Copper-catalyzed Azide-alkyne Cycloaddition Research Articles

Liposomal Permeation Assay for Droplet-Scale Pharmacokinetic Screening.

Combinatorial library screening increasingly explores chemical space beyond the Ro5 (bRo5), which is useful for investigating "undruggable" targets but suffers compromised cellular permeability and therefore bioavailability. Moreover, structure-permeation relationships for bRo5 molecules are unclear partially because high-throughput permeation measurement technology for encoded combinatorial libraries is still nascent. Here, we present a permeation assay that is scalable to combinatorial library screening. A liposomal fluorogenic azide probe transduces permeation of alkyne-labeled molecules into small unilamellar vesicles via copper-catalyzed azide-alkyne cycloaddition. Control alkynes (e.g., propargylamine, various alkyne-labeled PEGs) benchmarked the assay. Cell-permeable macrocyclic peptides, exemplary bRo5 molecules, were alkyne labeled and shown to retain permeability. The assay was miniaturized to microfluidic droplets with high assay quality (Z' ≥ 0.5), demonstrating excellent discrimination of photocleaved known membrane-permeable and -impermeable model library beads. Droplet-scale permeation screening will enable pharmacokinetic mapping of bRo5 libraries to build predictive models.

Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner.

The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined heparin mimetics by a controlled head-to-tail assembly of HS oligosaccharides having an alkyne or azide moiety by copper-catalyzed azide-alkyne cycloaddition (CuAAC). Alkyne- and azide-containing sulfated oligosaccharides were prepared from a common precursor by modifying an anomeric linker with 4-pentynoic acid and by enzymatic extension with an N-acetyl-glucosamine having an azide moiety at C-6 (GlcNAc6N3), respectively, followed by CuAAC. The process of enzymatic extension with GlcNAc6N3 followed by CuAAC with the desired alkyne-containing oligosaccharides could be repeated to give compounds composed of 20 and 27 monosaccharides, respectively. The heparin mimetics could inhibit the binding of the SARS-CoV-2 spike or RBD to immobilized heparin or to Vero E6 cells. The inhibitory potency increased with increasing chain length, and a compound composed of four sulfated hexasaccharides linked by triazoles had a similar potency as unfractionated heparin. Sequence analysis and HS microarray binding studies with a wide range of RBDs of variants of concern indicate that they have maintained HS-binding capabilities and selectivities. The heparin mimetics exhibit no or reduced binding to antithrombin-III and platelet factor 4, respectively, which are associated with side effects.

Sparse pseudocontact shift NMR data obtained from a non-canonical amino acid-linked lanthanide tag improves integral membrane protein structure prediction.

A single experimental method alone often fails to provide the resolution, accuracy, and coverage needed to model integral membrane proteins (IMPs). Integrating computation with experimental data is a powerful approach to supplement missing structural information with atomic detail. We combine RosettaNMR with experimentally-derived paramagnetic NMR restraints to guide membrane protein structure prediction. We demonstrate this approach using the disulfide bond formation protein B (DsbB), an α-helical IMP. Here, we attached a cyclen-based paramagnetic lanthanide tag to an engineered non-canonical amino acid (ncAA) using a copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reaction. Using this tagging strategy, we collected 203 backbone HN pseudocontact shifts (PCSs) for three different labeling sites and used these as input to guide de novo membrane protein structure prediction protocols in Rosetta. We find that this sparse PCS dataset combined with 44 long-range NOEs as restraints in our calculations improves structure prediction of DsbB by enhancements in model accuracy, sampling, and scoring. The inclusion of this PCS dataset improved the Cα-RMSD transmembrane segment values of the best-scoring and best-RMSD models from 9.57Å and 3.06Å (no NMR data) to 5.73Å and 2.18Å, respectively.

Development of Novel Pt(IV)-Carbohydrate Derivatives as Targeted Anticancer Agents against Osteosarcoma

Despite the enormous importance of cisplatin as a chemotherapeutic agent, its application is impacted by dose-limiting side effects and lack of selectivity for cancer cells. Researchers can overcome these issues by taking advantage of the pro-drug nature of the platinum(IV) oxidation state, and by modifying the coordination sphere of the metal centre with specific vectors whose receptors are overexpressed in tumour cell membranes (e.g., carbohydrates). In this paper we report the synthesis of four novel carbohydrate-modified Pt(IV) pro-drugs, based on the cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumour which is most common in adolescents and young adults. The carbohydrate-targeting vectors and Pt scaffold are linked using copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry, which is synonymous with mild and robust reaction conditions. The novel complexes are characterised using multinuclear 1D-2D NMR (1H, 13C and 195Pt), IR, HR-MS, Elem. Analyses, and CV. Cytotoxicity on 2D and 3D and cell morphology studies on OS cell lines, as well as non-cancerous human foetal osteoblasts (hFOBs), are discussed.

