Active Targeting Of Tumor Cells Research Articles

Hyaluronic acid-coated liposomes for enhanced in vivo efficacy of neogambogic acid via active tumor cell targeting and prolonged systemic exposure

Neogambogic acid (NGA), which possesses a variety of anticancer activities, is visualized as an anticancer bioactive ingredient. However, the huge vascular stimulation, poor aqueous solubility, and short half-life restricted its clinical use. In this work, an effective nanocarrier was explored to reduce toxicity and enhance the tumor-targeted delivery. Two liposomal formulations, neogambogic acid liposomes (NGA-L), and hyaluronic acid-coated neogambogic acid liposomes (HA-NGA-L) were prepared and characterized with high encapsulation efficiency, slow pattern of drug release, narrow size distribution and higher stability. The cytotoxicity and cellular uptake of HA-NGA-L were higher than those of NGA-L in MDA-MB-231 cells (high CD44 expression), while no obvious differences in MCF-7 cells with (low CD44 expression), suggesting the CD44-mediated cellular internalization of hyaluronic acid-modified liposomes enhanced the cytotoxicity. Mechanistically, elevation of Bax and caspase-3 as well as downregulation of Bcl-2 led to cell apoptosis. Besides, the vascular stimulation and the hemolysis test indicated good safety of HA-NGA-L. In addition, HA-NGA-L was the effective nanocarrier to repress tumor proliferation in MDA-MB-231 tumor xenograft mouse through CD44 mediated active targeting without any obvious histopathological abnormities on major organs. Immunohistochemistry analysis revealed the enhanced elevation of Bax and caspase-3, and reduced expression of Bcl-2 contribute to apoptosis in tumors. Meanwhile, HA-NGA-L increased the AUC and t1/2 by 5.34-fold and 3.94-fold, respectively. In summary, the present study shows that HA-NGA-L may be safe and effective for the tumor-targeted delivery of neogambogic acid.

Ultrasound-driven nanoreactor with USP39 ShRNAi-intensified ferroptosis for synergistic sono-chemodynamic therapy

The promotion of cellular ferroptosis through ultrasound (US)-assisted Fenton chemistry has emerged as a promising strategy for tumor therapy. To enhance the therapeutic effect, we designed a GSH-responsive ultrasound-driven nanoreactor for RNA interference (RNAi)-intensified ferroptosis in synergistic sono-chemodynamic therapy. Our nanoreactor comprises Fe3+/tetrasulfide bond (-s-s-s-s-) enriched dendritic organosilica encapsulating USP39 shRNA, along with co-loading of sinophoryrin sodium (DVDMS) and sulfasalazine (SAS). Hyaluronic acid surface functionalization ensures high tumor accumulation for active targeting of tumor cells. Upon internalization into tumor cells, the nanoreactor degrades upon the triggering of intracellular overproduced GSH. Ultrasound-triggered release of DVDMS generates large amounts of ROS, synergizing with Fe-catalyzed Fenton chemistry. The simultaneous depletion of glutathione peroxidase 4 and GSH by SAS and Fe3+ weakens the ROS-scavenging system, leading to tumoral redox dyshomeostasis via oxidative stress amplification. This results in the accumulation of lipid peroxide in tumor cells, efficiently inducing ferroptosis. Additionally, USP39 shRNA effectively silences the expression of the USP39 gene in cells, inhibiting tumor cell proliferation, while promoting ATG5 gene expression to intensify ferroptosis. Our work provides a promising nanoreactor for high-efficiency synergistic tumor therapy via RNAi-intensified ferroptosis, highlighting the potential of sono-chemodynamic therapy in cancer treatment.

Hybrid Extracellular Vesicles-Liposomes Camouflaged Magnetic Vesicles Cooperating with Bioorthogonal Click Chemistry for High-Efficient Melanoma Circulating Tumor Cells Enrichment.

