Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy

Evasion of apoptosis is a hallmark of cancer, attributed in part to overexpression of the antiapoptotic protein B-cell lymphoma 2(Bcl-2). In a variety of cancer types, including lymphoma, Bcl-2 is overexpressed. Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy. Therefore, the development of co-delivery systems for Bcl-2 targeting agents, such as small interfering RNA(siRNA), and chemotherapeut...     

Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy

Introduction: Cancer is the leading cause of death worldwide. Current cancer treatments in the clinic mainly include chemotherapy, radiotherapy and surgery, with chemotherapy being the most common.

Areas covered: Cancer treatments based on the single ‘magic-bullet’ concept are often associated with limited therapeutic efficacy, unwanted adverse effects, and drug resistance. The combination of multiple drugs is a promising strategy for effective cancer treatment due to the synergistic or additive effects. Small interfering RNA (siRNA) has the ability to knock down the expression of carcinogenic genes or drug efflux transporter genes, paving the way for cancer treatment. Treatment with both a chemotherapeutic agent and siRNA based on nanoparticle (NP)-mediated co-delivery is a promising approach for combination cancer therapy.

Expert opinion: The combination of chemotherapeutic agents and siRNAs for cancer treatment offers the potential to enhance therapeutic efficacy, decrease side effects, and overcome drug resistance. Co-delivery of chemical drug and siRNA in the same NP would be much more effective in cancer therapy than application of chemical agent or siRNA alone. With the development of material science, NPs have come to be the most widely used platform for co-delivery of chemotherapeutic drugs and siRNAs.     

Quantum rods as nanocarriers of gene therapy

Both antisense oligonucleotides (ASODN) and small interfering RNA (siRNA) have enormous potential to selectively silence specific cancer-related genes and could therefore be developed to be important therapeutic anti-cancer drugs. The use of nanotechnology may allow for significant advancement of the therapeutic potential of ASODN and siRNA, due to improved pharmacokinetics, bio-distribution and tissue specific targeted therapy. In this mini-review, we have discussed the advantages of using a nanocarrier such as a multimodal quantum rod (QR) complexed with siRNA for gene delivery. Comparisons are made between ASODN and siRNA therapeutic efficacies in the context of cancer and the enormous application potential of nanotechnology in oncotherapy is discussed. We have shown that a QR-interleukin-8 (IL-8) siRNA nanoplex can effectively silence IL-8 gene expression in the PC-3 prostate cancer cells with no significant toxicity. Thus, nanocarriers such as QRs can help translate the potent effects of ASODN/siRNA into a clinically viable anti-cancer therapy. Drug delivery for cancer therapy, with the aid of nanotechnology is one of the major translational aspects of nanomedicine, and efficient delivery of chemotherapy drugs and gene therapy drugs or their co-delivery continue to be a major focus of nanomedicine research.     

Membrane-camouflaged supramolecular nanoparticles for co-delivery of chemotherapeutic and molecular-targeted drugs with siRNA against patient-derived pancreatic carcinoma

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This “all-in-one” delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.     

Nanoparticles (NPs)-mediated lncBCMA silencing to promote eEF1A1 ubiquitination and suppress breast cancer growth and metastasis

Long non-coding RNAs (lncRNAs) play an important role in cancer metastasis. Exploring metastasis-associated lncRNAs and developing effective strategy for targeted regulation of lncRNA function in vivo are of utmost importance for the treatment of metastatic cancer, which however remains a big challenge. Herein, we identified a new functional lncRNA (denoted lncBCMA), which could stabilize the expression of eukaryotic translation elongation factor 1A1 (eEF1A1) via antagonizing its ubiquitination to promote triple-negative breast cancer (TNBC) growth and metastasis. Based on this regulatory mechanism, an endosomal pH-responsive nanoparticle (NP) platform was engineered for systemic lncBCMA siRNA (siBCMA) delivery. This NPs-mediated siBCMA delivery could effectively silence lncBCMA expression and promote eEF1A1 ubiquitination, thereby leading to a significant inhibition of TNBC tumor growth and metastasis. These findings show that lncBCMA could be used as a potential biomarker to predict the prognosis of TNBC patients and NPs-mediated lncBCMA silencing could be an effective strategy for metastatic TNBC treatment.     

