Tailored Viral-like Particles as Drivers of Medical Breakthroughs.

Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to conventional nanoparticles due to their safety, biocompatibility, immunogenicity, structural stability, scalability, and versatility. Furthermore, VLPs can be surface-functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. This review aims to address the different types of surface functionalization of VLPs, highlighting the more recent cutting-edge technologies that have been explored for the design of tailored VLPs, their importance, and their consequent applicability in the medical field.

The HIV-1 Matrix Protein p17 Does Cross the Blood-Brain Barrier.

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation in HIV-1-infected (HIV+) patients. Furthermore, detection of the HIV-1 matrix protein p17 (p17) in the central nervous system (CNS) and its ability to form toxic assemblies in the brain have been recently confirmed. Here, we show for the first time, using both an in vitro blood-brain barrier (BBB) model and in vivo biodistribution studies in healthy mice, that p17 can cross the BBB. There is rapid brain uptake with 0.35% ± 0.19% of injected activity per gram of tissue (IA/g) 2 min after administration, followed by brain accumulation with 0.28% ± 0.09% IA/g after 1 h. The interaction of p17 with chemokine receptor 2 (CXCR2) at the surface of brain endothelial cells triggers transcytosis. The present study supports the hypothesis of a direct role of free p17 in neuronal dysfunction in HAND by demonstrating its intrinsic ability to reach the CNS. IMPORTANCE The percentage of patients affected by HIV-1-associated neurocognitive disorder (HAND) ranges from 30% to 50% of HIV-infected (HIV+) patients. The mechanisms leading to HAND development need to be elucidated, but the roles of secreted viral proteins, chemokines, and proinflammatory molecules appear to be clear. In particular, the blood-brain barrier (BBB) represents a route for entry into the central nervous system (CNS) and thus plays an important role in HAND. Several findings suggest a key role for the HIV-1 matrix protein p17 (p17) as a microenvironmental factor capable of inducing neurocognitive disorders. Here, we show the ability of the p17 to cross the BBB and to reach the CNS, thus playing a crucial role in neuronal dysfunction in HAND.

Bioconjugate Supramolecular Pd2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and In Vivo.

The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd2L4]4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage (CPepH3) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro. Biodistribution studies of the radiolabeled cage [[99mTcO4]- ⊂ CPepH3] in the CD1 mice model demonstrate its brain penetration properties in vivo. Further DFT studies were conducted to model the structure of the [[99mTcO4]- ⊂ cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO4]- anion, the "cold" analogue of [99mTcO4]-, by 1H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.

Integrated in Silico and Experimental Approach towards the Design of a Novel Recombinant Protein Containing an Anti-HER2 scFv.

Biological therapies, such as recombinant proteins, are nowadays amongst the most promising approaches towards precision medicine. One of the most innovative methodologies currently available aimed at improving the production yield of recombinant proteins with minimization of costs relies on the combination of in silico studies to predict and deepen the understanding of the modified proteins with an experimental approach. The work described herein aims at the design and production of a biomimetic vector containing the single-chain variable domain fragment (scFv) of an anti-HER2 antibody fragment as a targeting motif fused with HIV gp41. Molecular modeling and docking studies were performed to develop the recombinant protein sequence. Subsequently, the DNA plasmid was produced and HEK-293T cells were transfected to evaluate the designed vector. The obtained results demonstrated that the plasmid construction is robust and can be expressed in the selected cell line. The multidisciplinary integrated in silico and experimental strategy adopted for the construction of a recombinant protein which can be used in HER2+-targeted therapy paves the way towards the production of other therapeutic proteins in a more cost-effective way.

Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells.

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

Ultrasonication Improves Solid Phase Synthesis of Peptides Specific for Fibroblast Growth Factor Receptor and for the Protein-Protein Interface RANK-TRAF6.

