Drug Delivery Vectors Research Articles

Designed inorganic porous nanovector with controlled release and MRI features for safe administration of doxorubicin

The inability of traditional chemotherapeutics to reach cancer tissue reduces the treatment efficacy and leads to adverse effects. A multifunctional nanovector was developed consisting of porous silicon, superparamagnetic iron oxide, calcium carbonate, doxorubicin and polyethylene glycol. The particles integrate magnetic properties with the capacity to retain drug molecules inside the pore matrix at neutral pH to facilitate drug delivery to tumor tissues. The MRI applicability and pH controlled drug release were examined in vitro together with in-depth material characterization. The in vivo biodistribution and compound safety were verified using A549 lung cancer bearing mice before proceeding to therapeutic experiments using CT26 cancer implanted mice. Loading doxorubicin into the porous nanoparticle negated the adverse side effects encountered after intravenous administration highlighting the particles’ excellent biocompatibility. Furthermore, the multifunctional nanovector induced 77% tumor reduction after intratumoral injection. The anti-tumor effect was comparable with that of free doxorubicin but with significantly alleviated unwanted effects. These results demonstrate that the developed porous silicon-based nanoparticles represent promising multifunctional drug delivery vectors for cancer monitoring and therapy.

Folic Acid‐Navigated and β‐Cyclodextrin‐Decorated Carbon‐Encapsulated Iron Nanoparticles as the Nanotheranostic Platform for Controlled Release of 5‐Fluorouracil

AbstractThe theranostic probe based on carbon‐encapsulated iron nanoparticles (CEINs) is presented. First, the conjugates of CEINs and polyethylenimine (PEI) were obtained to modify the surface of CEINs with amino groups. It was archived either by means of direct radical addition of PEI to CEINs (CEINs‐NH‐PEI material) or the amidation‐type reaction between CEINs∼COOH and the polymer (CEINs∼CONH‐PEI material obtained). β‐Cyclodextrin (βCD) was selected as the drug delivery vector. βCD was covalently anchored to the PEI‐functionalized CEINs via the 1,1’‐carbonyldiimidazole‐mediated reaction. The synthesis included the conjugation of folic acid (FA; targeting ligand) to CEINs via the carbodiimide‐mediated amidation‐type process. The innovative method for excluding a side process of the FA@βCD complex formation during the FA conjugation to PEI, was developed. 5‐Fluorouracil (5‐FU) was chosen as the representative drug molecule. 5‐FU was anchored to the CEINs∼PEI∼βCD∼FA nanoplatforms employing the host‐guest chemistry of βCD. The success of the reactions was confirmed by infrared spectroscopy and thermogravimetry. The content of anchored organic compounds depends on the type of linkage between PEI and CEINs. Additionally, 5‐FU release profile was examined at various pH. The highest release of 5‐FU was observed at pH 9.0, whilst the lowest at pH 4.7. This work sheds a new light on application of carbon‐encapsulated iron nanoparticles in nanomedicine as the novel drug delivery theranostic systems.

Chitosan-Based Nanomaterials for Drug Delivery.

This review discusses different forms of nanomaterials generated from chitosan and its derivatives for controlled drug delivery. Nanomaterials are drug carriers with multiple features, including target delivery triggered by environmental, pH, thermal responses, enhanced biocompatibility, and the ability to cross the blood-brain barrier. Chitosan (CS), a natural polysaccharide largely obtained from marine crustaceans, is a promising drug delivery vector for therapeutics and diagnostics, owing to its biocompatibility, biodegradability, low toxicity, and structural variability. This review describes various approaches to obtain novel CS derivatives, including their distinct advantages, as well as different forms of nanomaterials recently developed from CS. The advanced applications of CS-based nanomaterials are presented here in terms of their specific functions. Recent studies have proven that nanotechnology combined with CS and its derivatives could potentially circumvent obstacles in the transport of drugs thereby improving the drug efficacy. CS-based nanomaterials have been shown to be highly effective in targeted drug therapy.

A degradable triple temperature-, pH-, and redox-responsive drug system for cancer chemotherapy.

