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Hypervascularized glioblastoma is naturally sensitive to anti-angiogenesis but suffers from low efficacy of transient vasculature normalization. In this study, a lipid-polymer nanoparticle is synthesized to execute compartmentalized Cas9 and sgRNA delivery for a permanent vasculature editing strategy by knocking out the signal transducer and activator of transcription 3 (STAT3). The phenylboronic acid branched cationic polymer is designed to condense sgRNA electrostatically (inner compartment) and patch Cas9 coordinatively (outer compartment), followed by liposomal hybridization with angiopep-2 decoration for blood-brain barrier (BBB) penetration. The lipid-polymer nanoparticles can reach glioblastoma within 2 h post intravenous administration, and hypoxia in tumor cells triggers charge-elimination and degradation of the cationic polymer for burst release of Cas9 and sgRNA, accompanied by instant Cas9 RNP assembly, yielding ≈50% STAT3 knockout. The downregulation of downstream vascular endothelial growth factor (VEGF) reprograms vasculature normalization to improve immune infiltration, collaborating with interleukin-6 (IL-6) and interleukin-10 (IL-10) reduction to develop anti-glioblastoma responses. Collectively, the combinational assembly for compartmentalized Cas9/sgRNA delivery provides a potential solution in glioblastoma therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Immunosuppressive microenvironment and poor immunogenicity are two stumbling blocks in anti-tumor immune activation. Tumor associated macrophages (TAMs) play crucial roles in immunosuppressive microenvironment, while immunogenic cell death (ICD) is a typical strategy to boost immunogenicity. Herein, we developed a coordinative modular assembly-based self-reinforced nanoparticle, (CaO 2 /TA)-(Fe 3+ /BSA) which integrated CaO 2 , Fe 3+ -tannic acid coordinated networks and albumin under the instruction of molecular dynamics simulation. (CaO 2 /TA)-(Fe 3+ /BSA) could significantly enhance Fenton reaction through Fe 3+ self-reduction and H 2 O 2 self-sufficiency, and simultaneously increased intracellular accumulation of Ca 2+ . The self-augmented Fenton reaction with sufficient reactive oxygen species effectively repolarized TAMs and elicited ICD with Ca 2+ overload. Besides, (CaO 2 /TA)-(Fe 3+ /BSA) was confirmed to self-reinforce deep tumor drug delivery by "treatment-delivery" positive feedback based on gp60-mediated transcytosis and M2-like macrophages repolarization-mediated perfusion promotion. Resultantly, (CaO 2 /TA)-(Fe 3+ /BSA) effectively alleviated immunosuppression, provoked local and systemic immune response and potentiated anti-PD-1 antibody therapy. Our strategy highlights a facile and controllable approach to construct penetrated effective antitumor nano-immunotherapeutic agent., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pH e ) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pH e sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis. On the basis of significantly promoted drug availability, a strengthened "omnidirectional" inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Polydopamine (PDA) is capable of wide drug delivery for biomedical applications by virtue of an adjustable polymerization process, including surface coating and conjugation. Inspired by the polymerization of dopamine, we introduce a layer-by-layer hybrid co-assembly strategy for the incorporation of doxorubicin (DOX) and dopamine to form PDA "carrier-drug" hybrid assembly. The "carrier-drug" hybrid assembly relies on the π-π stacking interaction between the drug (DOX) and carrier (PDA), and such the stacked-layer structure enables PDA nanoparticles with a superior drug loading of 58%, which is about 1.7-fold higher than that of the DOX surface coating (∼35%). To further improve blood circulation stability and enhance tumor penetration, we herein propose the conjugation of native apolipoprotein A-I (apoA-I) with tumor-homing cyclic peptide iRGD for PDA surface modification. The "carrier-drug" hybrid assembly can respond to triple stimuli of the acidic pH, concentrated reactive oxygen species (ROS), and near-infrared (NIR) light irradiation for realizing site-specific and on-demand drug release. In chemo-photothermal synergy therapy, the "carrier-drug" hybrid assembly performs efficient tumor penetration and accumulation, dramatically suppressing tumor growth and metastasis in a 4T1 orthotopic tumor-bearing mice model at a safe level. Collectively, our findings share new insights into the design of "carrier-drug" hybrid assembly for enhanced chemo-photothermal oncotherapy.

Given the distinct pathological features of neoplasm tissues, multifunctional responsive nanocarriers have been recently considered as promising candidates to optimize the chemotherapy regime. As a result, we propose a graphene oxide-based pH-responsive drug delivery system via covalent assembly of "hairpin-like" cell penetrating peptides with acid sensitive and charge reversal properties to realize superior tumor specificity and lower toxicity. Graphene oxide here can serve as high doxorubicin-loading nanosheets and facilitate swift drug release in response to laser irradiation, which provides an efficient platform for the synergy of photo-chemotherapy. Structurally, polyglycol conjugation on the graphene oxide surface fulfils the function of nanocomposite stabilization. After administration, the elaborately acid sensitive cell penetrating peptides maintain the hairpin structure under physiological conditions, while after entering the tumor acidic microenvironment, they undergo charge reversal and structural conversion to promote the cellular uptake of nanoparticles. The evaluation of nanocomposites in vitro revealed their negligible systematic toxicity and remarkable antitumor effects. In vivo experiments also confirmed the impressive stability and tumor-specific targeting for alleviating breast cancer. In conclusion, hairpin peptide modified graphene oxide nanoparticles show multiple merits including high drug carrying capacity, selective tumor penetration, responsive drug release and effective combination oncotherapy.

A limited infiltration and the subsequent low effective drug concentration result in poor chemotherapeutic outcomes against tumors, and even further promote tumor resistance and metastatic. Herein, iRGD-modified graphene oxide (GO) nanosheets (IPHG) are developed for the intensive treatment of metastatic tumors using focus-specific penetrated delivery together with photothermal therapy-mediated chemosensitization and photothermal therapy-strengthened integrin targeting-based antimigration. In vitro and in vivo data verified the mechanism of the tumor-selective infiltration of IPHG is based on a rigid 2D structure-associated advantage regarding hemodynamics and endothelial contact, followed by iRGD-endowed transendothelial and intratumoral transport. Once IPHG-DOX-penetrated 4T1 tumors are exposed to near-infrared irradiation, hyperthermia stress and photothermal therapy-elevated effective drug concentrations result in chemosensitization and prominent tumor suppression. Meanwhile, the specific binding of iRGD to integrins and photothermal therapy leads to the synergistic perturbation of cytoskeleton remodeling and subsequent impairment of cell motility and metastasis. The tailored design of IPHG validates a promising paradigm for drug delivery to combat tumor resistance and metastasis resulting from poor target access for single chemotherapy., (© 2021 Wiley-VCH GmbH.)