Considering our interest in the use of peptides as potential target-specific drugs or as delivery vectors of metallodrugs for various biomedical applications, it is crucial to explore improved synthetic methodologies to accomplish the highest peptide crude purity in the shortest time possible. Therefore, we compared "classical" fluorenylmethoxycarbonyl (Fmoc)-solid phase peptide synthesis (SPPS) with ultrasound(US)-assisted SPPS based on the preparation of three peptides, namely the fibroblast growth factor receptor 3(FGFR3)-specific peptide Pep1 (VSPPLTLGQLLS-NH2) and the novel peptides Pep2 (RQMATADEA-NH2) and Pep3 (AAVALLPAVLLALLAPRQMATADEA-NH2), which are being developed aimed at interfering with the intracellular protein-protein interaction(PPI) RANK-TRAF6. Our results demonstrated that US-assisted SPPS led to a 14-fold (Pep1) and 4-fold time reduction (Pep2) in peptide assembly compared to the "classical" method. Interestingly, US-assisted SPPS yielded Pep1 in higher purity (82%) than the "classical" SPPS (73%). The significant time reduction combined with high crude peptide purity attained prompted use to apply US-assisted SPPS to the large peptide Pep3, which displays a high number of hydrophobic amino acids and homooligo-sequences. Remarkably, the synthesis of this 25-mer peptide was attained during a "working day" (347 min) in moderate purity (approx. 49%). In conclusion, we have reinforced the importance of using US-SPPS towards facilitating the production of peptides in shorter time with increased efficacy in moderate to high crude purity. This is of special importance for long peptides such as the case of Pep3.

Improved Fmoc-solid-phase peptide synthesis of an extracellular loop of CFTR for antibody selection by the phage display technology.

Cystic fibrosis (CF), a life-shortening genetic disease, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that codes for the CFTR protein, the major chloride channel expressed at the apical membrane of epithelial cells. The development of an imaging probe capable of non-invasively detect CFTR at the cell surface could be of great advantage for the management of CF. With that purpose, we synthesized the first extracellular loop of CFTR protein (ECL1) through fluorenylmethyloxycarbonyl (Fmoc)-based microwave-assisted solid-phase peptide synthesis (SPPS), according to a reported methodology. However, aspartimide formation, a well-characterized side reaction in Fmoc-SPPS, prompted us to adopt a different side-chain protection strategy for aspartic acid residues present in ECL1 sequence. The peptide was subsequently modified via PEGylation and biotinylation, and cyclized through disulfide bridge formation, mimicking the native loop conformation in CFTR protein. Herein, we report improvements in the synthesis of the first extracellular loop of CFTR, including peptide modifications that can be used to improve antigen presentation in phage display for selection of novel antibodies against plasma membrane CFTR.

NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor.

Linear and cyclic analogues of the α-melanocyte stimulating hormone (α-MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of α-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for α-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric α-MSH analogues, c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys]-Lys-NH2 (CycN-K6) and c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys-Lys]-NH2 (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by ¹H and 13C NMR. These results were compared to those of the previously reported analogue c[S-NO2-C6H3-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH2 (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 ± 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 ± 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC50 = 1770 ± 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle's side chains are favorably positioned for receptor interaction.

A Machine Learning Approach for Hot-Spot Detection at Protein-Protein Interfaces.

Understanding protein-protein interactions is a key challenge in biochemistry. In this work, we describe a more accurate methodology to predict Hot-Spots (HS) in protein-protein interfaces from their native complex structure compared to previous published Machine Learning (ML) techniques. Our model is trained on a large number of complexes and on a significantly larger number of different structural- and evolutionary sequence-based features. In particular, we added interface size, type of interaction between residues at the interface of the complex, number of different types of residues at the interface and the Position-Specific Scoring Matrix (PSSM), for a total of 79 features. We used twenty-seven algorithms from a simple linear-based function to support-vector machine models with different cost functions. The best model was achieved by the use of the conditional inference random forest (c-forest) algorithm with a dataset pre-processed by the normalization of features and with up-sampling of the minor class. The method has an overall accuracy of 0.80, an F1-score of 0.73, a sensitivity of 0.76 and a specificity of 0.82 for the independent test set.

Radiolabeled mannosylated dextran derivatives bearing an NIR-fluorophore for sentinel lymph node imaging.