Immunostimulation with chemotherapy of a ruthenium-arene complex via blockading CD47 signal in chronic myelogenous leukemia cells

Combination of novel immunomodulation and traditional chemotherapy has become a new tendency in cancer treatment. Increasing evidence suggests that blocking the “don't eat me” signal transmitted by the CD47 can promote the phagocytic ability of macrophages to cancer cells, which might be promising for improved cancer chemoimmunotherapy. In this work, we conjugated CPI-alkyne modified by Devimistat (CPI-613) with ruthenium-arene azide precursor Ru-N3 by copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to construct Ru complex CPI-Ru. CPI-Ru exhibited satisfactory cytotoxicity towards the K562 cells while nearly non-toxic towards the normal HLF cells. CPI-Ru has been demonstrated to cause severe damage to mitochondria and DNA, ultimately inducing cancer cell death through the autophagic pathway. Moreover, CPI-Ru could significantly downregulate the expression of CD47 on the surface of K562 accompanied by the enhanced immune response by targeting the blockade of CD47. This work provides a new strategy for utilizing metal-based anticancer agents to block CD47 signal to achieve chemoimmunotherapy in chronic myeloid leukemia treatment.

Arm-first synthesis of hyperbranched-core star polymers via copper-catalyzed azide-alkyne cycloaddition

A general method for the arm-first synthesis of star polymers through a formal A2 + B3 step-growth process is introduced. The synthesis relies on copper-catalyzed azide-alkyne cycloaddition (CuAAC) of N3-C(CR2)C-N3 macromonomers with a trifunctional alkyne crosslinker, and is enabled by the special mode of reactivity of 1,3-diazides in CuAAC. A variety of synthetic conditions were systematically evaluated, and effects of macromonomer size and feed ratio on the product structures have been investigated. Due to functional group tolerance of CuAAC, the presented methodology has a broad scope and can be extended to other macromonomers.

Synthesis and antiviral activity of 1,2,3-triazolyl nucleoside analogues with N-acetyl-d-glucosamine residue

A series of 1,2,3-triazolyl nucleoside analogues bearing N-acetyl-D-glucosamine residue was synthesized by the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction of N1-ω-alkynyl derivatives of uracil, 6-methyluracil, thymine and 3,4,6-tri-O-acetyl-2-deoxy-2-acetamido-β-D-glucopyranosyl azide. Antiviral assays revealed the lead compound 3f which showed both the same activity against the influenza virus A H1N1 (IC50=70.7 µM) as the antiviral drug Rimantadine in control (IC50=77 µM) and good activity against Coxsackievirus B3 (IC50=13.9 µM) which was one and a half times higher than the activity of the antiviral drug Pleconaril in control (IC50=21.6 µM). According to molecular docking simulations, the antiviral activity of the lead compound 3f against Coxsackie B3 virus can be explained by its binding to a key fragment of the capsid surface of this virus.

Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study.

Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound 9a was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound 9a to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound 9a exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment.

Synthesis, Characterization and Chemistry of Tetrakis(Propargylisocyanide) Copper(I) Complex

The kinetically unstable propargylisocyanide was reacted with the tetrakis(acetonitrile) copper(I) hexafluorophosphate and the formed complex was then involved in a copper-catalyzed alkyne-azide cycloaddition reaction (CuAAC). After the decomplexation of the adduct, the isocyanide was engaged in a Ugi reaction. By such a complexation, reactions can be carried out on the CC triple bond without the constraint of the instability of the free compound or the competitive reactivity of the isocyanide group.