A hypoxia-sensitive zwitterionic vehicle, D High -PEI-(A+P), with the ability for antifouling-mediated, stable biotransport and a photodynamic therapy (PDT)-sensitized hypoxic response for spatiotemporal controlled drug release, was developed for the tumor-specific delivery of chemotherapeutics and biomacromolecules. The amphiphilic D High -PEI-(A+P) was constructed from a betaine monomer (DMAAPS), a photosensitizer (PpIX), and an azobenzene-4,4'-dicarboxylic acid-modified polyethylenimine. Herein paclitaxel (PTX) was selected as a common model drug to verify the functions of the designed polymer. First, D High -PEI-(A+P) was demonstrated to spontaneously coassemble with PTX in aqueous solution with high drug loading (>35%). The desirable antifouling ability of D High -PEI-(A+P) was independently verified by efficient 4T1 endocytosis in serum alongside systemic tumor targeting. Furthermore, PpIX-mediated PDT was verified to aggravate and homogenize a hypoxic microenvironment at the cell and tissue levels for a sharp responsive disassembly of D High -PEI-(A+P) and thus a robust drug release in a well-controlled manner. As a result, D High -PEI-(A+P) amplified the therapeutic outcome of PTX on orthotopic 4T1 mouse models with minimal collateral damage. We proposed that D High -PEI-(A+P) may serve as a tailor-designed universal vehicle for the tumor-specific delivery of drugs with distinct physicochemical properties.

Remarkable advances in nano delivery systems have provided new hope for tumor prevention, diagnosis and treatment. However, only limited clinical therapeutic effects against solid tumors were achieved. One of the main reasons is the presence of abundant physiological and pathological barriers in vivo that impair tumoral penetration and distribution of the nanodrugs. These barriers are related to the components of tumor microenvironment (TME) including abnormal tumor vasculature, rich composition of the extracellular matrix (ECM), and abundant stroma cells. Herein, we review the advanced strategies of TME remodeling to overcome these biological obstacles against nanodrug delivery. This review aims to offer a perspective guideline for the implementation of promising approaches to facilitate intratumoral permeation of nanodrugs through alleviation of biological barriers. At the same time, we analyze the advantages and disadvantages of the corresponding methods and put forward possible directions for the future researches., (Copyright © 2021 Elsevier B.V. All rights reserved.)

rHDL is a synthesized drug delivery nanoplatform exhibiting excellent biocompatibility, which possesses most of the advantages of HDL. rHDL shows almost no toxicity and can be degraded to non-toxic substances in vivo. The severe limitation of the application of various antitumor agents is mainly due to their low bioavailability, high toxicity, poor stability, etc. Favorably, antitumor drug-loaded rHDL nanoparticles (NPs), which are known as an important drug delivery system (DDS), help to change the situation a lot. This DDS shows an outstanding active-targeting ability towards tumor cells and improves the therapeutic effect during antitumor treatment while overcoming the shortcomings mentioned above. In the following text, we will mainly focus on the various applications of rHDL in tumor targeted therapy by describing the properties, preparation, receptor active-targeting ability and antitumor effects of antineoplastic drug-loaded rHDL NPs.

The complex blood environment, heterogenic enhanced permeability and retention (EPR) effect, and dense matrix comprise the primary "leakage obstacles" impeding specific accumulation and penetration of nanodrugs against solid tumors, thus forming a key bottleneck for their clinical application. Herein, we present a biomineralization-inspired dasatinib (DAS) nanodrug (CIPHD/DAS) that sequentially permeates all of the abovementioned hindrances for efficient treatment of solid tumors. CIPHD/DAS exhibited a robust hybrid structure constructed from an iRGD-modified hyaluronic acid-deoxycholic acid organic core and a calcium phosphate mineral shell. In vitro and in vivo data demonstrated the mechanism of sequential tumoral infiltration was based on mineral-stiffened blood circulation with decreased premature drug leakage, iRGD-endowed tumor-specific transendothelial transport for "first-order promotion of accumulation" and DAS-mediated restoration of fibrotic stromal homeostasis for "second-order promotion of penetration". Resultantly, CIPHD/DAS showed remarkable distal drug availability in desmoplastic 4T1/CAFs orthotropic mouse models and significantly suppressed tumor growth and metastasis. This optimized strategy with sequential permeabilization of the capital "leakage obstacles" validates a promising paradigm to conquer the "impaired delivery and penetration" associated bottleneck of nanodrugs in the clinical treatment of solid tumors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus "synchronizing" the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Angiogenesis is the hallmark of melanoma that nurtures the tumor microenvironment (TME) for rapid tumor progression. Vessel normalization could benefit melanoma treatment through TME reconstruction, while its limited duration and extent are still the drag. Herein, two kinds of look-like nanodrugs, called Gemini-like nanodrugs (GLnano), were constructed separately with the same scaffold of antiangiogenic low molecular weight heparin (LMWH) and mixed upon administration in vivo . For one, doxorubicin (DOX) was encapsulated into LMWH-chrysin nanodrug (LCY) with DSPE-PEG-anisamide decoration (D-LCA nanodrugs) for active targeting and direct cell killing toward melanoma cells. For another, matrix metalloproteinases (MMPs)-sensitive peptide was conjugated to LMWH to encapsulate celecoxib (Cel) (C-Lpep nanodrugs), disassembling in TME by MMPs and releasing Cel for M2-to-M1 reprogramming of tumor-associated macrophages. Our results showed that GLnano could remarkably elongate the vessel normalization window up to 12 days with the highest pericyte coverage of nearly 75%, compared to only 4 days by LCY monotherapy. Furthermore, GLnano could spontaneously form the "treatment-delivery" loop to promote nanodrugs toward deep tumor regions, leading to a potent tumor inhibition, metastasis prevention, and overall TME improvements.

Since conventional chemotherapy has a variety of deficiencies and severe side effects, phototherapy has recently aroused great interest worldwide owing to its great potential towards theranostic applications. However, the physiological barrier of tumors hindered the penetration of therapeutic and imaging agents into the center of tumors. In this study, a novel biomimetic nanoplatform inspired by high-density lipoproteins (HDLs) was designed with deep tumor penetrating ability and integrated the clinical imaging agent indocyanine green (ICG) for synergistic phototherapy. Specifically, the HDL-protein was conjugated with the tumor-homing iRGD peptide via an applicable cross-linker to obtain a similar α helix structure, which served as an organizing scaffold for maintaining lipid nanoparticle structure. Our study illustrated that the mimicking nanoparticles shared nanosized diameters and superior biostability compared with free ICG. Once irradiated by NIR light, the encapsulated ICG could produce heat in localized ranges for photothermal therapy (PTT) and sufficient reactive oxygen species (ROS) for photodynamic therapy (PDT). Moreover, the fluorescence of ICG excited by NIR light effectively assisted in diagnosis. After intravenous injection, HDL mimicking nanoparticles could penetrate into deep tumors to realize enhanced phototherapy (PTT and PDT) under NIR laser irradiation. This biomimetic drug delivery system could open an avenue for the production of tailored theranostic nanoplatforms for personalized medicine in the near future.