In order to achieve a precise therapeutic effect of cancer treatment and improve the utilization of drugs, a temperature-, pH-, and redox-responsive drug delivery system were synthesized. Methacrylic acid (MAA), poly(N-isopropylacrylamide) (PNIPAM), 2-hydroxyethylmethacrylate (HEMA), and N,N'-bis(acryloyl)cystamine (BACy), a disulfide bond contained cross-linker, were polymerized by a distillation-precipitation polymerization. Doxorubicin (DOX), an anti-cancer drug, can be loaded into the loose nanoparticle (NP) effectively. The prepared drug delivery remains stable during blood circulation and, when the vectors accumulated at tumor tissues, the pH-response of MMA and temperature-response of PNIPAM makes volume shrinkage of vectors which benefit the diffusion of vectors into tumor tissues. After being endocytosed into tumor cell, the disulfide bond that contained in the drug delivery can be cleaved by glutathione (GSH), causing the decomposition of NPs, and then release all of the drug. Under the influence of three trigger factors, the triple stimuli-responsive drug delivery vectors can realize tumor accumulation, tumor penetration and controlled drug release. Thus, the prepared multi-responsive NP is ideal drug carriers for developing novel drug delivery systems. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3203-3210, 2018.

Steric interactions between mobile ligands facilitate complete wrapping in passive endocytosis

Receptor-mediated endocytosis is an ubiquitous process through which cells internalize biological or synthetic nanoscale objects, including viruses, unicellular parasites, and nanomedical vectors for drug or gene delivery. In passive endocytosis the cell plasma membrane wraps around the "invader" particle driven by ligand-receptor complexation. By means of theory and numerical simulations, here we demonstrate how particles decorated by freely diffusing and non-mutually-interacting (ideal) ligands are significantly more difficult to wrap than those where ligands are either immobile or interact sterically with each other. Our model rationalizes the relationship between uptake mechanism and structural details of the invader, such as ligand size, mobility and ligand/receptor affinity, providing a comprehensive picture of pathogen endocytosis and helping the rational design of efficient drug delivery vectors.

RECENT PROGRESS OF DENDRIMERS IN DRUG DELIVERY FOR CANCER THERAPY

With the recent advances of nanotechnology, dendrimers are emerging as a highly attractive class of drug delivery vectors for cancer therapy. Dendrimers are multifunctional smart Nanocarriers to deliver one or more therapeutic agent safely and selectively to cancer cells. The high level of control over the synthesis of dendritic architecture makes dendrimers a nearly perfect (spherical) nanocarrier for site-specific drug delivery. The presence of functional groups in the dendrimers exterior also permits the addition of other moieties that can actively target certain diseases which are now widely used as tumor targeting strategies. Drug encapsulation, solubilization and passive targeting also equally contribute to the therapeutic use of dendrimers. Dendrimers are ideal carrier vehicles on cytotoxicity, blood plasma retention time, biodistribution and tumor uptake. In this review we highlight the advantages of dendrimers over conventional chemotherapy, toxicity and its management, following anti-cancer drugs delivered by using dendrimers and recent advances in drug delivery by various types of dendrimers as well as its diagnostic applications.

Cholesterol and phosphatidylserine are engaged in adenoviral dodecahedron endocytosis

Adenoviral dodecahedron is a virus-like particle composed of twelve penton base proteins, derived from the capsid of human adenovirus type 3. Due to the high cell penetration capacity, it was used as a vector for protein, peptide and drug delivery. Two receptors are known to be involved in the endocytic dodecahedron uptake, namely αv integrins and heparan sulfate proteoglycans. Since it has been observed, that dodecahedron efficiently penetrates a wide range of cancer cells, it suggests that other cellular compounds may play a role in the particle endocytosis. To shed some light onto the interactions with membrane lipids and their potential role in dodecahedron entry, we performed a series of experiments including biochemical assays, fluorescence confocal imaging of giant unilamellar vesicles and surface plasmon resonance, which indicated specific preference of the particle to anionic phosphatidylserine. Experiments performed on cholesterol-depleted epithelial cells showed that cholesterol is essential in the endocytic uptake, however a direct interaction was not observed. We believe that the results will allow to better understand the role of lipids in dodecahedron entry and to design more specific dodecahedron-based vectors for drug delivery to cancer cells.

Exploring Factors for the Design of Nanoparticles as Drug Delivery Vectors.

