Non-conjugated Research Articles

Exceptional Electron-Rich Heteroaromatic Pentacycle for Ultralow Band Gap Conjugated Polymers and Photothermal Therapy.

Stable redox-active conjugated molecules with exceptional electron-donating abilities are key components for the design and synthesis of ultralow band gap conjugated polymers. While hallmark electron-rich examples such as pentacene derivatives have been thoroughly explored, their poor air stability has hampered their broad incorporation into conjugated polymers for practical applications. Herein, we describe the synthesis of the electron-rich, fused pentacyclic pyrazino[2,3-b:5,6-b']diindolizine (PDIz) motif and detail its optical and redox behavior. The PDIz ring system exhibits a lower oxidation potential and a reduced optical band gap than the isoelectronic pentacene while retaining greater air stability in both solution and the solid state. The enhanced stability and electron density, together with readily installed solubilizing groups and polymerization handles, allow for the use of the PDIz motif in the synthesis of a series of conjugated polymers with band gaps as small as 0.71 eV. The tunable absorbance throughout the biologically relevant near-infrared I and II regions enables the use of these PDIz-based polymers as efficient photothermal therapeutic reagents for laser ablation of cancer cells.

Kylin 1.0: An ab-initio density matrix renormalization group quantum chemistry program.

The accurate evaluation of electron correlations is highly necessary for the proper descriptions of the electronic structures in strongly correlated molecules, ranging from bond-dissociating molecules, polyradicals, to large conjugated molecules and transition metal complexes. For this purpose, in this paper, a new ab-initio quantum chemistry program Kylin 1.0 for electron correlation calculations at various quantum many-body levels, including configuration interaction (CI), perturbation theory (PT), and density matrix renormalization group (DMRG), is presented. Furthermore, fundamental quantum chemistry methods such as Hartree-Fock self-consistent field (HF-SCF) and the complete active space SCF (CASSCF) are also implemented. The Kylin 1.0 program possesses the following features: (1) a matrix product operator (MPO) formulation-based efficient DMRG implementation for describing static electron correlation within a large active space composed of more than 100 orbitals, supporting both and symmetries; (2) an efficient second-order DMRG-self-consistent field (SCF) implementation; (3) an externally contracted multi-reference CI (MRCI) and Epstein-Nesbet PT with DMRG reference wave functions for including the remaining dynamic electron correlation outside the large active spaces. In this paper, we introduce the capabilities and numerical benchmark examples of the Kylin 1.0 program.

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future.

Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody-drug conjugates, peptide/protein-PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody-oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.

Quantum Dot–Organic Molecule Conjugates as Hosts for Photogenerated Spin Qubit Pairs

The inherent spin polarization present in photogenerated spin-correlated radical pairs makes them promising candidates for quantum computing and quantum sensing applications. The spin states of these systems can be probed and manipulated with microwave pulses using electron paramagnetic resonance spectrometers. However, to date, there are no reports on magnetic resonance-based spin measurements of photogenerated spin-correlated radical pairs hosted on quantum dots. In the current work, we prepare dye molecule-inorganic quantum dot conjugates and show that they can produce photogenerated spin-polarized states. The dye molecule, D131, is chosen for its ability to undergo efficient charge separation, and the nanoparticle materials, ZnO quantum dots, are chosen for their promising spin properties. Transient and steady state optical spectroscopy performed on ZnO quantum dot-D131 conjugates shows that reversible photogenerated charge separation is occurring. Transient and pulsed electron paramagnetic resonance experiments are then performed on the photogenerated radical pair, which demonstrate that (1) the radical pair is polarized at moderate temperatures and well modeled by existing theories and (2) the spin states can be accessed and manipulated with microwave pulses. This work opens the door to a new class of promising qubit materials that can be photogenerated in polarized states and hosted by highly tailorable inorganic nanoparticles.

Biobased, Degradable, and Conjugated Poly(Azomethine)s.

Carotenoids are a class of biobased conjugated molecules that bear a resemblance to the substructure of polyacetylene, a well-known conductive but insoluble polymer. Solubility is an important physical attribute for processing materials using different techniques. To impart solubility in polymers, alkyl side chains are often included in the molecular design. While these design strategies are well explored in conjugated systems, they have not been implemented with carotenoids as a building block in polymers. Here, we show a series of carotenoid-based polymers with varying side chain lengths to tune solubility. Using carotenoid and p-phenylenediamine-based monomers, degradable and biobased poly(azomethine)s were synthesized via imine polycondensation. Maximum solubilities corresponding to the varying alkyl chain lengths were quantitatively determined by ultraviolet-visible (UV-vis) absorption spectroscopy. Since carotenoids are biobased with known degradation products, the effect of acidic and artificial sunlight-promoted degradation was systematically investigated using UV-vis spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, gel permeation chromatography (GPC), and high-resolution mass spectroscopy (HRMS). Our polymer system was found to have two modes of on-demand degradation, with acid hydrolysis accelerating the rate of polymer degradation and artificial sunlight generating additional degradation products. This work highlights carotenoid monomers as viable candidates in the design of biobased, degradable, and conjugated polymers.