Alzheimer's disease (AD) is a multifaceted and progressive neurodegenerative disease characterized by accumulation of amyloid-beta (Aβ) and deficits of acetylcholine. Accordingly, the intra-/extra-cerebral level of high density lipoprotein (HDL) is crucial on the pathogenesis of AD; and most of all, various HDL-protein subtypes play a double-edged role in AD pathology, of which apolipoprotein A-I (apoA-I) gives protective outcomes. Inspired from "HDL bionics", we proposed biologically reassembled nanodrugs, donepezil-loaded apolipoprotein A-I-reconstituted HDL (rHDL/Do) that concurrently executed dual-missions of Aβ-targeting clearance and acetylcholinesterase (AChE) inhibition in AD therapy. Once prepared, rHDL/Do nanodrug achieved high drug encapsulation efficiency of 90.47%, and mimicked the configurations and properties of natural lipoproteins aiming to significantly enhance BBB penetration and modulate Aβ-induced neuronal damage both in vitro and in vivo. Surface plasmon resonance (SPR) analysis confirmed that rHDL/Do facilitated microglial-mediated Aβ intake and degradation, demonstrating low KD value with Aβ affinity (2.45 × 10 -8 of Aβ monomer and 2.78 × 10 -8 of Aβ oligomer). In AD animal models, daily treatment of rHDL/Do efficiently inhibited AChE activity, ameliorated neurologic variation, promoted Aβ clearance, and rescued memory loss at a safe level. The collective findings indicated that the biological nanodrug was provided with the capacities of BBB penetration, Aβ capture and degradation via microglial cells, and cholinergic dysfunction amelioration after controlled donepezil release. In summary, rHDL/Do nanodrugs could offer a promising strategy to synergize both symptom control and disease modification in AD therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

It was widely accepted that polymeric nanodrugs held superiority in enhancing antitumor efficacy, reducing side effect and achieving better long-term prognosis. However, there still existed disputes that whether their therapeutic efficiency was closely related to insure effective release of hydrophobic drug located in their hydrophobic core in tumor site. In order to investigate this controversy, we constructed two polymeric nanodrugs (pH-activatable sLMWH-UOA and non-sensitive LMWH-UOA) with low molecular weight heparin (LMWH) and ursolic acid (UOA) for chemo-and anti-angiogenic combination therapy in hepatocellular carcinoma. The degradation ratio of pH-activatable sLMWH-UOA increased by 33% compared with non-sensitive LMWH-UOA in in vitro degradation study. Besides, confocal microscopy captured that sLMWH-UOA could effectively release drug in acidic microenvironment of lysosome while LMWH-UOA nearly could not. More importantly, in contrast with LMWH-UOA, sLMWH-UOA presented pH-dependent cytotoxicity, indicating that promoting drug release played a key role in enhancing the cytotoxicity of polymeric nanodrugs. Additionally, in vivo pharmacodynamic evaluation showed that although non-sensitive LMWH-UOA had benefited from enhanced tumor targeting drug delivery ability to achieve absolute advantage over free drug combination therapy in antitumor combination therapy, sLMWH-UOA could acquire further optimized combined therapeutic effect with better drug release in tumor. All above, application of tumor-triggered chemical bonds to construct polymeric nanodrugs held vast prospect for improving the therapeutic efficiency for tumor cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Both tumor metastasis resisting therapy (TMRT) and tumor metastasis targeting therapy (TMTT) attempt to improve tumor metastasis treatment, but they are limited by dynamic metastatic escape or insufficient micrometastases drug accumulation, respectively. Doxorubicin (DOX)-loaded functional peptide combination (PMC)-modified hydroxyapatite (HP) multi-mode nanoparticles (DPH) were developed to realize tumor metastasis amphibious therapy by balancing TMRT and TMTT. An in vivo imaging study showed that DPH had efficient drug delivery ability targeting to primary tumor and micrometastasis. Besides, it was found that cathepsin B-triggered intracellular mitochondria and nuclei dual-targeted treatment could enhance the antitumor effect of DOX by a synergistic effect. DPH treatment finally achieved both primary tumor and micrometastases reduction in 4T1 aggressive lung metastasis models. The tumor metastasis inhibition of DPH was attributed to blocking the mitochondrial escape signaling pathways. The results also showed the enhanced anticancer benefits of DPH, which could orchestrate TMRT and TMTT in contrast to a mixture of DOX and PH (PMC-modified HP nanoparticles). Overall, we generated multi-mode nanoparticles that could flexibly realize amphibious therapy for metastatic cancer while reducing systemic drug exposure and off-target toxicities.

Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer., Statement of Significance: Herein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]-reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug solution. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Curcumin (CUR) is a natural diketone with diverse bioactivities of inhibiting angiogenesis and tumor growth. However, its clinical application for cancer treatment was severely hindered by poor aqueous solubility and chemical instability. To overcome these drawbacks and achieve enhanced antitumor efficiency, low molecular weight heparin (LMWH) was conjugated to CUR via the one-step esterification reaction to yield LMWH-CUR (LCU) nanodrugs with the size of 180 nm, which exhibited enhanced accumulation within tumor site by EPR effect and long circulating capacity by LMWH hydrophilic shell. The solubility of conjugated CUR was increased to 0.12 mg/mL (equivalent of CUR) in comparison with 0.006 mg/mL of free CUR. The bioactivities of CUR were guaranteed because of the improved stability of LCU nanodrugs in low pH condition. Moreover, the stronger anti-angiogenesis efficacy of LCU nanodrugs than LMWH monotherapy was also verified. Notably, at a rather low dose of equivalent LMWH (5 mg/kg) and CUR (0.3 mg/kg), the tumor inhibition rate of LCU nanodrugs were much higher than that of LMWH (10 times) and LMWH plus CUR mixture (3.8 times) respectively, indicating its excellent in vivo antitumor efficacy. Overall, our study managed to obtain the novel nanodrugs with potent anti-angiogenesis and antitumor effects whereas avoiding tedious and complicated synthetic procedures. These results also suggested that LCU nanodrugs could be considered as a promising targeted delivery system for cancer treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Increasing understanding in tumor pathology reveals that tumor microenvironment (TME), which supports tumor progression and poses barriers for available therapies, takes a great responsibility in inefficient treatment and poor prognosis. In recent years, the versatile nanotechnology employed in TME regulation has made great progress. The nanoparticles (NPs) can be tailored as needed to accurately target TME components by distinguishing healthy tissues from malignancy, and to regulate TME to promote tumor regression. Meanwhile, the emerging microRNAs (miRNAs) demonstrate great potentials for TME regulation, but are regrettably restricted by quick degradation. NPs systems enable the successful delivery of miRNA to TME without the limitation, expanding the application of nucleic acid drug. In this review, we summarized recent NPs-based strategies aiming at regulating TME in different ways, including anti-angiogenesis, extracellular matrix (ECM) remodeling, tumor-associated fibroblasts (TAFs) treatment and tumor-associated macrophages (TAMs) treatment, along with the miRNAs-loaded NPs for TME regulation. Catching and utilizing the features of TME for NPs design can contribute to reversing drug-resistance, optimized drug distribution, and eventually more efficient cancer therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment., Methods: The redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model., Results: This HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 μg mL -1 . Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol ® , PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX., Conclusion: The results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In this paper, reconstituted high-density lipoprotein (rHDL), a lipoprotein-derived nanovector, was constructed for codelivery of paclitaxel (PTX) and wild-type p53 gene (p53). The particle size and the zeta potential of PTX-DODAB/p53-rHDL nanoparticles were 177.2 nm and -20.06 mV, respectively. Meanwhile, they exhibited great serum stability and satisfactory sustained release characteristics in vitro. PTX-DODAB/pDNA-rHDL nanoparticles simultaneously improved the cellular uptake of PTX and pDNA via scavenger receptor B type I (SR-BI) mediated lysosome-independent internalization and promoted the transfection of pDNA in MCF-7 cells, which were revealed by flow cytometry and confocal laser scanning microscopy analyses. The high p53 protein expression in MCF-7 cells after rHDL-mediated transfection was detected by Western blotting assay. Moreover, PTX-DODAB/p53-rHDL nanoparticles showed superior cytotoxicity and significantly induced apoptosis in SR-BI overexpressed MCF-7 cells. In in vivo studies, PTX-DODAB/p53-rHDL nanoparticles without obvious toxic effects to vessels, blood, or major organs exhibited efficient tumor targeting and encouraging antitumor effects on tumor-bearing nude mice compared with controls. All the results above indicated that PTX-DODAB/p53-rHDL nanoparticles held broad prospects in combination of chemotherapeutics and gene therapeutic agents for cancer-targeted therapy.

The effective combination of drugs promoting antiangiogenesis and apoptosis effects has proven to be a promising collaborative tumor antidote; and the codelivery of small interfering RNA (siRNA) and chemotherapy agents within one efficient vehicle has gained more attention over single regimen administration. Herein, vascular endothelial growth factor specific siRNA (siVEGF) and paclitaxel (PTX) were introduced as therapeutic companions and coencapsulated into naturally mimic high-density lipoproteins (rHDL/siVEGF-PTX), so that various mechanisms of treatment can occur simultaneously. The terminal nanoparticles share capacity of specific-targeting to tumor cells overexpressed scavenger receptor class B type I (SR-BI) and deliver siVEGF and PTX into cytoplasm by a nonendocytosis mechanism. By exchanging HDL core lipids with hydrophobic therapeutics, rHDL/siVEGF-PTX possessed particle size of ∼160 nm, surface potential of ∼-20 mV, and desirable long-term storage stability. In vitro results confirmed that the parallel activity of siVEGF and PTX displayed enhanced anticancer efficacy. The half-maximal inhibitory concentration (IC 50 ) of rHDL/siVEGF-PTX toward human breast cancer MCF-7 cell is 0.26 μg/mL (PTX concentration), which presents a 14.96-fold increase in cytotoxicity by taking Taxol as comparison. Moreover, in vivo results further demonstrated that rHDL/siVEGF-PTX performed enhanced tumor growth inhibition via natural targeting pathway, accompanied by remarkable inhibition of neovascularization in situ caused by siVEGF silencing in down-regulation of VEGF proteins. On the premise of effective drug codelivery, rHDL/siVEGF-PTX demonstrated high tumor targeting for collaborative antitumor efficacy without side effects after systemic administration, and this bioinspired strategy could open an avenue for exploration of combined anticancer therapy.

Oleanolic acid (OA), a pentacyclic triterpene, is used to safely and economically treat hepatopathy. However, OA, a Biopharmaceutics Classification System IV category drug, has low bioavailability owing to low solubility (<1 μg/mL) and biomembrane permeability. We developed a novel OA nanoparticle (OA-NP)-loaded lactoferrin (Lf) nanodelivery system with enhanced in vitro OA dissolution and improved oral absorption and bioavailability. The OA-NPs were prepared using NP albumin-bound technology and characterized using dynamic light scattering, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and in vitro dissolution test. The in vivo pharmacokinetics was investigated in Sprague Dawley rats using liquid chromatography-tandem mass spectrometry. OA-NPs (OA:Lf =1:6, w/w%) exhibited spherical morphology, 202.2±8.3 nm particle size, +(27.1±0.32) mV ζ potential, 92.59%±3.24% encapsulation efficiency, and desirable in vitro release profiles. An effective in vivo bioavailability (340.59%) was achieved compared to the free drug following oral administration to rats. The Lf novel nanodelivery vehicle enhanced the dissolution rate, intestinal absorption, and bioavailability of OA. These results demonstrate that Lf NPs are a new strategy for improving oral absorption and bioavailability of poorly soluble and poorly absorbed drugs., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the codelivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of codelivering ICG and TPZ in a single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy.

