Self-assembled peptide/polymer hybrid nanoplatform for cancer immunostimulating therapies.

Integrating peptide epitopes in self-assembling materials is a successful strategy to obtain nanovaccines with high antigen density and improved efficacy. In this study, self-assembling peptides containing MAGE-A3/PADRE epitopes were designed to generate functional therapeutic nanovaccines. To achieve higher stability, peptide/polymer hybrid nanoparticles were formulated by controlled self-assembly of the engineered peptides. The nanoparticles showed good biocompatibility to both human red blood- and dendritic cells. Incubation of the nanoparticles with immature dendritic cells triggered immune effects that ultimately activated CD8 + cells. The antigen-specific and IgG antibody responses of healthy C57BL/6 mice vaccinated with the nanoparticles were analyzed. The in vivo results indicate a specific response to the nanovaccines, mainly mediated through a cellular pathway. This research indicates that the immunogenicity of peptide epitope vaccines can be effectively enhanced by developing self-assembled peptide-polymer hybrid nanostructures.

Matrices Activated with Messenger RNA.

Over two decades of preclinical and clinical experience have confirmed that gene therapy-activated matrices are potent tools for sustained gene modulation at the implantation area. Matrices activated with messenger RNA (mRNA) are the latest development in the area, and they promise an ideal combination of efficiency and safety. Indeed, implanted mRNA-activated matrices allow a sustained delivery of mRNA and the continuous production of therapeutic proteins in situ. In addition, they are particularly interesting to generate proteins acting on intracellular targets, as the translated protein can directly exert its therapeutic function. Still, mRNA-activated matrices are incipient technologies with a limited number of published records, and much is still to be understood before their successful implementation. Indeed, the design parameters of mRNA-activated matrices are crucial for their performance, as they affect mRNA stability, device immunogenicity, translation efficiency, and the duration of the therapy. Critical design factors include matrix composition and its mesh size, mRNA chemical modification and sequence, and the characteristics of the nanocarriers used for mRNA delivery. This review aims to provide some background relevant to these technologies and to summarize both the design space for mRNA-activated matrices and the current knowledge regarding their pharmaceutical performance. Furthermore, we will discuss potential applications of mRNA-activated matrices, mainly focusing on tissue engineering and immunomodulation.

Viral protein-based nanoparticles (part 2): Pharmaceutical applications.

Viral protein nanoparticles (ViP NPs) such as virus-like particles and virosomes are structures halfway between viruses and synthetic nanoparticles. The biological nature of ViP NPs endows them with the biocompatibility, biodegradability, and functional properties that many synthetic nanoparticles lack. At the same time, the absence of a viral genome avoids the safety concerns of viruses. Such characteristics of ViP NPs offer a myriad of opportunities for theirapplication at several points across disease development: from prophylaxis to diagnosis and treatment. ViP NPs present remarkable immunostimulant properties, and thus the vaccination field has benefited the most from these platforms capable of overcoming the limitations of both traditional and subunit vaccines. This was reflected in the marketing authorization of several VLP- and virosome-based vaccines. Besides, ViP NPs inherit the ability of viruses to deliver their cargo to target cells. Because of that, ViP NPs are promising candidates as vectors for drug and gene delivery, and for diagnostic applications. In this review, we analyze the pharmaceutical applications of ViP NPs, describing the products that are commercially available or under clinical evaluation, but also the advances that scientists are making toward the implementation of ViP NPs in other areas of major pharmaceutical interest.

Viral protein nanoparticles (Part 1): Pharmaceutical characteristics.

Viral protein nanoparticles fill the gap between viruses and synthetic nanoparticles. Combining advantageous properties of both systems, they have revolutionized pharmaceutical research. Virus-like particles are characterized by a structure identical to viruses but lacking genetic material. Another type of viral protein nanoparticles, virosomes, are similar to liposomes but include viral spike proteins. Both systems are effective and safe vaccine candidates capable of overcoming the disadvantages of both traditional and subunit vaccines. Besides, their particulate structure, biocompatibility, and biodegradability make them good candidates as vectors for drug and gene delivery, and for diagnostic applications. In this review, we analyze viral protein nanoparticles from a pharmaceutical perspective and examine current research focused on their development process, from production to administration. Advances in synthesis, modification and formulation of viral protein nanoparticles are critical so that large-scale production of viral protein nanoparticle products becomes viable and affordable, which ultimately will increase their market penetration in the future. We will discuss their expression systems, modification strategies, formulation, biopharmaceutical properties, and biocompatibility.