The capture of melanoma circulating tumor cells (melanoma CTCs, MelCTCs) is of great significance for the early diagnosis and personalized treatment of melanoma. The rarity and heterogeneity of MelCTCs have greatly limited the development of MelCTCs capture methods, especially those based on immune/aptamer-affinity. Herein, an extracellular vesicles-camouflaged strategy is designed to functionalize the magnetic nanoparticles (Fe3 O4 ) and to generate magnetic vesicles (Fe3 O4 @lip/ev) with excellent antifouling and active tumor cell targeting properties. Combined with the bioorthogonal click chemistry, the engineered magnetic vesicles with dibenzocyclooctyne can be widely used to target and separate all the metabolically labeled CTCs with varied phenotypes, organ origin, and even the biological species. The capture efficiency exceeded 80% with an extremely low detection limitation of ten cells. Most importantly, the strategy proposed can be directly applied to enrich MelCTCs from 0.5mL blood samples of melanoma-bearing mice, with a greatly minimized residue of white blood cells (only 21-568) while ignoring the fluctuations of MelCTC phenotype.

A hierarchical tumor-targeting strategy for eliciting potent antitumor immunity against triple negative breast cancer

Triple negative breast cancer (TNBC) as a highly aggressive and metastatic malignancy lacks targeting therapies nowadays. Moreover, although immune checkpoint blockade (ICB) is known to trigger anti-tumor immune response, most TNBC falls into the immunologically “cold” category unsuitable for ICB therapy due to insufficient lymphocyte infiltration. Herein, we develop a hierarchical targeting strategy for preparing a core-shell-structural nanodrug to concurrently block the programmed death ligand 1 (PD-L1) and deliver a stimulator of interferon gene (STING) agonist into tumor-infiltrating antigen-presenting cells (APCs). The nanodrug complexed the interferon stimulatory DNA (ISD) for STING activation in its core, conjugated PD-L1 antibody (aPD-L1) on its shell through a matrix metalloproteinase-2 (MMP-2) substrate peptide, and incorporated “hidden” mannose in its sublayer. Through aPD-L1-mediated active targeting of tumor cells and tumor-infiltrating APCs, the nanodrug efficiently accumulated in tumor sites. Then, the PD-L1-conjugating peptide was cleaved by tumor-enriched MMP-2, leaving aPD-L1 on target cells for ICB while exposing mannose to mediate targeted delivery of ISD into tumor-infiltrating dendritic cells (DCs) and tumor-associated macrophages (TAMs). Activating the STING signaling in DCs and TAMs not only stimulated the APCs maturation to prime anti-tumor immunity but also induced their chemokine secretion to promote tumor infiltration of anti-tumor effector T cells, thus sensitizing TNBC to the ICB therapy. Consequently, a potent antitumor immunity was evoked to effectively inhibit the tumor growth and metastasis in mice bearing orthotopic 4T1 breast cancer, showing the great potential in treating immunologically “cold” tumors.

Genetically Engineered Protein Corona‐based Cascade Nanozymes for Enhanced Tumor Therapy

AbstractThe emergence of nanomedicine has provided a promising strategy to greatly enhance the therapeutic efficacy of O2‐dependent photodynamic therapy (PDT). However, plasma‐derived protein corona and/or discontinuous O2 supply substantially limit their tumor delivery efficiency and therapeutic outcomes. Herein, protein corona cloaking‐based cascade nanozymes are developed using genetically engineered human ferritin heavy chain nanocages (FTn) as unique pre‐coated protein corona and cascade nanozymes as steady O2 suppliers. Specifically, FTn is coated onto mesoporous silica nanoparticles (MSNs) to form FTn‐based protein corona, providing active targeting of tumor cells by binding with its receptor. In situ synthesis of ultra‐small Au nanoparticles in MSNs, and biomimetic incorporation of Ru nanoclusters into FTn inner cavity showed glucose oxidase‐like activity and catalase‐like activity, respectively. The two nanozymes are incorporated into MSNs nanoplatform to induce cascade and circular catalytic reactions by consuming glucose and H2O2 within the tumor microenvironment. Compared to MSNs alone, the FTn‐based protein corona is capable of efficiently diminishing plasma‐derived protein corona formation to prolong blood circulation time and improving in vitro tumor cell uptake and in vivo tumor accumulation, thereby providing significantly enhanced therapeutic benefits of PDT by combining with the continuously produced O2 of cascade nanozymes.