Co-delivery systems capable of transporting hydrophobic chemotherapeutics and hydrophilic siRNA to the same cell population with simultaneous burst release of both drugs to maximize synergistic anticancer efficacy remains elusive. In this light, a multifunctional nanoparticle (HA-PSR) consisting of a redox-sensitive core and detachable crosslinked hyaluronic acid (HA) shell was developed. Octyl modified PEI containing disulfide linkages (PSR) were synthesized as the core materials for co-encapsulation of chemotherapeutics and siRNA, while a HAase-sensitive thiolated HA (HA-SH) was collaboratively assembled to the anionic shell for CD44-mediated active targeting along with enhanced and detachable protection for drug loaded inner cores. Resultantly, HA de-protected redox-sensitive inner cores achieved co-burst release of both cargoes when triggered by glutathione (GSH) rich environments in cytoplasm. Results of in-vivo and in-vitro testing indicated successful co-encapsulation of hydrophobic drugs and hydrophilic siRNA with adjustable ratios. Selective delivery to CD44 overexpressing tumors was achieved through passive and active targeting, followed by HAase-triggered HA de-shielding and GSH-triggered burst release of both cargos. Rapid intracellular trafficking maximized synergistic cytotoxicities of chemotherapeutics and siRNA for remarkable tumor inhibition in a xenograft animal tumor model. Consequently, the HA-PSR nanoparticle holds great potential for combined chemotherapeutics/siRNA treatment in cancer with maximized synergistic antitumor efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Photodynamic therapy has emerged as a promising strategy for cancer treatment. To ensure the efficient delivery of a photosensitizer to tumor for anticancer effect, a safe and tumor-specific delivery system is highly desirable. Herein, we introduce a novel biomimetic nanoparticle named rHDL/ICG (rHDL/I), by loading amphiphilic near-infrared (NIR) fluorescent dye indocyanine green (ICG) into reconstituted high density lipoproteins (rHDL). In this system, rHDL can mediate photoprotection effect and receptor-guided tumor-targeting transportation of cargos into cells. Upon NIR irradiation, ICG can generate fluorescent imaging signals for diagnosis and monitoring therapeutic activity, and produce singlet oxygen to trigger photodynamic therapy (PDT). Our studies demonstrated that rHDL/I exhibited excellent size and fluorescence stability, light-triggered controlled release feature, and neglectable hemolytic activity. It also showed equivalent NIR response compared to free ICG under laser irradiation. Importantly, the fluorescent signal of ICG loaded in rHDL/I could be visualized subcellularly in vitro and exhibited metabolic distribution in vivo, presenting superior tumor targeting and internalization. This NIR-triggered image-guided nanoparticle produced outstanding therapeutic outcomes against cancer cells, demonstrating great potential of biomimetic delivery vehicles in future clinical practice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could be an ideal tumor-targeted nanovector for simultaneous transfer of insoluble anticancer drug and drug resistance reversal agents. The PTX-HZ08-rHDL NPs co-delivery system might be a new promising strategy to overcome tumor drug resistance., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers, and chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor, without apparent toxicity in normal tissues. Combining DCA and p53 gene could be an effective way to treat tumors. The progress towards broad applications of DCA/p53 combination requires the development of safe and efficient vectors that target to specific cells. In this study, we developed a DSPE-PEG-AA (1,2-distearoryl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide) modified reconstituted high-density lipoprotein-based DCA/p53-loaded nanoparticles (DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes), which was fabricated as a drug/gene dual-targeting co-delivery system for potential cancer therapy. Here, DCA-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL and to act as an antitumor drug to inhibit tumor cell growth. The DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge and low cytotoxicity for normal cells in vitro. The results of confocal laser scanning microscopy (CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug delivery and gene transfection in human lung adenocarcinoma cell line A549. And in vivo investigation on nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes possessed specific tumor targeting and strong antitumor activity. The work described here demonstrated that the DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes might offer a promising tool for effective cancer therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Dual-targeted nanoparticles have been increasingly used to realize greater anti-proliferation effect by attacking double key sites of tumor cells. In order to retain nuclei inhibition effect and enhance DOX-induced apoptosis by mitochondrial pathway simultaneously, hyaluronic acid (HA) modified hydroxyapatite (HAP) nanoparticles (HAP-HA), the functional calcium-based tumor targeting nanoparticles, have been developed. In this nanosystem, HA acts as an active tumor-targeting ligand to bind the CD44 receptors which are overexpressed on the surface of tumor cells while HAP can load and deliver DOX to both nuclei and mitochondria of tumor cells. In this study, DOX-loaded HAP-HA nanoparticles (DOX/HAP-HA) exhibited satisfactory drug loading efficiency which was up to 214.55 ± 51.05 μg mg(-1) and showed a uniform nano-scaled particle size. The mitochondrial and nuclei targetability of DOX/HAP-HA was confirmed by confocal laser scanning microscopy analyses. Besides, western blot assay demonstrated that DOX/HAP-HA could markedly enhance mitochondrial cytochrome C leakage and thereby activate apoptotic cascade associated with it. In addition, in vivo anti-tumor efficacy and toxicity evaluation of DOX/HAP-HA indicated that DOX/HAP-HA was more effective and less harmful compared to other groups. DOX/HAP-HA might be a new promising targeted delivery system for effective cancer therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Combination of antiangiogenesis and chemotherapy holds vast promise for effective inhibition of tumor proliferation and invasion. Herein, a multifunctional self-assembled nanosystem consisting of amphiphilic c(RGDyK)-functionalized low-molecular-weight heparin-gambogic acid conjugate (cRHG) is developed, using c(RGDyK) peptide as αv β3 integrin targeting moiety to realize a double-targeted delivery to both tumor cells and angiogenic vasculature. cRHG with a markedly decreased anticoagulant activity can self-assemble into nanosized particles (around 150 nm). cRHG nanoparticles effectively inhibit vascular endothelial growth factor (VEGF)-triggered tube-like formation of HUVEC and neovascularization of subcutaneous Matrigel plugs. More importantly, the targeting ability of cRHG nanoparticles is revealed by their efficient internalization by αv β3 integrin-positive cells (U87MG and HUVEC) in vitro and obvious accumulation of Cy7/cRHG in the tumor site with strong fluorescence signals in both cancer cells and neovasculature. Besides, cRHG maintains the in vitro cytotoxic activity of gambogic acid, while achieving the highest in vivo antitumor activity in U87MG mouse xenograft model and displaying better safety profile than free drugs solutions. Mechanistic investigations reveal the substantial inhibition of hypoxia-inducible factor-1 alpha, VEGF, and CD31 expression by cRHG nanoparticles with remarkable down-regulation of VEGFR2 phosphorylation. These results suggest that cRHG nanoparticles provide a versatile nanoplatform for efficacious combinatorial tumor therapy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Since its approval by the FDA, Abraxane™ has been established as a clinical standard of paclitaxel (PTX)-based therapy against a variety of cancers. Despite success, Abraxane™ is still limited by suboptimal biodistribution, unfavorable pharmacokinetics and chronic toxicities from chloroform used during preparation. Accordingly, a PTX-loaded nanosuspension based on human serum albumin (HSA) with PEG modifiers (PTX-PEG-HSA) has been developed to optimize the in-vivo biodistribution, pharmacokinetics and safety of PTX over traditional PTX-HSA nanosuspensions prepared using the accepted method for Abraxane™. Results of in-vivo pharmacokinetic (PK) studies indicated PTX-PEG-HSA achieved prolonged blood circulation, illustrated by an 8.8-fold and 4.8-fold increase in area-under-the-curve (AUC) of PTX over Taxol® and PTX-HSA, while the mean residence time (MRT) of PTX in PTX-PEG-HSA was increased by 3.2-fold and 1.5-fold, respectively. HSA mediated active targeting further suppressed non-specific distribution of PTX to normal tissues, which permitted enhanced antitumor efficacy in S180 mice over Taxol® and PTX-HSA. Safety of intravenously administered PTX-PEG-HSA was confirmed through lower hemolytic activity, a 2.2-fold and 1.2-fold increase in LD50 (113.4 mg/kg) over Taxol® and PTX-HSA alongside the absence of local venous irritation. Studies herein suggest the therapeutic and clinical applicability of PTX-PEG-HSA for tumor specific therapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Nanoparticles are widely recognized as a vehicle for tumor-targeted therapies. There are many factors that can influence the uptake of nanoparticles, such as the size of the nanoparticles, and/or their shape, elasticity, surface charge and even the cell cycle phase. However, the influence of the cell cycle on the active targeting of a drug delivery system has been unknown until now. In this study, we initially investigated the folate receptor α (FR-α) expression in different phases of HeLa cells by flow cytometric and immunocytochemical methods. The results obtained showed that FR-α expression was cell cycle-dependent, i.e. the S cells' folate receptor expression was the highest as the cell progressed through its cycle. Then, we used folate modified poly(L-amino acid) micelles (FA-PM) as an example to investigate the influence of the cell cycle on the active targeting drug delivery system. The results obtained indicated that the uptake of FA-PM by cells was influenced by the cell cycle phase, and the S cells took up the greatest number of folate conjugated nanoparticles. Our findings suggest that future studies on ligand-mediated active targeting preparations should consider the cell cycle, especially when this system is used for a cell cycle-specific drug.