To achieve optimal results when employing nanoparticles in biomedical fields, choosing the right type of nanoparticle and determining the correct procedure for drug loading are key factors. Each type of nanoparticle presents a determined set of characteristics that are, in some cases, unique. In general, their surface charge, geometry or hydrophilic character may be limiting factors, depending on what their intended application is. Once synthesized, additional factors, such as their interaction with biological systems and liberation mechanisms into the target cells, also need to be taken into account. Multiple advantages arise from the use of nanoparticles, such as the capability to solubilize hydrophobic compounds and an increased bioavailability. Those advantages justify the extensive and delicate study that should be undertaken in order to use them as drug delivery agents. One of the most important factors for the design of a drug delivery system with nanoparticles is achieving a high drug-to-nanoparticle ratio. In this Minireview, all of these key factors, both physicochemical and biological, are described, and special emphasis is placed on loading methods employed to introduce drugs into nanoparticles.

Development of self-nanoemulsifying drug delivery systems for oil extracts of Citrus aurantium L. blossoms and Rose damascena and evaluation of anticancer properties

In recent years, traditional medicine has increasingly attracted public attention in the treatment of various cancers. Herein, nanovehicles came onto the scene of drug therapy as a type of drug delivery vector. A self-nanoemulsifying drug delivery system (SNEDDS) has developed a new route to improve the efficacy of oil extracts of Citrus aurantium L. blossoms and Rose damascena. SNEDDSs were prepared from a mixture of castor oil, tween 80, and polyethylene glycol 600 under dilution with water. Cytotoxicity studies on MCF7 and PANC1 cell lines were performed. Oil extracts of Citrus aurantium L. blossoms- and Rose damascena-loaded SNEDDSs containing nanodroplets of oils were prepared without a sign of precipitation or phase separation. The size and shape of nanodroplets were evaluated by field emission scanning electron microscopy and particle size analysis. Cytotoxicity studies on MCF7 and PANC1 cell lines indicated a toxicity enhancement in the oil extracts by SNEDDS. SNEDDSs can be employed as a new route for the oral delivery of the extracts with a high effectiveness.

Fate of Liposomes in the Presence of Phospholipase C and D: From Atomic to Supramolecular Lipid Arrangement

Understanding the origins of lipid membrane bilayer rearrangement in response to external stimuli is an essential component of cell biology and the bottom-up design of liposomes for biomedical applications. The enzymes phospholipase C and D (PLC and PLD) both cleave the phosphorus–oxygen bonds of phosphate esters in phosphatidylcholine (PC) lipids. The atomic position of this hydrolysis reaction has huge implications for the stability of PC-containing self-assembled structures, such as the cell wall and lipid-based vesicle drug delivery vectors. While PLC converts PC to diacylglycerol (DAG), the interaction of PC with PLD produces phosphatidic acid (PA). Here we present a combination of small-angle scattering data and all-atom molecular dynamics simulations, providing insights into the effects of atomic-scale reorganization on the supramolecular assembly of PC membrane bilayers upon enzyme-mediated incorporation of DAG or PA. We observed that PC liposomes completely disintegrate in the presence of PLC, as conversion of PC to DAG progresses. At lower concentrations, DAG molecules within fluid PC bilayers form hydrogen bonds with backbone carbonyl oxygens in neighboring PC molecules and burrow into the hydrophobic region. This leads initially to membrane thinning followed by a swelling of the lamellar phase with increased DAG. At higher DAG concentrations, localized membrane tension causes a change in lipid phase from lamellar to the hexagonal and micellar cubic phases. Molecular dynamics simulations show that this destabilization is also caused in part by the decreased ability of DAG-containing PC membranes to coordinate sodium ions. Conversely, PLD-treated PC liposomes remain stable up to extremely high conversions to PA. Here, the negatively charged PA headgroup attracts significant amounts of sodium ions from the bulk solution to the membrane surface, leading to a swelling of the coordinated water layer. These findings are a vital step toward a fundamental understanding of the degradation behavior of PC lipid membranes in the presence of these clinically relevant enzymes, and toward the rational design of diagnostic and drug delivery technologies for phospholipase-dysregulation-based diseases.

Concise Review: Mesenchymal Stem Cell-Based Drug Delivery: The Good, the Bad, the Ugly, and the Promise.