Multi-scale modeling of folic acid-functionalized TiO2 nanoparticles for active targeting of tumor cells.

Strategies based on the active targeting of tumor cells are emerging as smart and efficient nanomedical procedures. Folic acid (FA) is a vitamin and a well-established tumor targeting agent because of its strong affinity for the folate receptor (FR), which is an overexpressed protein on the cell membranes of the tumor cells. FA can be successfully anchored to several nanocarriers, including inorganic nanoparticles (NPs) based on transition metal oxides. Among them, TiO2 is extremely interesting because of its excellent photoabsorption and photocatalytic properties, which can be exploited in photodynamic therapy. However, it is not yet clear in which respects direct anchoring of FA to the NP or the use of spacers, based on polyethylene glycol (PEG) chains, are different and whether one approach is better than the other. In this work, we combine Quantum Mechanics (QM) and classical Molecular Dynamics (MD) to design and optimize the FA functionalization on bare and PEGylated TiO2 models and to study the dynamical behavior of the resulting nanoconjugates in a pure water environment and in physiological conditions. We observe that they are chemically stable, even under the effect of increasing temperature (up to 500 K). Using the results from long MD simulations (100 ns) and from free energy calculations, we determine how the density of FA molecules on the TiO2 NP and the presence of PEG spacers impact on the actual exposure of the ligands, especially by affecting the extent of FA–FA intermolecular interactions, which are detrimental for the targeting ability of FA towards the folate receptor. This analysis provides a solid and rational basis for experimentalists to define the optimal FA density and the more appropriate mode of anchoring to the carrier, according to the final purpose of the nanoconjugate.

Tumor acidic microenvironment-induced drug release of RGD peptide nanoparticles for cellular uptake and cancer therapy

Spatial accuracy is crucial in drug delivery, especially to increase the efficacy and reduce the side effects of antitumor drugs. In this study, we developed a simple and broadly applicable strategy in which a target peptide ligand was introduced to construct a pH-responsive drug-loading system to achieve targeted delivery and drug release in lesions. In addition to reaching the tumor tissue through passive targeting modalities such as the enhanced permeability and retention (EPR) effect, active targeting nanoparticles used RGD motifs coupled to nanocarriers to specifically bind certain integrins, such as ανβ3, which is expressed on the surface of tumor cells, to achieve active tumor cell targeting. Self-assembling peptides have significant advantages in their structural design. The amphiphilic peptide LKR could form a spherical and self-assembled nanoparticle, which encapsulated the fat-soluble antitumor drug doxorubicin (Dox) in neutral medium. The Dox-encapsulating peptide nanoparticles swelled and burst, rapidly releasing Dox in an acidic microenvironment. Flow cytometry and fluorescence detection showed that the self-assembled LKR nanoparticles enhanced the drug accumulation in tumor cells compared with normal mammalian cells. The Dox-encapsulating peptide nanoparticles exhibited desirable antitumor effects in vivo. In summary, the acidic microenvironment of tumors was used to induce drug release from a targeted peptide drug-loading system to enhance cellular uptake and therapeutic effects in situ, providing a promising therapeutic approach for the treatment of major diseases such as hepatoma.