A Diversifiable Synthetic Platform for the Discovery of New Carbasugar SGLT2 Inhibitors Using Azide-Alkyne Click Chemistry.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are clinically available to control blood glucose levels in diabetic patients via an insulin-independent mechanism. It was found that some carbasugar analogs of known SGLT2 inhibitors exert a high inhibiting ability toward SGLT2 and have a prolonged blood glucose lowering effect. In this study, we designed new candidates of carbasugar SGLT2 inhibitor that can be synthesized using copper-catalyzed azide-alkyne cycloaddition (CuAAC) into an aromatic ring, which is a part of the pharmacophore at the final stage in the synthetic protocol for the easier discovery of superior SGLT2 inhibitors. Based on the results of molecular docking studies, some selected compounds have been synthesized. Evaluation of these compounds using a cell-based assay revealed that the majority of these compounds had SGLT2 inhibitory activity in a dose-dependent manner. The SGLT2 inhibitory activity of 7b and 7c was almost equal to that of SGLT2 inhibitors in current use. Furthermore, molecular dynamics simulations also revealed that 7c is a promising novel SGLT2 inhibitor.

It Takes Two to Tango, Part II: Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities.

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango!

Synthesis, relative configuration and CB1 receptor affinity studies for a set of 1,2,3-triazole derivatives

Extending the click chemistry concept, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used to synthesize a series of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles using 1-(2-hydroxycyclohexyl)-4-dimethylaminomethyl 1,2,3-triazole (AMTC) as the Cu-binding ligand. The 1,4,5-trisubstituted 1,2,3-triazoles were obtained through 5-lithiation followed by a reaction with an electrophile. This study also showed, that a 1,4-disubstituted 5-lithiotriazole can be acylated using N,N-dimethylbenzamide, as an extension of the dimethylformamide formylation. The synthesized compounds, designed to mimic the bicyclic non-classical cannabinoids, were evaluated for their affinity to the cannabinoid type 1 receptor (CB1R). For a subset of 4-(3-hydroxycyclohexyl) 1,2,3-triazoles, the cis/trans relative configuration was determined, using 1D and 2D NMR combined with DFT-based chemical shift prediction.

Monomeric and Polymeric Mesoionic N-Heterocyclic Carbene-Tethered Silver Nanoparticles: Synthesis, Stability, and Catalytic Activity.

In recent years, N-heterocyclic carbenes (NHCs) have garnered significant attention as promising alternatives to thiols to stabilize metallic nanoparticles and planar surfaces. While most studies thus far have focused on NHC-functionalized gold nanoparticles (AuNPs), as an ideal platform to investigate the role of NHCs in stabilizing such nanoparticles, their ability to protect more unstable coinage metal nanoparticles, such as silver nanoparticles (AgNPs), has been largely overlooked. This is despite the fact that AgNPs possess a much more sensitive optical response that, upon their enhanced stability, can broaden their scope of application in various fields, including nanomedicine and catalysis. In this study, the synthesis and use of monomeric and polymeric mesoionic NHC-Ag(I) complexes as precursors to mono- and multidentate NHC-tethered AgNPs are reported. The polymeric analog was obtained by first synthesizing a polymer, containing 1,2,3-triazole repeat units, employing the copper-catalyzed alkyne-azide cycloaddition click polymerization of monomers containing diazide- and dialkyne functional groups. Subsequent quaternization of the triazole moieties and Ag insertion yielded the target NHC-Ag-containing polymer. Using this polymer as well as its monomeric analog as substrates, AgNPs with either catenated networks of NHCs or monomeric NHCs were fabricated by their reduction using borane-tert-butylamine complex. Our stability studies demonstrate that while monomeric NHCs impart some degree of stability to AgNPs, particularly at elevated temperatures in aqueous as well as organic medium, their polymeric analogs further enhance their stability in acidic environment (pH = 2) and against glutathione (3 mM), as an example of a biologically relevant thiol, in aqueous media. To highlight the application of these NHC-functionalized AgNPs in catalysis, we explore the aqueous phase reduction of methyl orange and 4-nitrophenol.