The application of bio-derived nanoparticulates has gained a remarkable degree of interest as a promising sustained-release, site-targeted and completely biodegradable delivery system for chemotherapeutics. We hereby introduce a dual-functionalized biomimetic nanovector, cell-penetrating peptide (CPP)-anchored recombinant high density lipoproteins (cp-rHDL), which affords high payload and improved targeting of gambogic acid (GA), a therapeutic agent for apoptotic antitumor therapy. GA-loaded cp-rHDL nanoparticles (cp-rHDL/GA) consisted of hydrophobic core modulating GA, apolipoprotein A-I (apo A-I) for attractive integrating and tumor-homing, and lipophilic anchored R6H4 (RRRRRRHHHH, a pH-responsive CPP) offering a pH-controlled penetrating potential. Upon stepwise incubation with apo A-I and R6H4, cp-rHDL/GA presented several merits, including desirable physicochemical properties, superior biostability, and favorable buffering capacity resulting in proton sponge effect. Synergistic intracellular mechanism for scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, and pH-responsive R6H4 associated endocytotic pathway with rapid endo-lysosomal escape was also observed. This tailored cp-rHDL/GA displayed remarkable cytotoxicity and apoptotic effect via triggering p53 pathway, and provided approximately 5-fold increase in IC50 compared to free GA. Moreover, this rational biomimetic therapeutic strategy attained superior tumor accumulation and significant inhibition of tumor growth in HepG2 xenograft tumor animal models without measurable adverse effect. Results of this study demonstrated that bio-derived cp-rHDL/GA presents pH-responsive penetrating potential and efficient cellular internalization. This dual-functionalization model will open an avenue for exploration of multi-functional bio-derived drug delivery, thereby rendering potential broad applications in apoptotic anticancer therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of the current investigation is to explore graphene oxide (GO) special electric and electrochemical properties in modulating and tuning drug delivery in tumor special environment of electrophysiology. The electric-sensitive drug release and redox behavior of GO-bearing berberine (Ber) was studied. Drug release in cell potential was applied in a designed electrode system: tumor environment was simulated at pH 6.2 with 0.1 V pulse voltage, whereas the normal was at pH 7.4 with 0.2 V. Quite different from the pH-depended profile, the electricity-triggered behavior indicated a high correlation with the carriers' structure: GO-based nanocomposite showed a burst release on its special "skin effect," whereas the PEGylated ones released slowly owing to the electroviscous effect of polymer. Cyclic voltammetry was used to investigate the redox behaviors of colloid PEGylated GO toward absorbed Ber in pH 5.8 and 7.2 solutions. After drug loading, the oxidation of Ber was enhanced in a neutral environment, whereas the enhancement of PEG-GO was in an acidic one, which means a possible increased susceptibility of their biotransformation in vivo. The studies designed in this work may help to establish a kind of carrier system for the sensitive delivery and metabolic regulation of drugs according to the different electrophysiological environment in tumor therapy., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The purpose of this study was to develop a novel featured and flexible methotrexate (MTX) formulation, in which MTX was physically entrapped and chemically conjugated in the same drug delivery system. A series of poloxamer-MTX (p-MTX) conjugates was synthesized, wherein MTX was grafted to poloxamer through an ester bond. p-MTX conjugates could self-assemble into micelle-like structures in aqueous environment and the MTX end was in the inner-core of micelles. Moreover, free MTX could be physically entrapped into p-MTX micelles hydrophobic core region to increase the total drug loading. Importantly, the resulting MTX-loaded p-MTX micelles showed a biphasic release of MTX, with a relative fast release of the entrapped MTX (about 6-7h) followed by a sustained release of the conjugated MTX. The pharmacokinetics study showed that the mean residence time (MRT) was extended in the case of MTX-loaded p-MTX micelles, indicating a delayed MTX elimination from the bloodstream and prolonged in vivo residence time. Besides, the area under curve (AUC) of MTX-loaded p-MTX micelles was greater than free MTX, indicating a drug bioavailability improvement. Overall, MTX-loaded p-MTX micelles might be a promising nanosized drug delivery system for the cancer therapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