High-drug-loading capacity of redox-activated biodegradable nanoplatform for active targeted delivery of chemotherapeutic drugs

Challenges associated with low-drug-loading capacity, lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy. Herein, we constructed active-targeting, redox-activated polymeric micelles (HPGssML) self-assembled aptamer-decorated, amphiphilic biodegradable poly (benzyl malolactonate-co-ε-caprolactone) copolymer with disulfide linkage and π-conjugated moieties. HPGssML with a homogenous spherical shape and nanosized diameter (∼150 nm) formed a low critical micellar concentration (10−3 mg/mL), suggesting good stability of polymeric micelles. The anticancer drug, doxorubicin (DOX), can be efficiently loaded into the core of micelles with high-drug-loading content via strong π–π interaction, which was verified by a decrease in fluorescence intensity and redshift in UV adsorption of DOX in micelles. The redox sensitivity of polymeric micelles was confirmed by size change and in vitro drug release in a reducing environment. Confocal microscopy and flow cytometry assay demonstrated that conjugating aptamers could enhance specific uptake of HPGssML by cancer cells. An in vitro cytotoxicity study showed that the half-maximal inhibitory concentration (IC50) of DOX-loaded HPGssML was two times lower than that of the control group, demonstrating improved antitumor efficacy. Therefore, the multifunctional biodegradable polymeric micelles can be exploited as a desirable drug carrier for effective cancer treatment.

Folate targeted lipid chitosan hybrid nanoparticles for enhanced anti-tumor efficacy

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells.

A novel macrophage-mediated biomimetic delivery system with NIR-triggered release for prostate cancer therapy

BackgroundMacrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO.ResultsAt the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo.ConclusionsThe BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.

Polymeric Drug Delivery System with Actively Targeted Cell Penetration and Nuclear Targeting for Cancer Therapy.

Targeted tumor cell killing using polymeric micelles with active targeting strategies has been demonstrated to be effectively therapeutic for liver cancers. To implement this strategy, enhancing the cellular uptake of the drug delivery system with targeted anticancer drugs, such as doxorubicin toward nuclear targeting, is of vital importance for increasing drug efficiency and reducing the systemic side effects of encapsulated drugs. In this study, a multifunctional polymeric drug delivery system was designed with actively targeted cell penetration and nuclear targeting for efficient cancer therapy. The nanocarriers were self-assembled from poly(ethylene glycol)-block-poly(ε-caprolactone), decorated with folic acid (FA-PECL) for active targeting via amide reaction for selective delivery of drugs to tumors. A cell penetration peptide (CPP) was decorated with doxorubicin (DOX), and the conjugate (CPP-DOX) was encapsulated in the carrier system for efficient cell penetration and nuclear targeting of drugs. An in vitro study showed an enhanced in vitro cytotoxicity and showed that the tumor volume decreased more than 5 times compared with the nontargeted system, by utilizing the drug-loaded system (FA-PECL/CPP-DOX) with active tumor cell targeting and subsequent nuclear targeting. The FA-PECL/CPP-DOX drug-loading system was well-targeted and enriched on tumor sites, resulting in significant suppression of the liver tumor growth.

Hyaluronic acid modified bubble-generating magnetic liposomes for targeted delivery of doxorubicin