The development of mesenchymal stem cells (MSCs) as cell‐based drug delivery vectors for numerous clinical indications, including cancer, has significant promise. However, a considerable challenge for effective translation of these approaches is the limited tumor tropism and broad biodistribution observed using conventional MSCs, which raises concerns for toxicity to nontarget peripheral tissues (i.e., the bad). Consequently, there are a variety of synthetic engineering platforms in active development to improve tumor‐selective targeting via increased homing efficiency and/or specificity of drug activation, some of which are already being evaluated clinically (i.e., the good). Unfortunately, the lack of robust quantification and widespread adoption of standardized methodologies with high sensitivity and resolution has made accurate comparisons across studies difficult, which has significantly impeded progress (i.e., the ugly). Herein, we provide a concise review of active and passive MSC homing mechanisms and biodistribution postinfusion; in addition to in vivo cell tracking methodologies and strategies to enhance tumor targeting with a focus on MSC‐based drug delivery strategies for cancer therapy. Stem Cells Translational Medicine 2018;1–13

Cationic liposomes induce cytotoxicity in HepG2 via regulation of lipid metabolism based on whole-transcriptome sequencing analysis

BackgroudCationic liposomes (CLs) can be used as non-viral vectors in gene transfer and drug delivery. However, the underlying molecular mechanism of its cytotoxicity has not been well elucidated yet.MethodsWe herein report a systems biology approach based on whole-transcriptome sequencing coupled with computational method to identify the predominant genes and pathways involved in the cytotoxicity of CLs in HepG2 cell line.ResultsFirstly, we validated the concentration-dependent cytotoxicity of CLs with an IC50 of 120 μg/ml in HepG2 exposed for 24 h. Subsequently, we used whole-transcriptome sequencing to identify 220 (77 up- and 143 down-regulated) differentially expressed genes (DEGs). Gene ontology (GO) and pathway analysis showed that these DEGs were mainly related to cholesterol, steroid, lipid biosynthetic and metabolic processes. Additionally, “key regulatory” genes were identified using gene act, pathway act and co-expression network analysis, and expression levels of 11 interested altered genes were confirmed by quantitative real time PCR. Interestingly, no cell cycle arrest was observed through flow cytometry.ConclusionsThese data are expected to provide deep insights into the molecular mechanism of CLs cytotoxicity.

Genetically-engineered Salmonella typhimurium expressing TIMP-2 as a therapeutic intervention in an orthotopic glioma mouse model

Glioma is one of the most devastating and refractory cancers. The main factors underlying therapeutic failure include extremely invasive characteristics and lack of effective methods for drug delivery. Attenuated Salmonella strains presented a high concentration of tumor targets in various types of cancer models, suggesting a role as potential vectors for drug delivery. In this study, we genetically engineered an attenuated strain of Salmonella as an anti-invasive vector for the targeted delivery and expression of tissue inhibitor of metalloproteinases 2 (TIMP-2) in an orthotopic nude mouse model of glioma. The bioluminescence signals related to tumor size significantly declined in the TIMP-2-expressing Salmonella (SLpTIMP-2)-treated group compared with the control group. Compared with the control group with a survival rate of an average of 33 days, the SLpTIMP-2 group showed an extended survival rate by nearly 60% and lasted an average period of 53 days with TIMP-2 induction. These results indicated the promising therapeutic potential of S. typhimurium for targeted delivery and secretion of TIMP-2 in glioma.

Abstract 10.35 SILK A VERSATILE BIOMATERIAL FOR CLINICAL TRANSLATION

Chitosan, alginate and silk are representatives of natural biomaterials that have been extensively investigated for future clinical applications throughout the last years. Especially silk aroused the interest of biomedical research since the end of the last century. Until now silk is one of the most investigated and characterized biomaterials for clinical translation. Auspicious mechanical and thermal properties regarding tensile strength, elasticity and heat resistance combined with a unique cyto- and biocompatibility makes silk to a promising material for biomedical applications. Most studies rely on silk gained from spiders of species Nephilla clavipes or silk worms of species Bombyx mori. Silk can either be collected directly from the arthropods labial gland or respectively at the opisthosoma located spinnerets of spiders. Due to a complete characterization of the ultra-structural compositions of silk protein structures a recombinant production of silk is feasible. Research groups from Europe, Asia and North America are currently working on possible clinical translation of silk based biografts. Results indicating that a use of silk based materials could be beneficial for the reconstruction of muscle tendon, cruciate ligament, meniscus or peripheral nerves. Especially the use for chronic wound dressings and peripheral nerve reconstruction seems to be advantageous for the plastic and reconstructive surgery. Beside the use as biografts for possible future surgical approaches the use of single recombinant or non- recombinant silk fibers as pharmaceutical vectors for drug delivery e.g. charged with antibiotics have been discussed. This review gives a brief overview of the current state of the art in silk grafting and the ongoing biomaterial research for future clinical translation.

