaneous GBM- and TAMs-targeting delivery. GBM-targeted delivery of TMZ induces alkylation and triggers an anti-GBM immune response. Concurrently, TAM-targeted delivery of R848 reprograms their phenotype from M2 to pro-inflammatory M1, thereby diminishing GBM resistance to TMZ and amplifying the immune response. In vivo studies demonstrated that targeted modulation of TAMs using PCPA&PPM@TR significantly enhanced anti-GBM efficacy. In summary, this study proposes a promising brain-targeting delivery system for the targeted modulation of TAMs to combat GBM.

Receptor activator of nuclear factor-kappa B is enriched in CD9-positive extracellular vesicles released by osteoclasts.

Aim: Receptor activator of nuclear factor-kappa B (RANK)-containing extracellular vesicles (EVs) bind RANK-Ligand (RANKL) on osteoblasts, and thereby simultaneously inhibit bone resorption and promote bone formation. Because of this, they are attractive candidates for therapeutic bone anabolic agents. Previously, RANK was detected in 1 in every 36 EVs from osteoclasts by immunogold electron microscopy. Here, we have sought to characterize the subpopulation of EVs from osteoclasts that contains RANK in more detail. Methods: The tetraspanins CD9 and CD81 were localized in osteoclasts by immunofluorescence. EVs were visualized by transmission electron microscopy. A Single Particle Interferometric Reflectance Imaging Sensor (SP-IRIS) and immunoaffinity isolations examined whether RANK is enriched in specific types of EVs. Results: Immunofluorescence showed CD9 was mostly on or near the plasma membrane of osteoclasts. In contrast, CD81 was localized deeper in the osteoclast's cytosolic vesicular network. By interferometry, both CD9 and CD81 positive EVs from osteoclasts were small (56-83 nm in diameter), consistent with electron microscopy. The CD9 and CD81 EV populations were mostly distinct, and only 22% of the EVs contained both markers. RANK was detected by SP-IRIS in 2%-4% of the CD9-containing EVs, but not in CD81-positive EVs, from mature osteoclasts. Immunomagnetic isolation of CD9-containing EVs from conditioned media of osteoclasts removed most of the RANK. A trace amount of RANK was isolated with CD81. Conclusion: RANK was enriched in a subset of the CD9-positive EVs. The current study provides the first report of selective localization of RANK in subsets of EVs.

Light-induced high-efficient cellular production of immune functional extracellular vesicles.

Extracellular vesicle (EV)-based therapies and vaccines are emerging. However, employment at the scale for population-based dose development is always a huge bottleneck. In order to overcome such a roadblock, we introduce a simple and straightforward approach for promoting cellular production of dendritic cell derived EVs (DEVs) by leveraging phototherapy based light induction. Under the optimization of light wavelengths, intensities, and exposure times, we achieved more than 13-fold enhancement in DEV production rate, while maintaining good integral quality and immune function from produced EVs. The LED light at 365 nm is optimal to reliably trigger enhanced cellular production of EVs no matter cell line types. Our observation and other reported studies support longer near UV wavelength does not impair cell growth. We conducted a series of investigations in terms of size, zeta potential, morphology, immune surface markers and cytokines, biocompatibility, cellular uptake behaviour, and immune-modulation ability on eliciting cellular responses in vitro. We also validated the biodistribution, immunogenicity, and administration safety using light-promoted DEVs in mice models from both male and female genders. Overall data supports that light promoted DEVs are highly immune functional with great biocompatibility for serving as good therapeutic platforms. The in vivo animal study also demonstrated light-promoted DEVs are as well tolerated as native DEVs, with no safety concerns. Taken together, the data supports that light promoted DEVs are in excellent quality, high biocompatibility, in vivo tolerant, and viable for serving as an ideal therapeutic platform in scalable production.

Advanced Biomaterials for Cell-Specific Modulation and Restore of Cancer Immunotherapy.

The past decade has witnessed the explosive development of cancer immunotherapies. Nevertheless, low immunogenicity, limited specificity, poor delivery efficiency, and off-target side effects remain to be the major limitations for broad implementation of cancer immunotherapies to patient bedside. Encouragingly, advanced biomaterials offering cell-specific modulation of immunological cues bring new solutions for improving the therapeutic efficacy while relieving side effect risks. In this review, focus is given on how functional biomaterials can enable cell-specific modulation of cancer immunotherapy within the cancer-immune cycle, with particular emphasis on antigen-presenting cells (APCs), T cells, and tumor microenvironment (TME)-resident cells. By reviewing the current progress in biomaterial-based cancer immunotherapy, here the aim is to provide a better understanding of biomaterials' role in targeting modulation of antitumor immunity step-by-step and guidelines for rationally developing targeting biomaterials for more personalized cancer immunotherapy. Moreover, the current challenge and future perspective regarding the potential application and clinical translation will also be discussed.