Abstract The combination of liposomes and magnetic nanoparticles (MNPs) is a promising approach for cancer therapy due to its capability for magnetic field-directed targeted drug delivery at the diseased area. Contemporaneously, bubble-generating liposomes are of great interest in the field of cancer therapy, due to its triggered drug release properties and its ability to rupture cancer cells through cavitation induction. Therefore, the objective of the current study is to develop a bubble-generating magnetic liposomal (BMLs) drug delivery system with triggered drug release properties for targeted delivery of doxorubicin (DOX) in cancer therapy. Citric acid-coated iron oxide MNPs was co-entrapped with ammonium bicarbonate to produce BMLs by lipid film hydration method. BMLs were further modified by coating hyaluronic acid-polyethylene glycol (HA-PEG) on liposome surface to produce HA-PEG-BMLs for ligand-mediated active targeting of tumor cells. The resultant liposomes were found to be spherical in shape with an average particle size ranging from 100 to 170 nm. The physico-chemical properties and bubble-generating properties of liposomes were studied. In vitro drug release studies showed enhanced drug release under hyperthermia condition (43 °C) from BMLs/DOX and HA-PEG-BMLs/DOX due to more intense CO2 bubbles generation with faster decomposition rates of co-entrapped ammonium bicarbonate. In vitro cell culture studies using human glioblastoma cells (U87) were performed to evaluate the targeting efficiencies and anti-tumor efficacy of DOX-loaded liposomes. Magnetic targeted delivery of DOX was also demonstrated from LIVE/DEAD cell viability assays. The confocal microscopy and flow cytometry analysis confirmed enhanced intracellular uptake of HA-PEG-BMLs by U87 though binding of HA to overexpressed CD44 receptors on cell surface, which facilitated internalization of HA-PEG-BMLs/DOX through endocytosis and resulted in elevated DOX concentration in cancer cells. The combination of elevated intracellular DOX concentration and triggered DOX release at 43 °C led to enhanced cytotoxicity toward U87 cells in vitro. Thus, HA-PEG-BMLs will be useful for hyperthermia-induced targeted delivery of DOX for cancer therapy.

Peptide-Functionalized Hydrogel Cubes for Active Tumor Cell Targeting.

Conjugation of bioactive targeting molecules to nano- or micrometer-sized drug carriers is a pivotal strategy to improve their therapeutic efficiency. Herein, we developed pH- and redox-sensitive hydrogel particles with a surface-conjugated cancer cell targeting ligand for specific tumor-targeting and controlled release of the anticancer drug doxorubicin. The poly(methacrylic acid) (PMAA) hydrogel cubes of 700 nm and 2 μm with a hepsin-targeting (IPLVVPL) surface peptide are produced through multilayer polymer assembly on sacrificial cubical mesoporous cores. Direct peptide conjugation to the disulfide-stabilized hydrogels through a thiol-amine reaction does not compromise the structural integrity, hydrophilicity, stability in serum, or pH/redox sensitivity but does affect internalization by cancer cells. The cell uptake kinetics and the ultimate extent of internalization are controlled by the cell type and hydrogel size. The peptide modification significantly promotes the uptake of the 700 nm hydrogels by hepsin-positive MCF-7 cells due to ligand-receptor recognition but has a negligible effect on the uptake of 2 μm PMAA hydrogels. The selectivity of 700 nm IPLVVPL-PMAA hydrogel cubes to hepsin-overexpressing tumor cells is further confirmed by a 3-10-fold higher particle internalization by hepsin-positive MCF-7 and SK-OV-3 compared to that of hepsin-negative PC-3 cells. This work provides a facile method to fabricate enhanced tumor-targeting carriers of submicrometer size and improves the general understanding of particle design parameters for targeted drug delivery.

Large set data mining reveals overexpressed GPCRs in prostate and breast cancer: potential for active targeting with engineered anti-cancer nanomedicines.

Over 800 G-protein-coupled receptors (GPCRs) are encoded by the human genome and many are overexpressed in tumors. GPCRs are triggered by ligand molecules outside the cell and activate internal signal transduction pathways driving cellular responses. The receptor signals are desensitized by receptor internalization and this mechanism can be exploited for the specific delivery of ligand-linked drug molecules directly into cells. Detailed expression analysis in cancer tissue can inform the design of GPCR-ligand decorated drug carriers for active tumor cell targeting. The active targeting process utilizes ligand receptor interactions leading to binding and in most cases internalization of the ligand-attached drug carrier resulting in effective targeting of cancer cells. In this report public microarray data from the Gene Expression Omnibus (GEO) repository was used to identify overexpressed GPCRs in prostate and breast cancer tissues. The analyzed data confirmed previously known cancer receptor associations and identified novel candidates for potential active targeting. Prioritization of the identified targeting receptors is also presented based on high expression levels and frequencies in cancer samples but low expression in healthy tissue. Finally, some selected examples were used in ligand docking studies to assess the feasibility for chemical conjugation to drug nanocarriers without interference of receptor binding and activation. The presented data demonstrate a large untapped potential to improve efficacy and safety of current and future anti-cancer compounds through active targeting of GPCRs on cancer cells.