Delivery of transcription factors as modulators of cell differentiation.

Fundamental studies performed during the last decades have shown that cell fate is much more plastic than previously considered, and technologies for its manipulation are a keystone for many new tissue regeneration therapies. Transcription factors (TFs) are DNA-binding proteins that control gene expression, and they have critical roles in the control of cell fate and other cellular behavior. TF-based therapies have much medical potential, but their use as drugs depends on the development of suitable delivery technologies that can help them reach their action site inside of the cells. TFs can be used either as proteins or encoded in polynucleotides. When used in protein form, many TFs require to be associated to a cell-penetrating peptide or another transduction domain. As polynucleotides, they can be delivered either by viral carriers or by non-viral systems such as polyplexes and lipoplexes. TF-based therapies have extensively shown their potential to solve many tissue-engineering problems, including bone, cartilage and cardiac regeneration. Yet, their use has expanded beyond regenerative medicine to other prominent disease areas such as cancer therapy and immunomodulation. This review summarizes some of the delivery options for effective TF-based therapies and their current main applications.

Purification of Hollow Sporopollenin Microcapsules from Sunflower and Chamomile Pollen Grains.

Pollen grains are natural microcapsules comprised of the biopolymer sporopollenin. The uniformity and special tridimensional architecture of these sporopollenin structures confer them attractive properties such as high resistance and improved bioadhesion. However, natural pollen can be a source of allergens, hindering its biomedical applicability. Several methods have been developed to remove internal components and allergenic compounds, usually involving long and laborious processes, which often cannot be extended to other pollen types. In this work, we propose an abridged protocol to produce stable and pristine hollow pollen microcapsules, together with a complete physicochemical and morphological characterization of the intermediate and final products. The optimized procedure has been validated for different pollen samples, also producing sporopollenin microcapsules from Matricaria species for the first time. Pollen microcapsules obtained through this protocol presented low protein content (4.4%), preserved ornamented morphology with a nanoporous surface, and low product density (0.14 g/cm3). These features make them interesting candidates from a pharmaceutical perspective due to the versatility of this biomaterial as a drug delivery platform.

Nanoparticles based on PLGA:poloxamer blends for the delivery of proangiogenic growth factors.

New blood vessel formation is a critical requirement for treating many vascular and ischemia related diseases, as well as for many tissue engineering applications. Angiogenesis and vasculogenesis, in fact, represent crucial processes for the functional regeneration of complex tissues through tissue engineering strategies. Several growth factors (GFs) and signaling molecules involved in blood vessels formation have been identified, but their application to the clinical setting is still strongly limited by their extremely short half-life in the body. To overcome these limitations, we have developed a new injectable controlled release device based on polymeric nanoparticles for the delivery of two natural proangiogenic GFs: platelet derived growth factor (PDGF-BB) and fibroblast growth factor (FGF-2). The nanoparticle system was prepared by a modified solvent diffusion technique, encapsulating the GF both in presence and in the absence of two stabilizing agents: bovine serum albumin (BSA) and heparin sodium salt (Hp). The developed nanocarriers were characterized for morphology, size, encapsulation efficiency, release kinetics in vitro and GF activity in cell cultures. The results have indicated that the coencapsulation of stabilizing agents can preserve the GF active structure and, in addition, increase their encapsulation efficiency into nanoparticles. Through this optimization process, we were able to raise the encapsulation efficiency of FGF-2 to 63%, and that of PDGF-BB to 87%. These PLGA:poloxamer blend nanoparticles loaded with GFs were able to release PDGF-BB and FGF-2 in a sustained fashion for more than a month. This work also confirms other positive features of PLGA:poloxamer nanoparticles. Namely, they are able to maintain their stability in simulated biological medium, and they are also nontoxic to cell culture models. Incubation of nanoparticles loaded with FGF-2 or PDGF-BB with endothelial cell culture models has confirmed that GFs are released in a bioactive form. Altogether, these results underline the interest of PLGA:poloxamer nanoparticles for the controlled delivery of GFs and substantiate their potential for the treatment of ischemic diseases and for tissue engineering applications.