Extracellular Vesicles as an Advanced Delivery Biomaterial for Precision Cancer Immunotherapy.

In recent years, cancer immunotherapy has been observed in numerous preclinical and clinical studies for showing benefits. However, due to the unpredictable outcomes and low response rates, novel targeting delivery approaches and modulators are needed for being effective to more broader patient populations and cancer types. Compared to synthetic biomaterials, extracellular vesicles (EVs) specifically open a new avenue for improving the efficacy of cancer immunotherapy by offering targeted and site-specific immunity modulation. In this review, the molecular understanding of EV cargos and surface receptors, which underpin cell targeting specificity and precisely modulating immunogenicity, are discussed. Unique properties of EVs are reviewed in terms of their surface markers, intravesicular contents, intrinsic immunity modulatory functions, and pharmacodynamic behavior in vivo with tumor tissue models, highlighting key indications of improved precision cancer immunotherapy. Novel molecular engineered strategies for reprogramming and directing cancer immunotherapeutics, and their unique challenges are also discussed to illuminate EV's future potential as a cancer immunotherapeutic biomaterial.

Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release.

The past decades have witnessed great progress in nanoparticle (NP)-based brain-targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the majority of them are lost during the delivery process. Rational design of brain-targeting drug delivery systems requires a deep understanding of the entire delivery process along with the issues that they may encounter. Herein, this review first analyzes the typical delivery process of a systemically administrated NPs-based brain-targeting drug delivery system and proposes a six-step CRITID delivery cascade: circulation in systemic blood, recognizing receptor on blood-brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by diseased cells, and finally intracellular drug release. By dissecting the entire delivery process into six steps, this review seeks to provide a deep understanding of the issues that may restrict the delivery efficiency of brain-targeting drug delivery systems as well as the specific requirements that may guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these issues are reviewed and some state-of-the-art design features meeting these requirements are highlighted. The CRITID delivery cascade can serve as a guideline for designing more efficient and specific brain-targeting drug delivery systems.

Development of surface engineered antigenic exosomes as vaccines for respiratory syncytial virus.

Respiratory syncytial virus (RSV) is one of the main pathogens associated with lower respiratory tract infections in infants and young children worldwide. Exosomes secreted by antigen presenting cells (APCs) can elicit immune responses by carrying major histocompatibility complex (MHC) class I molecules complexed with antigenic peptides and other co-stimulating factors. Therefore, we developed novel immunomagnetic nanographene particles to sequentially isolate, surface engineer, and release intact dendritic cell (DC) exosomes for use as a potential vaccine platform against RSV. The H-2Db-restricted, immunodominant peptides from RSV (M187-195 and NS161-75) were introduced to MHC-I on DC-derived exosomes to express peptide/MHC-I (pMHC-I) complexes. A mouse model of RSV infection was used to define the immunogenicity of surface engineered exosomes for activating virus-specific immune responses. Ex vivo assays demonstrated that engineered exosomes carrying RSV-specific peptides can elicit interferon-gamma (IFN-γ) production by virus-specific CD8+ T cells isolated from RSV-infected C57BL/6 mice. In vivo assays demonstrated that subcutaneous administration of both M187-195 and NS161-75 engineered exosomes to mice, with or without additional adjuvant, appeared safe and well tolerated, however, did not prime antigen-specific CD8+ T cell responses. Surface engineered exosomes are immunogenic and promising for further development as a vaccine platform.

Furin-instructed aggregated gold nanoparticles for re-educating tumor associated macrophages and overcoming breast cancer chemoresistance.

Insufficient drug accumulation and chemoresistance remain two major challenges in cancer chemotherapy. Herein, we designed a furin-responsive aggregated nanoplatform loaded with doxorubicin (DOX) and hydroxychloroquine (HCQ) (AuNPs-D&H-R&C) to combine chemotherapy, autophagy inhibition and macrophage polarization. AuNPs-D&H-R&C could passively target breast tumor via enhanced permeability and retention (EPR) effect after systemic administration and further aggregate together triggered by furin overexpressed in breast cancer. The in situ aggregations hindered the back-flow of NPs to the bloodstream and exocytosis of tumor cells, leading to enhanced drug accumulation within tumors. Moreover, upon exposure to acidic pH in the endosomes/lysosomes, HCQ was efficiently released and it inhibited autophagy and thus restored the sensitivity of tumor cell to DOX. Meanwhile, autophagy inhibition could reprogram tumor-promoting M2-like TAMs to anti-tumor M1 phenotype, exerting a synergistic effect in overcoming chemoresistance. In vitro studies demonstrated the superiority of furin-triggered aggregated AuNPs delivery system in enhancing drug accumulation in breast tumor, compared with PEGlyated AuNPs. The co-delivery of DOX and HCQ showed much improved chemotherapeutic efficiency to chemoresistant MCF-7/ADR breast tumor, in large part due to macrophage polarization. In conclusion, we developed a stimulus-responsive delivery system and proposed a potential combination strategy to overcome chemoresistance in cancer chemotherapy.