Current methods for sentinel lymph node (SLN) mapping involve the use of radioactivity detection with technetium-99m sulfur colloid and/or visually guided identification using a blue dye. To overcome the kinetic variations of two individual imaging agents through the lymphatic system, we report herein on two multifunctional macromolecules, 5a and 6a, that contain a radionuclide ((99m)Tc or (68)Ga) and a near-infrared (NIR) reporter for pre- and/or intraoperative SLN mapping by nuclear and NIR optical imaging techniques. Both bimodal probes are dextran-based polymers (10 kDa) functionalized with pyrazole-diamine (Pz) or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating units for labeling with fac-[(99m)Tc(CO)3](+) or (68)Ga(III), respectively, mannose units for receptor targeting, and NIR fluorophore units for optical imaging. The probes allowed a clear visualization of the popliteal node by single-photon emission computed tomography (SPECT/CT) or positron emission tomography (PET/CT), as well as real-time optically guided excision. Biodistribution studies confirmed that both macromolecules present a significant accumulation in the popliteal node (5a: 3.87 ± 0.63% IA/organ; 6a: 1.04 ± 0.26% IA/organ), with minimal spread to other organs. The multifunctional nanoplatforms display a popliteal extraction efficiency >90%, highlighting their potential to be further explored as dual imaging agents.

A 99mTc(CO)3 -labeled benzylguanidine with persistent heart uptake.

We describe the synthesis and biological evaluation of the cationic (99m)Tc-tricarbonyl complex fac-[(99m)Tc(CO)3 (κ(3) -L1)](+) (Tc1) anchored by a pyrazole-diamine-methylbenzylguanidine-based ligand (L1), as potentially useful for myocardial imaging. The rhenium complex fac-[Re(CO)3 (κ(3)-L1)](+) (Re1) was prepared and characterized as a 'cold' surrogate of the radioactive complex. Cell uptake studies in a neuroblastoma cell line suggest that Tc1 uptake mechanism is related to the norepinephrine transporter (NET). Tissue distribution studies in CD1 mice showed that Tc1 presents high initial heart uptake and a slow washout from the heart (7.8 ± 1.3% injected dose per gram (ID/g), 30-min post-injection (p.i.); 6.3 ± 1.3% ID/g, 60-min p.i.), with heart to blood ratios of 11.8 and 9.0 at 30- and 60-min p.i., respectively. The uptake mechanism of Tc1 appears to be similar to that of metaiodobenzylguanidine (MIBG), as it can be reduced by coinjection with nonradioactive MIBG. The biodistribution profile of Tc2, where the benzylguanidine pharmacophore is absent, corroborates the fact that Tc1 does not accumulate in the heart by a simple diffusion mechanism but rather by a NET-mediated mechanism. The results confirm those obtained in the cell assays. Despite the persistent heart uptake found for Tc1, the high hepatic and renal uptake remains to be improved.

Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation.

Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with proven ability to traverse lipid membranes, will likewise behave as a BBBpS. The relationship between CPPs/BBBpS remains elusive and, to the best of our knowledge, has not hitherto been subject to thorough experimental scrutiny. In this work, we have identified/quantified the main physicochemical properties of BBBpS and then searched for CPPs with these properties, hence potential BBBpS. The specific features found for BBBpS are: (i) small size, (ii) none or few aromatic residues, (iii) hydrophobic, and (iv) slight cationic nature. Then, we selected the 10 scoring best in an ordinary least squares analysis, and tested them in vitro and in vivo. Overall, we identified the molecular determinants for brain targeting by peptides, devised a methodology that can be used to assist in the design of peptides with potential brain penetration from amino acid residue sequences, and found four new BBBpS within the CPP library.

Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of commonly targeted receptors. Unspecific chemotherapy is currently the main therapeutic option, with poor results. Another major challenge is the frequent appearance of brain metastasis (BM) associated with a significant decrease in patient overall survival. The treatment of BM is even more challenging due to the presence of the blood-brain barrier (BBB). Here, we present a dual-acting peptide (PepH3-vCPP2319) designed to tackle TNBC/BM, in which a TNBC-specific anticancer peptide (ACP) motif (vCPP2319) is joined to a BBB peptide shuttle (BBBpS) motif (PepH3). PepH3-vCPP2319 demonstrated selectivity and efficiency in eliminating TNBC both in monolayers (IC50≈5.0 µM) and in spheroids (IC50≈25.0 µM), with no stringent toxicity toward noncancerous cell lines and red blood cells (RBCs). PepH3-vCPP2319 was also able to cross the BBB in vitro and penetrate the brain in vivo, and was stable in serum with a half-life above 120 min. Tumor cell-peptide interaction is fast, with quick peptide internalization via clathrin-mediated endocytosis without membrane disruption. Upon internalization, the peptide is detected in the nucleus and the cytoplasm, indicating a multi-targeted mechanism of action that ultimately induces irreversible cell damage and apoptosis. In conclusion, we have designed a dual-acting peptide capable of brain penetration and TNBC cell elimination, thus expanding the drug arsenal to fight this BC subtype and its BM.

Exploiting click-chemistry: backbone post-functionalisation of homoleptic gold(I) 1,2,3-triazole-5-ylidene complexes.

The synthesis of a homoleptic azide-functionalised Au(I) bis-1,2,3-triazole-5-ylidene complex is reported, starting from a backbone-modified 1,2,3-triazolium salt ligand precursor. The incorporated azide handle allows for a straightforward modification of the complex according to click-chemistry protocols without impacting the steric shielding around the metal center, demonstrating the superiority of the presented triazole ligand framework over imidazole based systems. Employing the SPAAC and the CuAAC reactions, post-modification of the complex is facilitated with two model substrates, while retaining very high antiproliferative activity (nanomolar range IC50 values) in A2780 and MCF-7 human cancer cells.

Panobinostat-loaded folate targeted liposomes as a promising drug delivery system for treatment of canine B-cell lymphoma.

Introduction: Cancer is a major public health problem with over 19 million cases reported in 2020. Similarly to humans, dogs are also largely affected by cancer, with non-Hodgkin's lymphoma (NHL) among the most common cancers in both species. Comparative medicine has the potential to accelerate the development of new therapeutic options in oncology by leveraging commonalities between diseases affecting both humans and animals. Within this context, in the present study, we investigated the potential of panobinostat (Pan)-loaded folate-targeted PEGylated liposomes (FA-PEG-Pan-Lip) for the treatment of canine B-cell lymphoma, while contributing to new perspectives in comparative oncology. Methods and results: Two formulations were developed, namely: PEG-Pan-Lip and FA-PEG-Pan-Lip. Firstly, folate receptor expression in the CLBL-1 canine B-cell lymphoma cell line was assessed. After confirming receptor expression, both Pan-loaded formulations (PEG-Pan-Lip, FA-PEG-Pan-Lip) demonstrated dose-dependent inhibitory effects on CLBL-1 cell proliferation. The FA-PEG-Pan-Lip formulation (IC50 = 10.9 ± 0.03 nM) showed higher cytotoxicity than the non-targeted PEG-Pan-Lip formulation (IC50 = 12.9 ± 0.03 nM) and the free panobinostat (Pan) compound (IC50 = 18.32±0.03 nM). Moreover, mechanistically, both Pan-containing formulations induced acetylation of H3 histone and apoptosis. Flow cytometry and immunofluorescence analysis of intracellular uptake of rhodamine-labeled liposome formulations in CLBL-1 cells confirmed cellular internalization of PEG-Lip and FA-PEG-Lip formulations and higher uptake profile for the latter. Biodistribution studies of both radiolabeled formulations in CD1 and SCID mice revealed a rapid clearance from the major organs and a 1.6-fold enhancement of tumor uptake at 24 h for 111In-FA-PEG-Pan-Lip (2.2 ± 0.1 %ID/g of tumor) compared to 111In-PEG-Pan-Lip formulation (1.2±0.2 %ID/g of tumor). Discussion: In summary, our results provide new data validating Pan-loaded folate liposomes as a promising targeted drug delivery system for the treatment of canine B-cell lymphoma and open innovative perspectives for comparative oncology.