Extracellular matrix mechanics regulate transfection and SOX9-directed differentiation of mesenchymal stem cells.

Gene delivery within hydrogel matrices can potentially direct mesenchymal stem cells (MSCs) towards a chondrogenic fate to promote regeneration of cartilage. Here, we investigated whether the mechanical properties of the hydrogel containing the gene delivery systems could enhance transfection and chondrogenic programming of primary human bone marrow-derived MSCs. We developed collagen-I-alginate interpenetrating polymer network hydrogels with tunable stiffness and adhesion properties. The hydrogels were activated with nanocomplexed SOX9 polynucleotides to direct chondrogenic differentiation of MSCs. MSCs transfected within the hydrogels showed higher expression of chondrogenic markers compared to MSCs transfected in 2D prior to encapsulation. The nanocomplex uptake and resulting expression of transfected SOX9 were jointly enhanced by increased stiffness and cell-adhesion ligand density in the hydrogels. Further, transfection of SOX9 effectively induced MSCs chondrogenesis and reduced markers of hypertrophy compared to control matrices. These findings highlight the importance of matrix stiffness and adhesion as design parameters in gene-activated matrices for regenerative medicine. STATEMENT OF SIGNIFICANCE: Gene-activated matrices (GAMs) are biodegradable polymer networks integrating gene therapies, and they are promising technologies for supporting tissue regeneration. Despite this interest, there is still limited information on how to rationally design these systems. Here, we provide a systematic study of the effect of matrix stiffness and cell adhesion ligands on gene transfer efficiency. We show that high stiffness and the presence of cell-binding sites promote transfection efficiency and that this result is related to more efficient internalization and trafficking of the gene therapies. GAMs with optimized mechanical properties can induce cartilage formation and result in tissues with better characteristics for articular cartilage tissue engineering as compared to previously described standard methods.

mRNA-activated matrices encoding transcription factors as primers of cell differentiation in tissue engineering.

Gene-activated matrices (GAMs) encoding pivotal transcription factors (TFs) represent a powerful tool to direct stem cell specification for tissue engineering applications. However, current TF-based GAMs activated with pDNA, are challenged by their low transfection efficiency and delayed transgene expression. Here, we report a GAM technology activated with mRNAs encoding TFs SOX9 (cartilage) and MYOD (muscle). We find that these mRNA-GAMs induce a higher and faster TF expression compared to pDNA-GAMs, especially in the case of RNase resistant mRNA sequences. This potent TF expression was translated into a high synthesis of cartilage- and muscle-specific markers, and ultimately, into successful tissue specification in vitro. Additionally, we show that the expression of tissue-specific markers can be further modulated by altering the properties of the mRNA-GAM environment. These results highlight the value of this GAM technology for priming cell lineage specification, a key centerpiece for future tissue engineering devices.

Preparation and characterization of lamotrigine containing nanocapsules for nasal administration.

Nanocapsules (NCs) have become one of the most researched nanostructured drug delivery systems due to their advantageous properties and versatility. NCs can enhance the bioavailabiliy of hydrophobic drugs by impoving their solubility and permeability. Also, they can protect these active pharmaceutical agents (APIs) from the physiological environment with preventing e.g. the enzymatic degradation. NCs can be used for many administration routes: e.g. oral, dermal, nasal and ocular formulations are exisiting in liquid and solid forms. The nose is one of the most interesting alternative drug administration route, because local, systemic and direct central nervous system (CNS) delivery can be achived; this could be utilized in the therapy of CNS diseases. Therefore, the goal of this study was to design, prepare and investigate a novel, lamotrigin containing NC formulation for nasal administration. The determination of micrometric parameters (particle size, polydispersity index, surface charge), in vitro (drug loading capacity, release and permeability investigations) and in vivo characterization of the formulations were performed in the study. The results indicate that the formulation could be a promising alternative of lamotrigine (LAM) as the NCs were around 305 nm size with high encapsulation efficiency (58.44%). Moreover, the LAM showed rapid and high release from the NCs in vitro and considerable penetration to the brain tissues was observed during the in vivo study.

Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells.

Myeloid-Derived Suppressor Cells (MDSCs), immunosuppressive cells that promote tumor growth, represent an attractive target in cancer immunotherapy. However, the clinical success of this strategy is limited by the lack of efficient drug delivery vehicles targeting this cell compartment. The objective of this work was to develop a delivery carrier, multilayer polymer nanocapsules, with the capacity to co-encapsulate two types of immunomodulatory drugs, a chemokine and an RNAi sequence, aimed at reverting MDSC-mediated immunosuppression. The chemokine CCL2, intended to attract monocyte-macrophage MDSCs, was encapsulated within the L2 inverse micellar aqueous domains of the lipid core of these nanocapsules. On the other hand, two different RNAi sequences that modulate the CCAAT/enhancer-binding protein beta (C/EBPß) pathway, shC/EBPß and miR 142-3p, were successfully associated to their polymer shell. These RNAi sequences were covered by subsequent layers of polyarginine and hyaluronic acid, thereby creating multi-layered assemblies that protected them and facilitated their targeted delivery. The in vitro studies performed in primary MDSCs cultures showed the capacity of miR 142-3p-loaded nanocapsules to reduce the highly immunosuppressive monocyte-macrophage subset. Additionally, the encapsulation of CCL2 within the nanocapsules induced a potent monocyte-macrophage chemoattraction that could be used to direct the therapy to these cell subsets. Finally, in vitro and in vivo studies showed the capacity of shC/EBPß-loaded nanocapsules to downregulate C/EBPß levels in MDSCs and to reduce monocyte differentiation into tumor-associated macrophages in an MCA-203 fibrosarcoma mice model. In conclusion, the multilayer polymer nanocapsules described here are efficient vehicles for the co-delivery of proteins and RNA, and are potential candidates as nanomedicines for the modulation of MDSCs.

Self-assembled hyaluronan nanocapsules for the intracellular delivery of anticancer drugs.

Preparation of sophisticated delivery systems for nanomedicine applications generally involve multi-step procedures using organic solvents. In this study, we have developed a simple self-assembling process to prepare docetaxel-loaded hyaluronic acid (HA) nanocapsules by using a self-emulsification process without the need of organic solvents, heat or high shear forces. These nanocapsules, which comprise an oily core and a shell consisting of an assembly of surfactants and hydrophobically modified HA, have a mean size of 130 nm, a zeta potential of -20 mV, and exhibit high docetaxel encapsulation efficiency. The nanocapsules exhibited an adequate stability in plasma. Furthermore, in vitro studies performed using A549 lung cancer cells, showed effective intracellular delivery of docetaxel. On the other hand, blank nanocapsules showed very low cytotoxicity. Overall, these results highlight the potential of self-emulsifying HA nanocapsules for intracellular drug delivery.

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness.

PURPOSE: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. EXPERIMENTAL DESIGN: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo. RESULTS: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB. CONCLUSIONS: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.

The effect of hyaluronic acid on silk fibroin conformation.

The molecular conformation of silk fibroin drastically changes the physical properties of this biomaterial. Herein, we investigated the capacity of hyaluronic acid to modify the conformational transition of silk fibroin into its crystalline beta-sheet form. For this aim, matrices composed of these two polymers were prepared and studied. Instrumental analysis confirmed the presence of two intermixed phases: one of pure hyaluronic acid, and another consisting of a molecular dispersion of silk fibroin and hyaluronic acid. Studies performed with silk fibroin/hyaluronic acid matrices indicated that hyaluronic acid induces molecular transition of silk fibroin into a beta-sheet structure when incubated in water, and that it synergistically enhances beta-sheet formation together with methanol treatment. The enhancement of beta-sheet content observed for silk fibroin/hyaluronic acid matrices correlated with improved mechanical properties: blended matrices had higher compressive moduli and higher breaking strengths than pure silk fibroin matrices. These new properties, together with the capacity of silk fibroin/hyaluronic acid to form partially insoluble matrices without any treatment with organic solvents, make this blend composition an interesting material for biomedical applications.

Biomaterials to suppress cancer stem cells and disrupt their tumoral niche.