About 40% of the marketed drugs and 70-90% of new drug candidates are insoluble in water and therefore poorly bioavailable, which significantly compromises their therapeutic effects. A formulation of nanosuspensions achieved by reducing the pure drug particle size down to seb-micron range is one of the most promising approaches to overcome the insolubility. However, the nanosuspension formulations are subject to instability because of nucleation and particle growth. Therefore, a stabilizer is needed to be incorporated into the nanosuspension formulation during the preparation process to suppress the aggregation of drug particles. β-LG, a globular protein, is broken by heat-induced denaturation, and its hydrophobic area is exposed, which allows it to associate with organic particles. PTX, an insoluble drug, is widely used for the clinical treatment of human cancer. However, this drug's clinical application is greatly limited by intrinsic defects including poor solubility, adverse side effects, and poor tumor penetration. In this study, we prepared β-LG-stabilized PTX nanosuspensions (PTX-NS) by coating the protein onto nanoscaled drug particles, investigating the stabilization effect of β-LG on PTX-NS, and evaluating its in vitro and in vivo performance. PTX-NS with a diameter of approximately 200 nm was easily prepared. β-LG produced significantly stabilized effect on PTX-NS via the interaction between the hydrophobic area of the protein and the hydrophobic surface of the drug particles, which resulted in a conformational change of the protein, the loss of both secondary and tertiary structures, and the transition of Trp residues to a less hydrophobic condition. Importantly, unlike other conventional nanoparticles, PTX-NS could directly translocated across the membrane into the cytosol in an energy-independent manner, without entrapment within the endosomal-lysosomal system. Moreover, compared with Taxol, PTX-NS increased AUC and Cmax by 26- and 16-fold, respectively, and prolonged T1/2 by 314-fold. As expected, PTX-NS had better in vitro and in vivo antitumor activity compared to PTX alone. Additionally, β-LG is cyto- and bio-compatible, and PTX-NS is not toxic to healthy tissues. In conclusion, the present study has suggested the high potency of globular proteins, such as β-LG, as novel biomaterials for nanosuspension platform to improve the drug delivery for disease treatment.

Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH-ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH-ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH-ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH-ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.

To obtain efficient therapeutics, drug release into the cytosol is required because drug targets are often located in the cytosol or have active sites that require intracellular machinery in the cytosolic compartment. However, typical nanocarriers gain cellular entry by endocytic mechanisms, confining the internalized nanocarriers to the endosomal-lysosomal system, thus resulting in the rapid destruction of active drugs without release into the cytosol. Herein, hybrid nanoparticles (HNs) with a core-shell structure, which was based on nanoemulsion-templates stabilized by both β-lactoglobulin (β-LG) and lecithin, were developed. Additionally, its formation mechanism and structure were also studied. Importantly, the HNs could directly penetrate the cell membrane and enter the cytosol, without entrapment within the endosomal-lysosomal system via the lipid raft-like pathway, thus enhancing its antitumor activities. We therefore concluded that HNs are promising targeting delivery systems for drugs, especially for pharmaceutical proteins and gene-targeting drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Herein, we describe the preparation of a targeted cellular delivery system for morin hydrate (MH), based on a low-molecular-weight hyaluronic acid-poly(butyl cyanoacrylate) (HA-PBCA) block copolymer. In order to enhance the therapeutic effect of MH, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was mixed with HA-PBCA during the preparation process. The MH-loaded HA-PBCA "plain" nanoparticle (MH-PNs) and HA-PBCA/TPGS "mixed" nanoparticles (MH-MNs) were concomitantly characterized in terms of loading efficiency, particle size, zeta potential, critical aggregation concentration, and morphology. The obtained MH-PNs and MH-MNs exhibited a spherical morphology with a negative zeta potential and a particle size less than 200 nm, favorable for drug targeting. Remarkably, the addition of TPGS resulted in about 1.6-fold increase in drug-loading. The in vitro cell viability experiment revealed that MH-MNs enhanced the cytotoxicity of MH in A549 cells compared with MH solution and MH-PNs. Furthermore, blank MNs containing TPGS exhibited selective cytotoxic effects against cancer cells without diminishing the viability of normal cells. In addition, the cellular uptake study indicated that MNs resulted in 2.28-fold higher cellular uptake than that of PNs, in A549 cells. The CD44 receptor competitive inhibition and the internalization pathway studies suggested that the internalization mechanism of the nanoparticles was mediated mainly by the CD44 receptors through a clathrin-dependent endocytic pathway. More importantly, MH-MNs exhibited a higher in vivo antitumor potency and induced more tumor cell apoptosis than did MH-PNs, following intravenous administration to S180 tumor-bearing mice. Overall, the results imply that the developed nanoparticles are promising vehicles for the targeted delivery of lipophilic anticancer drugs.

In order to enhance the in vivo codelivery efficiency of gambogic acid (GA) and all-trans retinoic acid (ATRA), our strategy was to entrap GA in the self-assembled nanoparticles based on amphiphilic hyaluronic acid (HA)-ATRA (HRA) conjugate. In this way, GA and ATRA were loaded simultaneously in a nanocarrier and codelivered into the tumor cell through HA receptor-mediated endocytosis. GA-loaded HRA nanoparticles (GA-HRA) were prepared by a dialysis method, and their physicochemical characteristics were investigated as well. GA-HRA exhibited a high drug loading capacity (31.1%), had a particle size in the range of 100-150 nm, and good biocompatibility. HRA nanoparticles were effectively internalized by MCF-7 cells and translocated into the nucleus in a time-dependent manner. The in vivo imaging analysis demonstrated that the fluorescent signals in the tumor were markedly increased with DiR-loaded nanoparticles after intravenous administration compared to free DiR solution, suggesting it has excellent tumor targeting properties. More importantly, GA-HRA exhibited excellent in vivo efficacy with dramatically reduced toxicity. In conclusion, with the assistance of HRA nanoparticles, GA and ATRA can successfully realize an effective combination chemotherapy as well as tumor-targeted delivery.

An amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor-targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA) and paclitaxel (PTX). The HRA conjugate was synthesized by an imine reaction between HA-COOH and ATRA-NH2. PTX-loaded HRA nanoparticles possessed a high loading capacity, nanoscale particle sizes, and good biocompatible characteristics. Cell viability assays indicated that PTX-loaded HRA nanoparticles exhibited concentration- and time-dependent cytotoxicity. Moreover, they displayed obvious superiority in inducing the apoptosis of tumor cells. Cellular uptake analysis suggested that HRA nanoparticles could be efficiently taken up by cells via endocytic pathway and transport into the nucleus, contributing to HA receptor-mediated endocytosis and ATRA-induced nuclear translocation, respectively. Moreover, in vivo imaging analysis indicated that the accumulation of DiR-loaded HRA nanoparticles in tumor was increased obviously after intravenous administration as compared to free DiR solution, which confirmed that the HRA nanoparticles could assist the drugs targeting to the tumor. Furthermore, PTX-loaded HRA nanoparticles exhibited greater tumor growth inhibition effect in vivo with reducing the toxicity. Therefore, HRA nanoparticles can be considered as a promising targeted codelivery system for combination cancer chemotherapy.