Rabbit derived VL single-domains as promising scaffolds to generate antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs. Most rabbit light chains have an extra disulfide bridge, that links the variable and constant domains, between Cys80 and Cys171, which is not found in the human or mouse. Thus, to develop a new generation of ADCs, we explored the potential of rabbit-derived VL-single-domain antibody scaffolds (sdAbs) to selectively conjugate a payload to Cys80. Hence, a rabbit sdAb library directed towards canine non-Hodgkin lymphoma (cNHL) was subjected to in vitro and in vivo phage display. This allowed the identification of several highly specific VL-sdAbs, including C5, which specifically target cNHL cells in vitro and present promising in vivo tumor uptake. C5 was selected for SN-38 site-selective payload conjugation through its exposed free Cys80 to generate a stable and homogenous C5-DAB-SN-38. C5-DAB-SN-38 exhibited potent cytotoxicity activity against cNHL cells while inhibiting DNA-TopoI activity. Overall, our strategy validates a platform to develop a novel class of ADCs that combines the benefits of rabbit VL-sdAb scaffolds and the canine lymphoma model as a powerful framework for clinically translation of novel therapeutics for cancer.

Evaluation of novel 99mTc(I)-labeled homobivalent α-melanocyte-stimulating hormone analogs for melanocortin-1 receptor targeting.

Aiming to apply the multivalency concept to melanoma imaging, we have assessed the in vivo melanocortin type 1 receptor (MC1R)-targeting properties of (99m)Tc(I)-labeled homobivalent peptide conjugates which contain copies of the α-melanocyte-stimulating hormone (α-MSH) analog [Ac-Nle(4), Asp(5), D-Phe(7), Lys(11)]α-MSH4-11 separated by linkers of different length (L(2) nine atoms and L(3) 14 atoms). The MC1R-binding affinity of L(2) and L(3) is significantly higher than that of the monovalent conjugate L(1). Metallation of these conjugates yielded the complexes fac-[M(CO)(3)(k(3)-L)](+) (M is (99m)Tc/Re; 1/1a, L is L(1); 2/2a, L is L(2); 3/3a, L is L(3)), with IC(50) values in the subnanomolar and nanomolar range. The MC1R-mediated internalization of 2 and 3 is higher than that of 1 in B16F1 melanoma cells. Biodistribution studies in melanoma-bearing mice have shown low nonspecific accumulation with a tumor uptake that correlates with IC(50) values. However, no correlation between tumor uptake and valency was found. Nevertheless, 2 displayed the highest tumor retention, and the best tumor to nontarget organ ratios.

Construction of HER2-Specific HIV-1-Based VLPs.

Virus-like particles (VLPs) are nanoplatforms comprised of one or more viral proteins with the capacity to self-assemble without viral genetic material. VLPs arise as promising nanoparticles (NPs) that can be exploited as vaccines, as drug delivery vehicles or as carriers of imaging agents. Engineered antibody constructs, namely single-chain variable fragments (scFv), have been explored as relevant molecules to direct NPs to their target. A vector containing the scFv of an antibody, aimed at the human epidermal growth factor receptor 2 (HER2) and fused to the human immunodeficiency virus (HIV) protein gp41, was previously constructed. The work herein describes the early results concerning the production and the characterization of HIV-1-based VLPs expressing this protein, which could function as potential non-toxic tools for transporting drugs and/or imaging agents.

How promising are HIV-1-based virus-like particles for medical applications.

New approaches aimed at identifying patient-specific drug targets and addressing unmet clinical needs in the framework of precision medicine are a strong motivation for researchers worldwide. As scientists learn more about proteins that drive known diseases, they are better able to design promising therapeutic approaches to target those proteins. The field of nanotechnology has been extensively explored in the past years, and nanoparticles (NPs) have emerged as promising systems for target-specific delivery of drugs. Virus-like particles (VLPs) arise as auspicious NPs due to their intrinsic properties. The lack of viral genetic material and the inability to replicate, together with tropism conservation and antigenicity characteristic of the native virus prompted extensive interest in their use as vaccines or as delivery systems for therapeutic and/or imaging agents. Owing to its simplicity and non-complex structure, one of the viruses currently under study for the construction of VLPs is the human immunodeficiency virus type 1 (HIV-1). Typically, HIV-1-based VLPs are used for antibody discovery, vaccines, diagnostic reagent development and protein-based assays. This review will be centered on the use of HIV-1-based VLPs and their potential biomedical applications.