Lack of improvement in the treatment options of several types of cancer can largely be attributed to the presence of a subpopulation of cancer cells with stem cell signatures and to the tumoral niche that supports and protects these cells. This review analyses the main strategies that specifically modulate or suppress cancer stem cells (CSCs) and the tumoral niche (TN), focusing on the role of biomaterials (i.e. implants, nanomedicines, etc.) in these therapies. In the case of CSCs, we discuss differentiation therapies and the disruption of critical cellular signaling networks. For the TN, we analyze diverse strategies to modulate tumor hypervascularization and hypoxia, tumor extracellular matrix, and the inflammatory and tumor immunosuppressive environment. Due to their capacity to control drug disposition and integrate diverse functionalities, biomaterial-based therapies can provide important benefits in these strategies. We illustrate this by providing case studies where biomaterial-based therapies either show CSC suppression and TN disruption or improved delivery of major modulators of these features. Finally, we discuss the future of these technologies in the framework of these emerging therapeutic concepts.

New scaffolds encapsulating TGF-ß3/BMP-7 combinations driving strong chondrogenic differentiation.

The regeneration of articular cartilage remains an unresolved question despite the current access to a variety of tissue scaffolds activated with growth factors relevant to this application. Further advances might result from combining more than one of these factors; here, we propose a scaffold composition optimized for the dual delivery of BMP-7 and TGF-ß3, two proteins with described chondrogenic activity. First, we tested in a mesenchymal stem cell micromass culture with TGF-ß3 whether the exposure to microspheres loaded with BMP-7 would improve cartilage formation. Histology and qRT-PCR data confirmed that the sustained release of BMP-7 cooperates with TGF-ß3 towards chondrogenic differentiation. Then, we optimized a scaffold prototype for tissue culture and dual encapsulation of BMP-7 and TGF-ß3. The scaffolds were prepared from poly(lactic-co-glycolic acid), and BMP-7/TGF-ß3 were loaded as nanocomplexes with heparin and Tetronic 1107. The scaffolds showed the sustained release of both proteins over four weeks, with minimal burst effect. We finally cultured human mesenchymal stem cells on these scaffolds, in the absence of exogenous chondrogenic factor supplementation. The cells cultured on the scaffolds loaded with BMP-7 and TGF-ß3 showed clear signs of cartilage formation macroscopically and histologically. RT-PCR studies confirmed a clear upregulation of cartilage markers SOX9 and Aggrecan. In summary, scaffolds encapsulating BMP-7 and TGF-ß3 can efficiently deliver a cooperative growth factor combination that drives efficient cartilage formation in human mesenchymal stem cell cultures. These results open attractive perspectives towards in vivo translation of this technology in cartilage regeneration experiments.

Polyarginine Nanocapsules as a Potential Oral Peptide Delivery Carrier.

We have previously reported the development of novel nanocapsules made of polyarginine (PArg) specifically designed for the delivery of small anticancer drugs into cells. Our goal, in this work, has been to investigate the potential of these nanocarriers for oral delivery of peptide anticancer drugs. To reach this objective, we chose the antitumoral peptide, elisidepsin, and evaluated the characteristics of the PArg nanocapsules in terms of drug loading capacity, stability in simulated intestinal fluids, and ability to interact with the intestinal epithelium both in vitro (Caco-2 model cell line) and in vivo. Our results suggest that elisidepsin can be effectively loaded into the nanocapsules by adjusting the formulation parameters, using a solvent displacement technique. The resulting nanocapsules were stable upon incubation in simulated intestinal fluids and had the ability to reduce, in a transient manner, the transepithelial electrical resistance of the Caco-2 cell monolayer. Confocal images also revealed that PArg nanocapsules were internalized by the monolayer without evident signs of cytotoxicity. Finally, the in vivo fluorescent imaging study illustrates the retention of the nanocapsules in the gastrointestinal tract upon oral administration. Overall, the results underline the potential interest of PArg nanocapsules as carriers for the oral administration of peptide drugs.

The performance of nanocarriers for transmucosal drug delivery.