Suppression of tumor growth in lung cancer xenograft model mice by poly(sorbitol-co-PEI)-mediated delivery of osteopontin siRNA

Small interfering RNA (siRNA)-mediated gene silencing represents a promising strategy for treating diseases such as cancer; however, specific gene silencing requires an effective delivery system to overcome the instability and low transfection efficiency of siRNAs. To address this issue, a polysorbitol-based transporter (PSOT) was prepared by low molecular weight branched polyethylenimine (bPEI) crosslinked with sorbitol diacrylate (SDA). Osteopontin (OPN) gene, which is highly associated with non-small cell lung cancer (NSCLC) was targeted by siRNA therapy using siRNA targeting OPN (siOPN). Characterization study confirmed that PSOT formed compact complexes with siOPN and protected siOPN against degradation by RNase. PSOT/siOPN complexes demonstrated low cytotoxicity and enhanced transfection efficiency in vitro, suggesting that this carrier may be suitable for gene silencing. In the A549 and H460 lung cancer cell lines, PSOT/siOPN complexes demonstrated significant silencing efficiency at both RNA and protein levels. To study in vivo tumor growth suppression, two lung cancer cell-xenograft mouse models were prepared and PSOT/siOPN complexes were delivered into the mice through intravenous injection. The siOPN-treated groups demonstrated significantly reduced OPN expression at both the RNA and protein levels as well as suppression of tumor volume and weight. Taken together, siOPN delivery using PSOT may present an effective and novel therapeutic system for lung cancer treatment.     

Silencing of DNA repair sensitizes pediatric brain tumor cells to γ-irradiation using gold nanoparticles

We present a nanoparticle (NP)-mediated delivery vehicle that effectively carries and protects siRNA in pediatric ependymoma (EP) and medulloblastoma (MB) cells. The delivery vehicle consists of gold NPs coated with a polymeric shell comprising polyethylene glycol (PG), chitosan and polyethyleneimine (Au-CP-PEI). NPs loaded with siRNA knocked down Ape1 expression by over 75% in both MB and EP cells. Further, this reduction in Ape1 expression is associated with an increase in DNA damage after irradiation. The results indicate that NP-associated delivery of siApe1 is a feasible approach to circumventing pediatric brain tumor resistance to radiation therapy.     

Mannose-conjugated layered double hydroxide nanocomposite for targeted siRNA delivery to enhance cancer therapy

Sheet-like layered double hydroxide nanoparticles (LDH NPs) have showed great potentials in biomedical applications such as nanocarriers for drug and gene delivery, biosensors and imaging agents. However, target delivery of drugs and genes using LDH NPs to the desired tumor sites is a major challenge in cancer therapy. The aim of this study is to develop a functional LDH-based nanocomposite for target delivery of siRNA to cancer cells. Mannose as a targeting moiety was firstly conjugated onto SiO₂-coated LDH nanocomposite. Cellular uptake data have demonstrated that siRNA is more efficiently delivered to osteosarcoma (U2OS) cells by mannose-conjugated SiO₂ coated LDH nanocomposite (Man-SiO₂@LDH) compared to unmodified LDH NP. A commercial cell death-siRNA (CD-siRNA) delivered by Man-SiO₂@LDH can kill cancer cells more effectively. These results reveal that the Man-SiO₂@LDH nanocomposite is capable of target-delivering siRNA or drugs to tumor cells for more effective cancer treatment, which provides great potentials in cancer therapy.     

Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA

A tumor targeted mesoporous silica nanoparticles (MSN)-based drug delivery system (DDS) was developed for inhalation treatment of lung cancer. The system was capable of effectively delivering inside cancer cells anticancer drugs (doxorubicin and cisplatin) combined with two types of siRNA targeted to MRP1 and BCL2 mRNA for suppression of pump and nonpump cellular resistance in non-small cell lung carcinoma, respectively. Targeting of MSN to cancer cells was achieved by the conjugation of LHRH peptide on the surface of MSN via poly(ethylene glycol) spacer. The delivered anticancer drugs and siRNA preserved their specific activity leading to the cell death induction and inhibition of targeted mRNA. Suppression of cellular resistance by siRNA effectively delivered inside cancer cells and substantially enhanced the cytotoxicity of anticancer drugs. Local delivery of MSN by inhalation led to the preferential accumulation of nanoparticles in the mouse lungs, prevented the escape of MSN into the systemic circulation, and limited their accumulation in other organs. The experimental data confirm that the developed DDS satisfies the major prerequisites for effective treatment of non-small cell lung carcinoma. Therefore, the proposed cancer-targeted MSN-based system for complex delivery of drugs and siRNA has high potential in the effective treatment of lung cancer.     