Layered Copper Hydroxide Salts as Catalyst for the “Click” Reaction and Their Application in Methyl Orange Photocatalytic Discoloration

The 1,2,3-triazoles are an important class of organic compounds that are found in a variety of biologically active compounds. The most usual and efficient methodology to synthetize these compounds is the Copper-catalyzed Azide–Alkyne Cycloaddition (CuAAC), preferably by use of click chemistry principles. Therefore, the development of simple, robust, easily accessible and efficient materials as catalysts for this kind of reaction is highly desirable. In this sense, layered hydroxide salts (LHS) emerge as an interesting alternative for the click reaction. Thus, we describe herein the preparation and characterization of copper (II) layered hydroxide salts and their application as catalysts for the CuAAC reaction under solvent-free conditions. This synthetic methodology of CuAAC reaction is attractive as it follows several concepts of green chemistry, such as being easy to perform, allowing purification without chromatographic column, the process forming no sub-products, affording the desired 1,2,3-traizoles in the specific 1,4-disubstituted position in high yield, and having a short reaction time. Moreover, the photocatalysis for the degradation of methyl orange was also highly efficient using the same catalyst.

Click chemistry: A fascinating, Nobel-winning method for the improvement of biological activity

Click chemistry is totally an approach consisting of efficient and reliable reactions that bind two molecular building blocks and require no complex purification techniques. The aspire of achieving molecules with the desired characteristics and behaviour is the key to the click chemistry concept. In this concept, in order to obtain 1,2,3-triazole products as diversely functionalized molecules, copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been widely used for years in the field of materials science, organic synthesis and the biochemistry. This review focusses on the importance of click chemistry for obtaining biologically active triazole molecules and therefore the applications of such 1,2,3-triazole derivatives in medicinal chemistry field are highlighted.

Process-Divergent Syntheses of 4- and 5-Sulfur-Functionalized 1,2,3-Triazoles via Copper-Catalyzed Azide-Alkyne Cycloadditions of 1-Phosphinyl-2-sulfanylethynes.

4-Sulfanyl-substituted 1,2,3-triazoles were provided regioselectively with good yields and broad scope via consecutive t-BuOK-promoted dephosphinylation of 1-phosphinyl-2-sulfanylethynes and copper-catalyzed azide-alkyne cycloadditions (CuAAC) with alkyl azides. Unsymmetrically substituted ditriazoles were successfully obtained using a tandem dephosphinylative CuAAC protocol with diazides. Direct CuAAC of the 1-phosphinyl-2-sulfanylethynes with azides afforded regioisomeric mixtures of 4-phosphinyl-5-sulfanyl- and 5-phosphinyl-4-sulfanyl-1,2,3-triazoles that were easily separable from one another. When the phosphinyl- and sulfanyl-substituted triazoles were treated with t-BuOK, the dephosphination proceeded smoothly, yielding the corresponding 5- and 4-sulfanyltriazoles, respectively. 5-(1-Aryl-1-hydroxymethyl)-4-sulfanyltriazoles were synthesized by stepwise treatment of 5-phosphinyl-4-sulfanyltriazole with MeMgBr and arylaldehydes. Additionally, Ph2P(O) and RS groups in the triazoles were easily converted to Ph2P and RSO2 by PhSiH3-reduction and m-CPBA-oxidation, respectively. Following the dephosphinylative CuAAC of 1-phosphinyl-2-(4-t-butylphenylsulfanyl)ethyne with aryl azides and m-CPBA-oxidation, potent antagonists of pregnane X receptor LC-58 and LC-59 were successfully produced.

Decoration of Polyfluorene-Wrapped Carbon Nanotubes with Photocleavable Side-Chains.

Functionalizing polyfluorene-wrapped carbon nanotubes without damaging their properties is effective via Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC). However, the length and nature of polymer side-chains can impact the conductivity of polyfluorene-SWNT films by preventing close contact between the nanotubes. Here, we investigate the functionalization of a polyfluorene-SWNT complex using photocleavable side-chains that can be removed post-processing. The cleavage of the side-chains containing an ortho-nitrobenzyl ether derivative is efficient when exposed to a UV lamp at 365 nm. The photoisomerization of the o-nitrobenzyl ether linker into the corresponding o-nitrosobenzaldehyde was first monitored via UV-Vis absorption spectroscopy and 1H-NMR spectroscopy on the polymer, which showed efficient cleavage after 2 h. We next investigated the cleavage on the polyfluorene-SWNT complex via UV-Vis-NIR absorption spectroscopy. The precipitation of the nanotube dispersion and the broad absorption peaks after overnight irradiation also indicated effective cleavage. In addition, Raman spectroscopy post-irradiation showed that the nanotubes were not damaged upon irradiation. This paper reports a proof of concept that may find applications for SWNT-based materials in which side-chain removal could lead to higher device performance.