Most of the newly designed drug molecules are characterised by low solubility in aqueous medium, low permeability through biological membranes and/or an insufficient stability in the biological environment. Fundamental studies have provided proof-of-concept of the potential of particulate nanocarriers for overcoming these unsuitable properties. For example, it is known that polymeric nanosystems may enhance transmucosal transport of drugs with poor penetration capacities while preserving their biological activity. Moreover, in recent years it has become clear that through an appropriate selection of the nanosystem components it is possible to enhance its affinity for the mucosa and, hence, the residence time of the drug in contact with the absorptive epithelium. These properties, combined with a suitably tailored release profile can markedly increase the efficacy of pharmaceuticals. Overall, the properties that have been identified as critical for the performance of these delivery systems are particle size, surface charge and surface chemical composition. These properties are known to affect the physical and chemical stability of the nanoparticles in the biological environment as well as their ability to interact (unspecific bioadhesion, receptor-mediated interaction and so on) and, eventually, overcome biological barriers. The present article aims to critically review the latest advances in this area and to provide some insights into these complex issues. Thus, herein the most widely investigated transmucosal drug delivery nanosystems and their most promising applications are reported.

A new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin.

The objective of the present work was to develop a new drug nanocarrier consisting of nanoparticles made of chitosan and cyclodextrins. The rationale behind the design of this new nanosystem was to simultaneously implement the cyclodextrin drug complexation power and the inherent properties of chitosan nanoparticles, in a unique delivery system. The complexation with the cyclodextrin permits the solubilization as well as the protection for sensitive drugs, whereas the entrapment in the chitosan network is expected to facilitate their absorption. Chitosan nanoparticles including hydroxypropylcyclodextrins could be prepared by the ionic crosslinking of chitosan with sodium tripolyphosphate in the presence of cyclodextrins. Two hydrophobic drugs, triclosan and furosemide, were selected as models for complexation with the cyclodextrin and further entrapment in the chitosan nanocarrier. The resulting nanosystems were thoroughly characterized for their size and zeta potential and also for their ability to associate and deliver the complexed drugs. The results showed that the size of the nanoparticles was slightly affected by the incorporation of cyclodextrins, whereas the zeta potential did not suffer a significant modification. Moreover, the complexation of the drugs with the cyclodextrin facilitated their entrapment into the nanoparticles, increasing up to 4 and 10 times (for triclosan and furosemide, respectively) the final drug loading of the nanoparticles. These results led to the conclusion that the drug-cyclodextrin complex was efficiently retained in the nanoparticulate structure. Finally, the in vitro release profile observed for these nanoparticles was characterized by an initial fast release followed by a delayed release phase. In conclusion, this new nanosystem offers an interesting potential for the transmucosal delivery of hydrophobic compounds.

Docetaxel-loaded polyglutamic acid-PEG nanocapsules for the treatment of metastatic cancer.

The design of nanomedicines with suitable physicochemical characteristics for the lymphatic targeting of drugs is critical in order to reach the lymph nodes, where metastatic cells often accumulate. Based on the known effect of particle size and surface hydrophilicity on the capacity of nanocarriers to reach the lymph nodes, here we report the formation and characterization of 100nm polyglutamic acid-polyethylene glycol (PGA-PEG) nanocapsules together with the assessment of their potential for the treatment of cancer with lymphatic metastatic spread. To this purpose, we first studied the biodistribution of fluorescently labeled PGA-PEG nanocapsules (100nm), following, either intravenous or subcutaneous administration. The results confirmed the accumulation of nanocapsules in the lymphatic system, especially upon subcutaneous administration. Next, we evaluated the efficacy and toxicity of the docetaxel-loaded nanocapsules in an orthotopic lung cancer model that metastasizes to the lymph nodes. As expected from the rational design, DCX-loaded PGA-PEG nanocapsules exhibited a greatly enhanced antitumoral efficacy and a reduced toxicity when compared with the commercial formulation Taxotere®. Furthermore, the administration of DCX-loaded PGA-PEG nanocapsules resulted in the practical elimination of the metastatic load in the mediastinal lymph nodes, whereas the treatment with the commercial formulation had a minor effect. Overall, these findings underscore the potential of PGA-PEG nanocapsules for the delivery of anticancer drugs to both, the tumor tissue and the metastatic lymph nodes. Therefore, they represent a promising therapy for the treatment of lung metastatic cancer.