Quantum rods as nanocarriers of gene therapy

Both antisense oligonucleotides (ASODN) and small interfering RNA (siRNA) have enormous potential to selectively silence specific cancer-related genes and could therefore be developed to be important therapeutic anti-cancer drugs. The use of nanotechnology may allow for significant advancement of the therapeutic potential of ASODN and siRNA, due to improved pharmacokinetics, bio-distribution and tissue specific targeted therapy. In this mini-review, we have discussed the advantages of using a nanocarrier such as a multimodal quantum rod (QR) complexed with siRNA for gene delivery. Comparisons are made between ASODN and siRNA therapeutic efficacies in the context of cancer and the enormous application potential of nanotechnology in oncotherapy is discussed. We have shown that a QR-interleukin-8 (IL-8) siRNA nanoplex can effectively silence IL-8 gene expression in the PC-3 prostate cancer cells with no significant toxicity. Thus, nanocarriers such as QRs can help translate the potent effects of ASODN/siRNA into a clinically viable anti-cancer therapy. Drug delivery for cancer therapy, with the aid of nanotechnology is one of the major translational aspects of nanomedicine, and efficient delivery of chemotherapy drugs and gene therapy drugs or their co-delivery continue to be a major focus of nanomedicine research.     

Diammine Dicarboxylic Acid Platinum Enhances Cytotoxicity in Platinum-Resistant Ovarian Cancer Cells through Induction of Apoptosis and S-Phase Cell Arrest

Purpose  Polysaccharides such as chondroitin play a potent role in tumor growth, tissue repair and angiogenesis. These properties make chondroitin a good candidate for novel drug delivery systems. Diammine dicarboxylic acid platinum (DDAP), a novel polymeric platinum compound, was developed by conjugating the platinum analogue to aspartate–chondroitin for drug delivery to tumor cells. DDAP improves platinum solubility which may reduce systemic toxicity and be more efficacious than cisplatin in killing tumor cells. Methods  We tested and compared the cytotoxic effects of DDAP and CDDP on the platinum-sensitive 2008 and A2780 ovarian cancer cell lines and their platinum-resistant sublines 2008.C13 and A2780cis; we also investigated DDAP’s mechanism of action. Results  In the platinum-sensitive cell lines, the cytotoxic effects of DDAP and CDDP were comparable. However, in the platinum-resistant sublines, significantly greater cell-growth inhibition was induced by DDAP than by CDDP, especially at lower doses. DDAP also induced more apoptosis than CDDP did in the 2008.C13 subline, which was partially mediated by the caspase 3-dependent pathway. In addition, lower (but not higher) doses of DDAP arrested 90% of S-phase 2008.C13 cells, which might be associated with up-regulation of p21 and maintenance of low cyclin A expression. Furthermore, greater cellular uptake of DDAP was seen in platinum-resistant than in platinum-sensitive ovarian cancer cells. Conclusions  Low-dose DDAP enhances drug delivery to platinum-resistant ovarian cancer cells and substantially inhibits their growth by inducting apoptosis and arresting cells in the S-phase, suggesting that DDAP may overcome platinum resistance in ovarian cancer.     

Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells

Selective gene inhibition by antisense oligodeoxynucleotide (AS-ODN) or by small interference RNA (siRNA) therapeutics promises the treatment of diseases that cannot be cured by conventional drugs. However, antisense therapy is hindered due to poor stability in physiological fluids and limited intracellular uptake. To address these problems, a ligand targeted and sterically stabilized nanoparticle formulation has been developed in our lab. Human lung cancer cells often overexpress the sigma receptor and, thus, can be targeted with a specific ligand such as anisamide. AS-ODN or siRNA against human survivin was mixed with a carrier DNA, calf thymus DNA, before complexing with protamine, a highly positively charged peptide. The resulting particles were coated with cationic liposomes consisting of DOTAP and cholesterol (1:1, molar ratio) to obtain LPD (liposome-polycation-DNA) nanoparticles. Ligand targeting and steric stabilization were then introduced by incubating preformed LPD nanoparticles with DSPE-PEG-anisamide, a PEGylated ligand lipid developed earlier in our lab, by the postinsertion method. Nontargeted nanoparticles coated with DSPE-PEG were also prepared as a control. Antisense activities of nanoparticles were determined by survivin mRNA down-regulation, survivin protein down-regulation, ability to trigger apoptosis in tumor cells, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to anticancer drugs. We found that tumor cell delivery and antisense activity of PEGylated nanoparticles were sequence dependent and rely on the presence of anisamide ligand. The uptake of oligonucleotide in targeted, PEGylated nanoparticles could be competed by excess free ligand. Our results suggest that the ligand targeted and sterically stabilized nanoparticles can provide a selective delivery of AS-ODN and siRNA into lung cancer cells for therapy.     

Co-delivery of curcumin and STAT3 siRNA using deformable cationic liposomes to treat skin cancer

Skin cancer is one of the most widely prevalent cancer types with over expression of multiple oncogenic signaling molecules including STAT3. Curcumin is a natural compound with effective anti-cancer properties. The objective of this work was to investigate the liposomal co-delivery of curcumin and STAT3 siRNA by non-invasive topical iontophoretic application to treat skin cancer. Curcumin was encapsulated in cationic liposomes and then complexed with STAT3 siRNA. The liposomal nanocomplex was characterized for particle size, zeta-potential, drug release and stability. Human epidermoid (A431) cancer cells were used to study the cell uptake, growth inhibition and apoptosis induction of curcumin-loaded liposome–siRNA complex. Topical iontophoresis was applied to study the skin penetration of nanocomplex in excised porcine skin model. Results showed that curcumin-loaded liposome–siRNA complex was rapidly taken up by cells preferentially through clathrin-mediated endocytosis pathway. The co-delivery of curcumin and STAT3 siRNA using liposomes resulted in significantly (p?<?.05) greater cancer cell growth inhibition and apoptosis events compared with neat curcumin and free STAT3 siRNA treatment. Furthermore, topical iontophoresis application enhanced skin penetration of nanocomplex to penetrate viable epidermis. In conclusion, cationic liposomal system can be developed for non-invasive iontophoretic co-delivery of curcumin and siRNA to treat skin cancer.     

VCAM-1 specific PEGylated SAINT-based lipoplexes deliver siRNA to activated endothelium in vivo but do not attenuate target gene expression

In recent years much research in RNA nanotechnology has been directed to develop an efficient and clinically suitable delivery system for short interfering RNA (siRNA). The current study describes the in vivo siRNA delivery using PEGylated antibody-targeted SAINT-based-lipoplexes (referred to as antibody-SAINTPEGarg/PEG2%), which showed superior siRNA delivery capacity and effective down-regulation of VE-cadherin gene expression in vitro in inflammation-activated primary endothelial cells of different vascular origins. PEGylation of antibody-SAINTPEGarg resulted in more desirable pharmacokinetic behavior than that of non-PEGylated antibody-SAINTPEGarg. To create specificity for inflammation-activated endothelial cells, antibodies against vascular cell adhesion molecule-1 (VCAM-1) were employed. In TNFα-challenged mice, these intravenously administered anti-VCAM-1-SAINTPEGarg/PEG2% homed to VCAM-1 protein expressing vasculature. Confocal laser scanning microscopy revealed that anti-VCAM-1-SAINTPEGarg/PEG2% co-localized with endothelial cells in lung postcapillary venules. Furthermore, they did not exert any liver and kidney toxicity. Yet, lack of in vivo gene silencing as assessed in whole lung and in laser microdissected lung microvascular segments indicates that in vivo internalization and/or intracellular trafficking of the delivery system and its cargo in the target cells are not sufficient, and needs further attention, emphasizing the essence of evaluating siRNA delivery systems in an appropriate in vivo animal model at an early stage in their development.     