A trypanosome-derived immunotherapeutics platform elicits potent high-affinity antibodies, negating the effects of the synthetic opioid fentanyl.

Poorly immunogenic small molecules pose challenges for the production of clinically efficacious vaccines and antibodies. To address this, we generate an immunization platform derived from the immunogenic surface coat of the African trypanosome. Through sortase-based conjugation of the target molecules to the variant surface glycoprotein (VSG) of the trypanosome surface coat, we develop VSG-immunogen array by sortase tagging (VAST). VAST elicits antigen-specific memory B cells and antibodies in a murine model after deploying the poorly immunogenic molecule fentanyl as a proof of concept. We also develop a single-cell RNA sequencing (RNA-seq)-based computational method that synergizes with VAST to specifically identify memory B cell-encoded antibodies. All computationally selected antibodies bind to fentanyl with picomolar affinity. Moreover, these antibodies protect mice from fentanyl effects after passive immunization, demonstrating the ability of these two coupled technologies to elicit therapeutic antibodies to challenging immunogens.

Photoexcitation dynamics and energy engineering in supramolecular doping of organic conjugated molecules

Doping and blending strategies are crucial means to precisely control the excited states and energy level in conjugated molecular systems. However, effective models and platforms are rarely proposed to systematically explore the effects of the formation of trapped doped centers on heterogeneous structures, energy level and ultrafast photophysical process. Herein, for deeply understanding the impact of molecular doping in film energy levels and photoexcitation dynamics, we set a supramolecular N-B coordination composed by the conjugated molecules of pyridine functionalized diarylfluorene (host material), named as ODPF-Phpy and ODPF-(Phpy)2, and the molecule of tris(perfluorophenyl)borane (BCF) (guest material). The generation of the molecular-level coordination bond increased the binding energy of N atoms and tuned the band-gap, leading to a new fluorescent emission center with longer excitation wavelength and emission wavelength. The intermolecular Förster resonance energy transfer (FRET) in blending films make it present inconsistent fluorescent behaviors compared to that in solution. The charge transfer (CT) state of N-B coordinated compounds and the changed dielectric constant of blending films resulted in a large PL spectra red-shift with the increased dopant ratio, causing a wide-tunable fluorescent color. The excited state behaviors of two compounds in blending system was further investigated by the transient absorption (TA) spectroscopy. Finally, we found supramolecular coordination blending can effectively improve the films’ photoluminescence quantum yield (PLQY) and conductivity. We believe this exploration in the internal coordination mechanisms would deepen the insights about doped semiconductors and is helpful in developing novel high-efficient fluorescent systems.

An organic semiconductor obtained with a low-temperature process for light-addressable potentiometric sensors

In this study, the first trial of donor and acceptor bulk heterojunctions (BHJs) is proposed for light-addressable potentiometric sensors (LAPSs) due to organic conjugated molecules with the advantages of energy level/band gap modification and high absorption of visible light. The benzodithiophene-based polymer PTB7-Th and fullerene PC71BM are selected for integration with an Al2O3 sensing membrane using atomic layer deposition at temperatures lower than 100 ℃ for pH sensing LAPS. In the stability performance, the hysteresis width of the best condition with a mixing weight ratio of PC71BM to PTB7-Th of 1.5 is 4.4 mV, which is inferior to that of the conventional inorganic semiconductor-based LAPSs. By means of an additional spin-coated zinc oxide (ZnO) layer, the signal-to-noise ratio of the photocurrent of this fabricated LAPS can be maintained at 3.2 after 170 min of measurement with an acceptable sensitivity, linearity, drift coefficient and hysteresis of 50.2 mV/pH, 99.9%, − 3.1 mV/h and 1.4 mV, respectively. With the proper adjustment of illumination with low power and large spots, chemical imaging with a scanning step of 25 µm can be conducted to indicate the feasibility of this low-temperature process developed for spin-coated organic semiconductor-based LAPSs.

Tailored design and preparation of magnetic nanocomposite particles for the isolation of exosomes