Ligand Size and Conformation Affect the Behavior of Nanoparticles Coated with in Vitro and in Vivo Protein Corona.

Protein corona is immediately established on the surface of nanoparticles upon their introduction into biological milieu. Several studies have shown that the targeting efficiency of ligand-modified nanoparticles is attenuated or abolished owing to the protein adsorption. Here, transferrin receptor-targeting ligands, including LT7 (CHAIYPRH), DT7 (hrpyiahc, all d-form amino acids), and transferrin, were used to identify the influence of the ligand size and conformation on protein corona formation. The results showed that the targeting capacity of ligand-modified nanoparticles was lost after incubation with plasma in vitro, whereas it was partially retained after in vivo corona formation. Results from sodium dodecyl sulfate polyacrylamide gel electrophoresis and liquid chromatography-mass spectrometry revealed the difference in the composition of in vitro and in vivo corona, wherein the ligand size and conformation played a critical role. Differences were observed in cellular internalization and exocytosis profiles on the basis of the ligand and corona source.

Coadministration of iRGD with Multistage Responsive Nanoparticles Enhanced Tumor Targeting and Penetration Abilities for Breast Cancer Therapy.

Limited tumor targeting and poor penetration of nanoparticles are two major obstacles to improving the outcome of tumor therapy. Herein, coadministration of tumor-homing peptide iRGD and multistage-responsive penetrating nanoparticles for the treatment of breast cancer are reported. This multistage-responsive nanoparticle, IDDHN, was comprised of an NO donor-modified hyaluronic acid (HN) shell and a small-sized dendrimer, namely, dendri-graft-l-lysine conjugated with doxorubicin and indocyanine (IDD). The results showed that IDDHN could be degraded rapidly from about 330 nm to a smaller size that was in a size range of 35 to 150 nm (most at 35-60 nm) after hyaluronidase (HAase) incubation for 4 h; in vitro cellular uptake demonstrated that iRGD could mediate more endocytosis of IDDHN into 4T1 cells, which was attributed to the overexpression of αvß3 integrin receptor. Multicellular spheroids penetration results showed synergistically enhanced deeper distribution of IDDHN into tumors, with the presence of iRGD, HAase incubation, and NO release upon laser irradiation. In vivo imaging indicated that coadministration with iRGD markedly enhanced the tumor targeting and penetration abilities of IDDHN. Surprisingly, coadministration of IDDHN with iRGD plus 808 nm laser irradiation nearly suppressed all tumor growth. These results systematically revealed the excellent potential of coadministration of iRGD with multistage-responsive nanoparticles for enhancing drug delivery efficiency and overcoming the 4T1 breast cancer.

Enzyme-triggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy.

Chemotherapy remains restricted by poor drug delivery efficacy due to the heterogenous nature of tumor. Herein, we presented a novel nanoparticle that could not only response to the tumor microenvironment but also modulate it for deep tumor penetration and combination therapy. The intelligent nanoparticle (IDDHN) was engineered by hyaluronidase (HAase)-triggered size shrinkable hyaluronic acid shells, which were modified with NIR laser sensitive nitric oxide donor (HN), small-sized dendrimeric prodrug (IDD) of doxorubicin (DOX) as chemotherapy agent and indocyanine green (ICG) as photothermal agent into a single nanoparticle. IDDHN displayed synergistic deep penetration both in vitro and in vivo, owing to the enzymatically degradable HN shell mediated by HAase and laser-enhanced NO release triggered deep penetration upon strong hyperthermia effect of ICG under the NIR laser irradiation. The therapeutic effect of IDDHN was verified in 4T1 xenograft tumor model, and IDDHN showed a much better antitumor efficiency with few side effects upon NIR laser irradiation. Therefore, the valid of this study might provide a novel tactic for engineering nanoparticles both response to and modulate the tumor microenvironment for improving penetration and heterogeneity distribution of therapeutic agents in tumor.

Ligand-Mediated and Enzyme-Directed Precise Targeting and Retention for the Enhanced Treatment of Glioblastoma.