Co-delivery of gambogic acid and TRAIL plasmid by hyaluronic acid grafted PEI-PLGA nanoparticles for the treatment of triple negative breast cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based combination therapy and gene therapy are new strategies to potentially overcome the limitations of TRAIL, however, the lack of efficient and low toxic vectors remains the major obstacle. In this study, we developed a hyaluronic acid (HA)-decorated polyethylenimine-poly(d,l-lactide-co-glycolide) (PEI-PLGA) nanoparticle (NP) system for targeted co-delivery of TRAIL plasmid (pTRAIL) and gambogic acid (GA) in triple-negative breast cancer (TNBC) therapy. GA was encapsulated into the core of the PEI-PLGA NPs while pTRAIL was adsorbed onto the positive NP surface via charge adsorption. The coating of HA on PEI-PLGA NPs functions as a targeting ligand by binding to CD44 receptor of TNBC cells and a shell to neutralize the excess positive charge of inner NPs. The resultant pTRAIL and GA co-loaded HA-coated PEI-PLGA NPs exhibited spherical shape (121.5?nm) and could promote the internalization of loaded cargoes into TNBC cells through the CD44-dependent endocytic pathway. The dual drug-loaded NPs significantly augmented apoptotic cell death in vitro and inhibited TNBC tumor growth in vivo. This multifunctional NP system efficiently co-delivered GA and pTRAIL, thus representing a promising strategy to treat TNBC and bringing forth a platform strategy for co-delivery of therapeutic DNA and chemotherapeutic agents in combinatorial TNBC therapy.     

Delivery of small interfering RNAs by nanovesicles for cancer therapy

Small interfering ribonucleic acids (siRNAs) are originally recognized as an intermediate of the RNA interference (RNAi) pathway. They can inhibit or silence various cellular pathways by knocking down specific messenger RNA molecules. In cancer cells, siRNAs can suppress the expression of several multidrug-resistant genes, leading to the increased deposition of chemotherapeutic drugs at the tumor site. siRNA therapy can be used to selectively increase apoptosis of cancer cells or activate an immune response to the cancer. However, delivering siRNAs to the targeted location is the main limitation in achieving safe and effective delivery of siRNAs. This review highlights some representative examples of nonviral delivery systems, especially nanovesicles such as exosomes, liposomes, and niosomes. Nanovesicles can improve the delivery of siRNAs by increasing their intracellular delivery, and they have demonstrated excellent potential for cancer therapy. This review focuses on recent discoveries of siRNA targets for cancer therapy and the use of siRNAs to successfully silence these targets. In addition, this review summarizes the recent progress in designing nanovesicles (liposomes or niosomes) for siRNA delivery to cancer cells and the effects of a combination of anticancer drugs and siRNA therapy in cancer therapy.     

Utilizing RNA nanotechnology to construct negatively charged and ultrasound-responsive nanodroplets for targeted delivery of siRNA

Ultrasound nanodroplets (NDs) have been reported as a promising nanocarrier for siRNA delivery depending on its unique strengths of sonoporation. Presently, common means for NDs-mediated siRNA delivery is through electrostatic interaction, but challenges like cationic toxicity still exist. In this study, we demonstrated a novel strategy to construct negatively charged and ultrasound (US)-responsive O-carboxymethyl chitosan (O-CMS) NDs as a siRNA targeted delivery system through three-way junction of bacteriophage phi29 DNA packaging motor (3WJ-pRNA) nanotechnology. 39nt A10-3.2 aptamer targeting prostate specific membrane antigen (PSMA) and 21nt siRNA against cationic amino acid transporter 1 (siCAT-1) were annealed to 3WJ-pRNA scaffold via complementation with an extended sequence. The cholesterol molecule attached to one branch facilitates the 3WJ-pRNA nanoparticles anchoring onto NDs. The desired O-CMS NDs with siRNA-loading and RNA-aptamer modification (A10-3.2/siCAT-1/3WJ-NDs) were successfully prepared, which were with spherical shapes, core–shell structures and uniform in sizes (198 nm with PDI 0.3). As a main proportion of shell, O-CMC showed a certain anti-tumor effects. In vitro studies demonstrated that A10-3.2/siCAT-1/3WJ-NDs exhibited good contrast-enhanced US imaging, buffering capacity and high bio-safety, were able to deliver siCAT-1 to PSMA-overexpressed prostate cancer cells under US irradiation, thus silence the CAT-1 expression, and consequently suppressing 22RV1 cell proliferation and migration. Taken overall, our findings provide a promising strategy to develop negatively charged and US-responsive NDs for tumor-targeted siRNA delivery.     