Fluorescent Gold Nanoparticles in Suspension as an Efficient Theranostic Agent for Highly Radio-Resistant Cancer Cells

Gold nanoparticles are a promising candidate for developing new strategies of therapy against cancer. Due to their high atomic number and relative biocompatibility, they are commonly investigated as radiosensitizers to locally increase the dose of radiotherapy. In order to optimize this radiosensitizing effect, it is necessary to control the positioning of the nanoparticles in the cells. The purpose of this study is to investigate, by means of fluorescent gold nanoparticles in suspension, the dose enhancement on highly radio-resistant cancer cells. These nanoparticles were successfully produced using modern click-chemistry methods, first by attaching a chelating agent Diethylenetriamine pentaacetate benzylamine to L-cysteine, bonding the resulting ligand to a gold core, grafting propargylamine and then utilizing copper-catalyzed azide-alkyne cycloaddition (CuAAC) to fuse AlexaFluor 647 to the ligands. The results of this study prove the success of the reactions to produce a minimally cytotoxic and highly stable nanoparticle suspension that increases the radiosensitivity of gliosarcoma 9L tumor cells, with a 35% increase in cell death using 5 Gy kilovoltage radiation. Their fluorescent functionalization allowed for their simple localization within living cells and detection in vivo post-mortem.

Synthesis and conformational studies of hyperbranched-core star polymers with poly(γ-benzyl-l-glutamate) arms

A general methodology for the synthesis of star polymers with large number of polypeptide arms is described. The synthesis is based on the arm-first step-growth polymerization of bifunctional macromonomers by copper-catalyzed azide-alkyne cycloaddition. Star polymers with up to 18 poly-γ-benzyl-l-glutamate (PBLG) arms have been synthesized and characterized. It is shown that the preferred secondary structure of PBLG is significantly affected by the degree of chain packing/crowding.

PEGylated reduced graphene oxide as nanoplatform for targeted gene and drug delivery

Combination therapies involving anticancer drugs and gene therapy agents have become a potential treatment for different cancer types reducing the side effects of anticancer drugs while enhancing their effectiveness. Here, we improved our previously published strategy that uses multiple pyrene groups of poly(ethylene glycol) (PEG) brushed graft copolymer to enhance the biological use of reduced graphene oxide (rGO) and introduced an azide containing monomer in the copolymer for further modifications to carry hydrophobic drugs like doxorubicin (Dox) along with oligonucleotides such as small interfering RNAs (siRNA). Azide functionality on the side chain of coated copolymer enables not only the conjugation of alkyne end group functional cationic copolymer but also allows the addition of targeting moieties like EPPT1 peptide that selectively binds MUC1, an early hallmark of tumorigenesis. To achieve the outlined carrier, first, a well-defined PEG, pyrene, azide, and methyl methacrylate containing poly[(poly(ethylene glycol) methyl ether methacrylate)-co-(3-azidopropyl methacrylate)-co-(methyl methacrylate)-co-(1-pyrenemethyl methacrylate)] (P(PEGMA-co-AzPMA-co-MMA-co-PMA), PAMP) copolymer was synthesized via ATRP and through its azide group another well-defined, cationic copolymer composed of hexyl methacrylate, 2-dimethyl amino ethyl methacrylate, and N,N,N-trimethylaminoethyl methacrylate iodide (P(HMA-co-DMAEMA-co-TMAEMA) was coupled via copper-catalyzed azide-alkyne cycloaddition (CuAAC). This cationic copolymer was synthesized using a unique ATRP initiator to allow click reaction as described as well as pH-dependent degradation through its hydrazone linkage. The obtained graft copolymer (PAMP-CP) was then coated on a graphene oxide (GO) surface and GO was in situ reduced to rGO (PAMP-CP-rGO) to have an rGO-based PEGylated nanoplatform that can be highly loaded with doxorubicin and successfully condensed with anti-GAPDH siRNA. Consequently, this dual drug delivery nanoplatform showed a controlled drug release that switches between release kinetics by the change of pH and high transfection efficiency regarding targeted GAPDH protein levels. Moreover, in vitro cytotoxicity tests showed that EPPT1-targeted Dox-loaded PAMP-CP-rGO shows concentration-dependent and selective cellular toxicity against cancer cells compared to its non-targeted versions. These results demonstrated the potential of a highly adaptable, multifunctional nanoplatform for safely and selectively transporting different cargoes to the tumor site.