PEGylated hyaluronic acid-coated liposome for enhanced in vivo efficacy of sorafenib via active tumor cell targeting and prolonged systemic exposure

This study aimed to design an effective formulation for enhancing the tumor-targeted delivery of sorafenib. Three sorafenib-loaded liposomal formulations including uncoated liposome (SF-Lip), hyaluronic acid-coated liposome (HA-SF-Lip), and PEGylated hyaluronic acid-coated liposome (PEG-HA-SF-Lip) were developed with narrow size distribution and high encapsulation efficiency. The cellular uptake and cytotoxicity of HA-SF-Lip and PEG-HA-SF-Lip were greater than those of SF-Lip in MDA-MB-231 cells overexpressing CD44, whereas there were no significant differences in MCF-7 cells with low CD44 expression, indicating the CD44-mediated cellular uptake of coated liposomes. In comparison with sorafenib solution, PEG-HA-SF-Lip increased the systemic exposure and plasma half-life in rats by 3-fold and 2-fold, respectively. Consistently, PEG-HA-SF-Lip was the most effective for tumor growth inhibition through CD44 targeting in the MDA-MB-231 tumor xenograft mouse model. Taken together, the present study suggests that PEG-HA-SF-Lip might be effective for the tumor-targeted delivery of sorafenib with enhanced systemic exposure and longer blood circulation.

Enhanced In Vivo Tumor Detection by Active Tumor Cell Targeting Using Multiple Tumor Receptor-Binding Peptides Presented on Genetically Engineered Human Ferritin Nanoparticles.

Human ferritin heavy-chain nanoparticle (hFTH) is genetically engineered to present tumor receptor-binding peptides (affibody and/or RGD-derived cyclic peptides, named 4CRGD here) on its surface. The affibody and 4CRGD specifically and strongly binds to human epidermal growth factor receptor I (EGFR) and human integrin αvβ3, respectively, which are overexpressed on various tumor cells. Through in vitro culture of EGFR-overexpressing adenocarcinoma (MDA-MB-468) and integrin-overexpressing glioblastoma cells (U87MG), it is clarified that specific interactions between receptors on tumor cells and receptor-binding peptides on engineered hFTH is critical in active tumor cell targeting. After labeling with the near-infrared fluorescence dye (Cy5.5) and intravenouse injection into MDA-MB-468 or U87MG tumor-bearing mice, the recombinant hFTHs presenting either peptide or both of affibody and 4CRGD are successfully delivered to and retained in the tumor for a prolonged period of time. In particular, the recombinant hFTH presenting both affibody and 4CRGD notably enhances in vivo detection of U87MG tumors that express heterogeneous receptors, integrin and EGFR, compared to the other recombinant hFTHs presenting either affibody or 4CRGD only. Like affibody and 4CRGD used in this study, other multiple tumor receptor-binding peptides can be also genetically introduced to the hFTH surface for actively targeting of in vivo tumors with heterogenous receptors.

Peptide-Drug Conjugate GnRH-Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth.

The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys(6)]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R-expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (∼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation.

Temperature-Tunable Nanoparticles for Selective Biointerface

Drugs can be delivered by a temperature change-driven shrinking of the nanocarrier followed by the cargo release. This paper describes a different structural response to temperature, performed by nanoparticles of poly(N-isopropylacrylamide) and hyaluronic acid. Around 35 °C, the hydrophobicity of the vinyl polymer drives a core-shell rearrangement with the acrylamide chains confined in the core and the polysaccharide moiety forming the shell. In this arrangement, the nanoparticles enable the active targeting of tumor cells, due to the specific interaction of hyaluronic acid with the CD44 receptors. When doxorubicin-loaded nanoparticles are up-taken, the polysaccharide part degrades in the cytoplasm and the cytotoxic effect of the anticancer drug in colon adenocarcinoma cells has a 2-fold increase with respect to healthy fibroblasts. These core-shell particles have hyaluronic acid as the key factor for the specific targeting of tumor cells and drug release with poly(N-isopropylacrylamide) driving the transition.