Interaction of Poly(l-lysine)/Polysaccharide Complex Nanoparticles with Human Vascular Endothelial Cells.

Short TitlePolyelectrolyte nanoparticles and vascular endothelial cells.Angiogenesis plays an important role in both soft and hard tissue regeneration, which can be modulated by therapeutic drugs. If nanoparticles (NP) are used as vectors for drug delivery, they have to encounter endothelial cells (EC) lining the vascular lumen, if applied intravenously. Herein the interaction of unloaded polyelectrolyte complex nanoparticles (PECNP) composed of cationic poly(l-lysine) (PLL) and various anionic polysaccharides with human vascular endothelial cells (HUVEC) was analyzed. In particular PECNP were tested for their cell adhesive properties, their cellular uptake and intracellular localization considering composition and net charge. PECNP may form a platform for both cell coating and drug delivery. PECNP, composed of PLL in combination with the polysaccharides dextran sulfate (DS), cellulose sulfate (CS) or heparin (HEP), either unlabeled or labeled with fluorescein isothiocyanate (FITC) and either with positive or negative net charge were prepared. PECNP were applied to human umbilical cord vein endothelial cells (HUVEC) in both, the volume phase and immobilized phase at model substrates like tissue culture dishes. The attachment of PECNP to the cell surface, their intracellular uptake, and effects on cell proliferation and growth behavior were determined. Immobilized PECNP reduced attachment of HUVEC, most prominently the systems PLL/HEP and PLL/DS. A small percentage of immobilized PECNP was taken up by cells during adhesion. PECNP in the volume phase showed no effect of the net charge sign and only minor effects of the composition on the binding and uptake of PECNP at HUVEC. PECNP were stored in endosomal vesicles in a cumulative manner without apparent further processing. During mitosis, internalized PECNP were almost equally distributed among the dividing cells. Both, in the volume phase and immobilized at the surface, PECNP composed of PLL/HEP and PLL/DS clearly reduced cell proliferation of HUVEC, however without an apparent cytotoxic effect, while PLL/CS composition showed minor impairment. PECNP have an anti-adhesive effect on HUVEC and are taken up by endothelial cells which may negatively influence the proliferation rate of HUVEC. The negative effects were less obvious with the composition PLL/CS. Since uptake and binding for PLL/HEP was more efficient than for PLL/DS, PECNP of PLL/HEP may be used to deliver growth factors to endothelial cells during vascularization of bone reconstitution material, whereas those of PLL/CS may have an advantage for substituting biomimetic bone scaffold material.

Novel Bletilla striata polysaccharide microneedles: Fabrication, characterization, and in vitro transcutaneous drug delivery

Dissolving microneedles (MNs) have been widely studied for their applications in effective transdermal drug delivery due to their ability to dissolve within the skin. This study details the first reported successful preparation of novel dissolving MNs using Bletilla striata polysaccharide (BSP), a natural glucomannan material, and investigates the potential for using such MNs as a transdermal drug delivery vector. The prepared dissolving Bletilla striata polysaccharide microneedles (BMNs) had excellent moldability and were easily detached from the mold. Texture analysis and histological examination confirmed BMNs were strong enough to insert into the skin. The skin appeared slight irritation after removal of BMNs, but recovered within 24 h. Confocal laser scanning microscopy (CLSM) studies indicated that rhodamine B (RB) loaded in BMNs (as a model drug) could be gradually released, along with the dissolution of BSP in vivo, and then diffused from the insertion site to the periphery. Furthermore, we found that the RB-loaded BMNs could provide sustained drug release via the in vitro Franz cell experiment. These findings demonstrate that novel dissolving BMNs can be easily-manufactured, loaded with drug, and inserted into the skin for drug delivery.

Silver Nanoparticles: Synthetic Routes, In Vitro Toxicity and Theranostic Applications for Cancer Disease.