RNA interference holds tremendous potential as a therapeutic approach of malignant tumors. However, safe and efficient nanovectors are extremely lack for systemic delivery of small interfering RNA (siRNA). The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted cholesterol-conjugated siRNA (Chol-siRNA) delivery for Pokemon gene silencing therapy. Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were prepared using thin-film dispersion method and their characteristics were investigated in detail. RHDL/Chol-siRNA complexes at the optimal volume ratio (lipid: Chol-siRNA) exhibited high Chol-siRNA-loading efficiency (~99%), desirable nanoparticle size and excellent stability in serum. In addition, by analyzing Chol-siRNA release profile, rHDL/Chol-siRNA complexes displayed sustained-release characteristic and storage stability. Observations from FACS and confocal microscopic analyses revealed that rHDL-mediated carboxyfluorescein tagged Chol-siRNA (FAM-Chol-siRNA) transfection resulted in highly efficient uptake and specific cytoplasmic delivery of FAM-Chol-siRNA into human hepatocellular carcinoma cell line HepG2 via HDL-receptor mediated mechanism. In vitro cytotoxicity, apoptosis and Western-blot analyses revealed significant cellular growth inhibition and decrease of Pokemon and Bcl-2 protein expression in HepG2 cells treated with Chol-siRNA-Pokemon-loaded rHDL nanoparticles (rHDL/Chol-siRNA-Pokemon complexes), respectively. In in vivo studies, the near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-siRNA complexes) obviously accumulated in tumor of nude mice after i.v. administration as compared with Cy5-Chol-siRNA-loaded lipoplexes (Lipos/Cy5-Chol-siRNA complexes). Morover, rHDL/Chol-siRNA-Pokemon complexes demonstrated great tumor growth inhibition and significant decrease of Pokemon and Bcl-2 protein expression in vivo. These results suggested that rHDL should be an ideal non-viral tumor-targeting vector for Chol-siRNA transfer, and rHDL-mediated Chol-siRNA-Pokemon delivery might be a promising new strategy for gene therapy in hepatocellular carcinoma., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Amphiphilic low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate, as a drug carrier for cancer therapy, was found to have markedly low toxicity and to form self-assembled nanoparticles for simultaneous delivery of paclitaxel (PTX) and all-trans-retinoid acid (ATRA) in our previous study. In the present study, PTX-loaded LHR nanoparticles were prepared and demonstrated a spherical shape with particle size of 108.9 nm. Cellular uptake analysis suggested rapid internalization and nuclear transport of LHR nanoparticles. In order to investigate the dynamic behaviors and targeting ability of LHR nanoparticles on tumor-bearing mice, near-infrared fluorescent (NIFR) dye DiR was encapsulated into the nanoparticles for ex vivo optical imaging. The results indicated that LHR nanoparticles could enhance the targeting and residence time in tumor site. Furthermore, in vivo biodistribution study also showed that the area under the plasma concentration time curve (AUC (0→inf)) values of PTX and ATRA for PTX-loaded LHR nanoparticles in tumor were 1.56 and 1.62-fold higher than those for PTX plus ATRA solution. Finally, PTX-loaded LHR nanoparticles demonstrated greater tumor growth inhibition effect in vivo without unexpected side effects, compared to PTX solution and PTX plus ATRA solution. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising targeted delivery system for combination cancer chemotherapy to improve therapeutic efficacy and minimize adverse effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The aim of this study was to propose novel solid lipid nanoparticles (SLNs) loaded with cell-penetrating peptide (CPP), and to evaluate their potential for oral administration of insulin. Octaarginine (R8) was used as the CPP. SLNs loaded with insulin and R8 (Ra-Ins-SLNs) were prepared using the spontaneous emulsion solvent diffusion method. The morphological study of R8-Ins-SLNs showed its spherical shape using transmission electron microscopy (TEM) photography. The mean particle size, zeta potential, encapsulation efficiency (EE %) of insulin and R8 were 150.8 +/- 23.4 nm, 32.65 +/- 2.02 mV, 62.29 +/- 0.52% and 58.05 +/- 0.66%, respectively. The in vitro release of insulin or R8 from R8-Ins-SLNs was characterized by an initial rapid release and subsequent sustained release in pH 6.8 dissolution media. In vivo absorption experiments provided a relative pharmacological bioavailability (PA%) value of R8-Ins-SLN of 10.39 +/- 0.46%. These results suggest that SLNs loaded with CPP could be a promising perioral carrier for insulin.

Abstract: As a novel nanocarrier for simultaneous delivery of multiple anticancer drugs, low molecular weight heparin-all-trans-retinoid acid (ATRA) (LHR) conjugate was developed. Amphiphilic LHR conjugate had markedly lower anticoagulant activity, and could self-assemble to form nanoparticles for loading hydrophobic drugs. The critical aggregation concentrations of LHR conjugates were varied from 407 to 40mg/L. Paclitaxel (PTX)-loaded LHR nanoparticles were prepared by the dialysis method, with particle sizes in the range of 228.0–108.9nm. The maximum drug-loading was as much as 33.1% with an entrapment efficiency of 93.1%. They displayed enhanced PTX-induced cytotoxicity to HepG2 cells compared to PTX solution. Hemolysis and cytotoxicity studies showed that LHR conjugate was a safe material for intravenous administration. Moreover, the pharmacokinetic profiles indicated that PTX-loaded LHR nanoparticles contributed to an extended circulation of PTX and ATRA. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising anticancer drug delivery system for combination chemotherapy. [Copyright &y& Elsevier]

• PVA has been regarded as a superior material for preparing hydrogels because of unique structure with hydroxyl groups, excellent biocompatibility. • However, PVA hydrogel prepared by traditional method has some inherent shortcomings, such as severe evaporation of water and poor healing effect. • To address this issue, borax (chemical cross-link agent) and polydopmine nanoparticles have been introduced into traditional PVA hydrogels. • The new hydrogel composites exhibit stronger mechanical properties and super fast speed (10 min) of healing at room temperature. • The versatility of preparing approach are expected to find widespread interest in biomaterials, electrical skin, drug delivery and soft robots. Self-healing is a very hot topic in hydrogel community since its close relationship with broad applications such as injectable hydrogels for cell delivery, bioinks for 3D printing, and drug delivery carriers. Considerable efforts have been devoted to fabricate hydrogels with superior self-healing ability and moderate mechanical property. But more of the reported self-healing hydrogels do not own fast self-healing behavior and high mechanical strength at the same time. Herein we report a tough hybrid hydrogel which can realize ultra-fast self-healing process. This hydrogel was prepared based on polyvinyl alcohol (PVA), borax and poly-dopamine particles (PDAPs). With the incorporation of PDAPs particles, the hybrid hydrogels exhibited higher mechanical strength and faster self-healing property than PVA-borax hydrid hydrogel only. Benefited from the rapid self-healing performance, enhanced mechanical properties, good biocompatibility and simple preparation method, this novel hybrid hydrogel is expected to have great potentials in widespread applications such as electrical skin, tissue engineering, drug delivery, 3D printing and soft robots. [ABSTRACT FROM AUTHOR]

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