Chitosan (CMD)-mediated co-delivery of SN38 and Snail-specific siRNA as a useful anticancer approach against prostate cancer

Background

Prostate cancer is known as the most common malignancy in men. Chitosan has generated great interest as a useful biopolymer for the encapsulation of small interfering RNA (siRNA). Due to cationic nature, chitosan is able to efficiently encapsulate siRNA molecules and form nanoparticles. Furthermore, the biocompatible and biodegradable attributes of chitosan have paved the way for its potential application in the in vivo delivery of therapeutic siRNAs. In this study, we aimed to design chitosan/CMD nanoparticles for the efficient encapsulation of the anti-cancer drugs SN38 and Snail-specific siRNA.

Small interfering RNA therapy in cancer: mechanism,potential targets,and clinical applications

Background: Small interfering RNA (siRNA) has become a powerful tool in knocking down or silencing gene expression in most cells. siRNA-based therapy has shown great promise for many diseases such as cancer. Major targets for siRNA therapy include oncogenes and genes that are involved in angiogenesis, metastasis, survival, antiapoptosis and resistance to chemotherapy. Objectives: This review briefly summarizes current advances in siRNA therapy and clinical applications in cancers, especially in pancreatic cancer. Methods: This review article covers several aspects of siRNA therapy in cancer, which include the types of siRNA, the delivery systems for siRNA, and the major targets for siRNA therapy. Specific attention is given to siRNA in pancreatic cancer, which is our main research focus. Results/conclusion: siRNA can be introduced into the cells by using either chemically synthesized siRNA oligonucleotides (oligos), or vector-based siRNA (shRNA), which allows long lasting and more stable gene silencing. Nanoparticles and liposomes are commonly used carriers, delivering the siRNA with better transfection efficiency and protecting it from degradation. In combination with standard chemotherapy, siRNA therapy can also reduce the chemoresistance of certain cancers, demonstrating the potential of siRNA therapy for treating many malignant diseases. This review will provide valuable information for clinicians and researchers who want to recognize the newest endeavors within this field and identify possible lines of investigation in cancer.     

Enhancement of cancer therapy efficacy by trastuzumab-conjugated and pH-sensitive nanocapsules with the simultaneous encapsulation of hydrophilic and hydrophobic compounds

Trastuzumab-conjugated pH-sensitive double emulsion nanocapsules (DENCs) stabilized by a single-component Poly (vinyl alcohol) (PVA) with magnetic nanoparticles can be fabricated through a two-step double emulsion process; these nanocapsules can be used to encapsulate hydrophilic doxorubicin (Dox) and hydrophobic paclitaxel (PTX) simultaneously. When PMA_SH was attached to the shell of the DENCs, enhanced dual drug release of PTX/Dox was detected, specifically in intracellular acidic pH environments. The targeting ability of these Trastuzumab-conjugated DENCs was demonstrated with confocal images, which revealed a significantly elevated cellular uptake in HER-2 overexpressing SkBr3 cells. More importantly, an intravenous injection of this co-delivery system followed by magnetic targeting (MT) chemotherapy suppressed cancer growth in vivo more efficiently than the delivery of either PTX or Dox alone. The integration of the functionalities makes this combination therapy system a powerfully new tool for in vitro/in vivo cancer therapy, especially for in HER-2 positive cancers.From the Clinical EditorTrastuzumab-conjugated pH-sensitive nanocapsules were used in this study for simultaneous targeted delivery of hydrophobic (PTX) and hydrophilic (Dox) anti-cancer agents to HER-2 positive cancer cells. Additional use of magnetic targeting demonstrated superior efficacy of this delivery system compared to PTX or Dox alone.