Glucose transporter and folic acid receptor-mediated Pluronic P105 polymeric micelles loaded with doxorubicin for brain tumor treating

In this study, glucose transporter and folic acid (FA) receptor-mediated Pluronic P105 polymeric micelles loaded with DOX (GF-DOX) were prepared for enhancing the blood–brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. The pH-triggered DOX release of GF-DOX indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The transport of GF-DOX across the in vitro BBB model showed that GF-DOX exhibited higher BBB transportation ability with the transporting ratio of 21.47% in 4 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model for the combined effect of the brain targeting by transportation of glucose transporter and active tumor cell targeting by FA receptor-mediated endocytosis. Moreover, minimized weight changes and high suppression ratio of tumor growth were observed after intravenous injection of GF-DOX. In conclusion, the glucose transporter and FA dual-targeting micelles would provide a safe and effective strategy for new modalities to treat brain tumor.

Nanomedicines for active targeting: Physico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies on target cells

Paclitaxel (Tx)-loaded anti-HER2 immunonanoparticles (NPs-Tx-HER) were prepared by the covalent coupling of humanized monoclonal anti-HER2 antibodies (trastuzumab, Herceptin ®) to Tx-loaded poly ( dl-lactic acid) nanoparticles (NPs-Tx) for the active targeting of tumor cells that overexpress HER2 receptors. The physico-chemical properties of NPs-Tx-HER were compared to unloaded immunonanoparticles (NPs-HER) to assess the influence of the drug on anti-HER2 coupling to the NP surface. The immunoreactivity of sulfo-MBS activated anti-HER2 mAbs and the in vitro efficacy of NPs-Tx-HER were tested on SKOV-3 ovarian cancer cells that overexpress HER2 antigens. Tx-loaded nanoparticles (NPs-Tx) obtained by a salting-out method had a size of 171 ± 22 nm (P.I. = 0.1) and an encapsulation efficiency of about of 78 ± 10%, which corresponded to a drug loading of 7.8 ± 0.8% (w/w). NPs-Tx were then thiolated and conjugated to activated anti-HER2 mAbs to obtain immunonanoparticles of 237 ± 43 nm (P.I. = 0.2). The influence of the activation step on the immunoreactivity of the mAbs was tested on SKOV-3 cells using 125I-radiolabeled mAbs, and the activity of the anti-HER2 mAbs was minimally affected after sulfo-MBS functionalization. Approximately 270 molecules of anti-HER2 mAbs were bound per nanoparticle. NPs-Tx-HER exhibited a zeta potential of 0.2 ± 0.1 mV. The physico-chemical properties of the Tx-loaded immunonanoparticles were very similar to unloaded immunonanoparticles, suggesting that the encapsulation of the drug did not influence the coupling of the mAbs to the NPs. No drug loss was observed during the preparation process. DSC analysis showed that encapsulated Tx is in an amorphous or disordered-crystalline phase. These results suggest that Tx is entrapped in the polymeric matrix and not adsorbed to the surface of the NPs. In vitro studies on SKOV-3 ovarian cancer cells demonstrated the greater cytotoxic effect of NPs-Tx-HER compared to other Tx formulations. The results showed that at 1 ng Tx/ml, the viability of cells incubated with drug encapsulated in NP-Tx-HER was lower (77.32 ± 5.48%) than the viability of cells incubated in NPs-Tx (97.4 ± 12%), immunonanoparticles coated with Mabthera ®, as irrelevant mAb (NPs-Tx-RIT) (93.8 ± 12%) or free drug (92.3 ± 9.3%).