Glioblastoma (GBM), one of the most lethal cancers, remains as a hard task to handle. The major hurdle of nanostructured therapeutic agents comes from the limited retention at the GBM site and poor selectivity. In this study, we reported dual-functional gold nanoparticles (AuNPs) to figure out the biological barrier and improve their accumulation in GBM. The nanoparticles, AuNP-A&C-R, were composed of two functional particles: one was Ala-Ala-Asn-Cys-Asp (AK) and R8-RGD-comodified AuNPs (AuNP-AK-R) and the other was 2-cyano-6-amino-benzothiazole and R8-RGD-comodified AuNPs (AuNP-CABT-R). AuNP-A&C-R could aggregate in the presence of legumain, resulting in a size increase from 41.4 ± 0.6 to 172.9 ± 10.2 nm after 8 h incubation. After entering the circulatory system, AuNP-A&C-R actively targeted the integrin αvß3 receptor on blood-brain barrier (BBB), mediated transcytosis of particles across BBB, and then targeted the receptor on the GBM cells. Once AuNP-A&C-R entered into GBM, they formed further aggregates with increased size extracellularly or intracellularly because of the overexpressed legumain, which in turn blocked their backflow to the bloodstream or limited their exocytosis by cells. In vivo optical imaging demonstrated that AuNP-A&C-R were efficiently delivered to the GBM site and retained with high selectivity. We further confirmed that AuNP-A&C-R acquired a higher accumulation at the GBM site than AuNP-A&C and AuNP-R because of the synergistic effect. More importantly, the doxorubicin (DOX)-loaded AuNP-A&C-R showed an improved chemotherapeutic effect to C6 GBM-bearing mice, which significantly prolonged the median survival time by 1.22-fold and 1.27-fold compared with the DOX-loaded AuNP-A&C and the DOX-loaded AuNP-R, respectively. These results suggested that the dual-functional nanoplatform is promising for the GBM treatment.

Cabazitaxel and indocyanine green co-delivery tumor-targeting nanoparticle for improved antitumor efficacy and minimized drug toxicity.

Cabazitaxel (CBX) is an effective antineoplastic agent for the treatment of many kinds of cancers. However, the poor water solubility remains a serious deterrent to the utilization of CBX as a commercial drug. In this study, we designed a strategy that integrated CBX into albumin nanoparticles (ANs) formed with human serum albumin (HSA) to improve the water solubility and targeting ability. Meanwhile, we utilized a photothermal agent-indocyanine green (ICG), which could cooperate with CBX to enhance the antitumor effect. The obtained ANs containing ICG and CBX (AN-ICG-CBX) exhibited good mono-dispersity. In vitro cytotoxicity study showed the effectiveness of CBX and ICG, respectively, whereas AN-ICG-CBX with irradiation exhibited the most efficient antiproliferative ability (83.7%). In vivo safety evaluation studies demonstrated the safety of AN-ICG-CBX. Furthermore, the in vivo antitumor study indicated that the AN-ICG-CBX with irradiation achieved higher tumor inhibition rate (91.3%) compared with CBX-encapsulated AN (AN-CBX) (83.3%) or ICG-encapsulated AN (AN-ICG) plus irradiation (60.1%) in 4T1 tumor-bearing mice. To sum up, a safety and effective formulation AN-ICG-CBX was developed in this study and successfully reduced the drug toxicity, improved the targeting efficiency and enhanced the therapeutic effects, becoming a promising candidate for clinical application.

A New Concept of Enhancing Immuno-Chemotherapeutic Effects Against B16F10 Tumor via Systemic Administration by Taking Advantages of the Limitation of EPR Effect.

The enhanced permeability and retention (EPR) effect has been comfortably accepted, and extensively assumed as a keystone in the research on tumor-targeted drug delivery system. Due to the unsatisfied tumor-targeting efficiency of EPR effect being one conspicuous drawback, nanocarriers that merely relying on EPR effect are difficult to access the tumor tissue and consequently trigger efficient tumor therapy in clinic. In the present contribution, we break up the shackles of EPR effect on nanocarriers thanks to their universal distribution characteristic. We successfully design a paclitaxel (PTX) and alpha-galactosylceramide (αGC) co-loaded TH peptide (AGYLLGHINLHHLAHL(Aib)HHIL-Cys) -modified liposome (PTX/αGC-TH-Lip) and introduce a new concept of immuno-chemotherapy combination via accumulation of these liposomes at both spleen and tumor sites naturally and simultaneously. The PTX-initiated cytotoxicity attacks tumor cells at tumor sites, meanwhile, the αGC-triggered antitumor immune response emerges at spleen tissue. Different to the case that liposomes are loaded with sole drug, in this concept two therapeutic processes effectively reinforce each other, thereby elevating the tumor therapy efficiency significantly. The data demonstrates that the PTX/αGC-TH-Lip not only possess therapeutic effect against highly malignant B16F10 melanoma tumor, but also adjust the in vivo immune status and induce a more remarkable systemic antitumor immunity that could further suppress the growth of tumor at distant site. This work exhibits the capability of the PTX/αGC-TH-Lip in improving immune-chemotherapy against tumor after systemic administration.