The large use of nanomaterials in many fields of application and commercial products highlights their potential toxicity on living organisms and the environment, despite their physico-chemical properties. Among these, silver nanoparticles (Ag NPs) are involved in biomedical applications such as antibacterial agents, drug delivery vectors and theranostics agents. In this review, we explain the common synthesis routes of Ag NPs using physical, chemical, and biological methods, following their toxicity mechanism in cells. In particular, we analyzed the physiological cellular pathway perturbations in terms of oxidative stress induction, mitochondrial membrane potential alteration, cell death, apoptosis, DNA damage and cytokines secretion after Ag NPs exposure. In addition, their potential anti-cancer activity and theranostic applications are discussed.

Contrasting roles for actin in the cellular uptake of cell penetrating peptide conjugates

The increased need for macromolecular therapeutics, such as peptides, proteins and nucleotides, to reach intracellular targets necessitates more effective delivery vectors and a higher level of understanding of their mechanism of action. Cell penetrating peptides (CPPs) can transport a range of macromolecules into cells, either through direct plasma membrane translocation or endocytosis. All known endocytic pathways involve cell-cortex remodelling, a process shown to be regulated by reorganisation of the actin cytoskeleton. Here using flow cytometry, confocal microscopy and a variety of actin inhibitors we identify how actin disorganisation in different cell types differentially influences the cellular entry of three probes: the CPP octaarginine – Alexa488 conjugate (R8-Alexa488), octaarginine conjugated Enhanced Green Fluorescent Protein (EGFP-R8), and the fluid phase probe dextran. Disrupting actin organisation in A431 skin epithelial cells dramatically increases the uptake of EGFP-R8 and dextran, and contrasts strongly to inhibitory effects observed with transferrin and R8 attached to the fluorophore Alexa488. This demonstrates that uptake of the same CPP can occur via different endocytic processes depending on the conjugated fluorescent entity. Overall this study highlights how cargo influences cell uptake of this peptide and that the actin cytoskeleton may act as a gateway or barrier to endocytosis of drug delivery vectors.

Cyclic peptide-poly(HPMA) nanotubes as drug delivery vectors: In vitro assessment, pharmacokinetics and biodistribution

Size and shape have progressively appeared as some of the key factors influencing the properties of nanosized drug delivery systems. In particular, elongated materials are thought to interact differently with cells and therefore may allow alterations of in vivo fate without changes in chemical composition. A challenge, however, remains the creation of stable self-assembled materials with anisotropic shape for delivery applications that still feature the ability to disassemble, avoiding organ accumulation and facilitating clearance from the system. In this context, we report on cyclic peptide-polymer conjugates that self-assemble into supramolecular nanotubes, as confirmed by SANS and SLS. Their behaviour ex and in vivo was studied: the nanostructures are non-toxic up to a concentration of 0.5 g L−1 and cell uptake studies revealed that the pathway of entry was energy-dependent. Pharmacokinetic studies following intravenous injection of the peptide-polymer conjugates and a control polymer to rats showed that the larger size of the nanotubes formed by the conjugates reduced renal clearance and elongated systemic circulation. Importantly, the ability to slowly disassemble into small units allowed effective clearance of the conjugates and reduced organ accumulation, making these materials interesting candidates in the search for effective drug carriers.

A Rational Approach to Metal Loading of Organic Multi-Site Polymers: Illusion or Reality?

Since its identification as an independent topic after the first world war, the chemistry of (bio)polymers and macromolecules rapidly benefited from intense synthetic activities driven by contributors focusing on formulation and structural aspects. Satisfying rationalization and predictions concerning polymer organization, stability, and reactivity were, however, delayed until the late fifties, when physical chemists set the basis of an adapted thermodynamic modeling. The recent emergence of metal-containing (bio)organic polymers (i.e., metallopolymers) thus corresponds to a logical extension of this field with the ultimate goal of combining the rich magnetic and optical properties of open-shell transition metals with the processability and structural variety of polymeric organic scaffolds. Since applications as energy storage materials, drug delivery vectors, shape-memory materials, and photonic devices can be easily envisioned for these materials, the development of metallopolymers is faced with some urgency in producing novel exploitable structures, while the rational control of their formation, organization, and transformation remains elusive. Caught between the sometimes antagonistic requirements of economic efficiency on one side and of scientific pertinence on the other side, the ongoing achievements in the control of the metal loadings of multi-site polymers are highlighted here with some tutorial discussions of luminescent lanthanidopolymers as proof-of-concept.