Here, we prepared a magnetic nanocomposite system composed of a cluster of magnetite nanoparticles coated with silica shell (MSNPs) with an average diameter of 140 ± 20 nm and conjugated with CD9 antibody (AntiCD9) using different strategies including adsorption or chemical conjugation of antibody molecules to either aminated MSNPs (AMSNPs) or carboxylated MSNPs (CMSNPs). Then, MSNPs were employed to isolate exosomes from ultracentrifuge-enriched solution, PC3 cell-culture medium, or exosome-spiked simulated plasma samples. Quantitative tests using nanoparticle-tracking analysis confirmed antibody-covalently conjugated MSNPs, i.e. the AntiCD9-AMSNPs and AntiCD9-CMSNPs enabled >90% recovery of exosomes. Additionally, the exosomes isolated with AntiCD9-CMSNPs showed higher recovery efficiency compared to the AntiCD9-AMSNPs. For both nanoadsorbents, lower protein impurities amounts were obtained as compared to that of exosomes isolated by ultracentrifugation and Exocib kit. The mean diameter assessment of the isolated exosomes indicates that particles isolated by using AntiCD9-AMSNPs and AntiCD9-CMSNPs have smaller sizes (136 ± 2.64 nm and 113 ± 11.53 nm, respectively) than those obtained by UC-enriched exosomes (140.9 ± 1.6 nm) and Exocib kit (167 ± 10.53 nm). Such promising results obtained in the isolation of exosomes recommend magnetic nanocomposite as an efficient tool for the simple and fast isolation of exosomes for diagnosis applications.

Dual-reactive hydrogels functionalizable using "Huisgen click" and "Schiff base" reactions.

Hydrogels incorporating different reactive groups are important platforms for the fabrication of functional materials through the conjugation of diverse molecules. In this study, a dual-reactive hydrogel system was designed utilizing aldehyde and azide groups containing methacrylate monomers. Hydrogels were obtained in the presence of a dimethacrylate crosslinker with a combination of hydrophilic PEG-based monomers via free-radical polymerization. The azide and aldehyde sites of the hydrogel network are reactive towards alkyne and amine functional groups, respectively. The advantage of the different reactivities of these functional groups was demonstrated through the attachment of two different dye molecules onto the hydrogel platform via the "Huisgen click" and "Schiff base" reactions to obtain a sensing platform for various applications, such as indicating change in pH of the environment.

The electrochemically enabled α-C(sp3)-H azolation of ketones.

C-H/N-H cross-coupling has become a key technology for the selective conjugation of azole drug molecules. However, the development of new synthetic models and green chemical methods is imperative to enhance the construction of multi-functional compounds and compounds with unique functional groups. We herein reported an electrochemical synthesis of α-tetrazolyl ketones with excellent yields and broad substrate scope, encompassing electron-donating and electron-withdrawing groups of aryl ketones, heterocycles, and alkyl and various ketone drugs. It was further proved that α-iodoketone was involved in this transformation of the reaction as a critical intermediate.

A membrane intercalating metal-free conjugated organic photosensitizer for bacterial photodynamic inactivation.

Photodynamic inhibition (PDI) of bacteria represents a powerful strategy for dealing with multidrug-resistant pathogens and infections, as it exhibits minimal development of antibiotic resistance. The PDI action stems from the generation of a triplet state in the photosensitizer (PS), which subsequently transfers energy or electrons to molecular oxygen, resulting in the formation of reactive oxygen species (ROS). These ROS are then able to damage cells, eventually causing bacterial eradication. Enhancing the efficacy of PDI includes the introduction of heavy atoms to augment triplet generation in the PS, as well as membrane intercalation to circumvent the problem of the short lifetime of ROS. However, the former approach can pose safety and environmental concerns, while achieving stable membrane partitioning remains challenging due to the complex outer envelope of bacteria. Here, we introduce a novel PS, consisting of a metal-free donor-acceptor thiophene-based conjugate molecule (BV-1). It presents several advantageous features for achieving effective PDI, namely: (i) it exhibits strong light absorption due to the conjugated donor-acceptor moieties; (ii) it exhibits spontaneous and stable membrane partitioning thanks to its amphiphilicity, accompanied by a strong fluorescence turn-on; (iii) it undergoes metal-free intersystem crossing, which occurs preferentially when the molecule resides in the membrane. All these properties, which we rationalized via optical spectroscopies and calculations, enable the effective eradication of Escherichia coli, with an inhibition concentration that is below that of current state-of-the-art treatments. Our approach holds significant potential for the development of new PS for controlling bacterial infections, particularly those caused by Gram-negative bacteria.

Self-assembled A-D-A type indacenodithiophene-based small conjugated molecule/TiO2 for enhancing the photocatalytic activity.

Herein, A-D-A type indacenodithiophene-based small conjugated molecule IDT-COOH and IDT-COOH/TiO2 photocatalysts with stable non-covalent bonding have been successfully synthesized via in situ electrostatic assembly. The self-assembled three-dimensional π-conjugation structure IDT-COOH with high crystallinity not only broadens the visible absorption to produce more photogenerated carriers but also provides directional charge-transfer channels to accelerate the charge mobility. Thus, 7 log inactivation of S. aureus in 2 h and 92.5% decomposition of TC in 4 h under visible light exposure are achieved for optimized 30% IDT-COOH/TiO2. The dynamic constants (k) of S. aureus disinfection and TC degradation for 30% IDT-COOH/TiO2 are 3.69 and 2.45 times compared to those of self-assembled IDT-COOH, respectively. The notable inactivation performance is among the best reported for conjugated semiconductor/TiO2 photocatalysts for photocatalytic sterilization. ˙O2-, e- and ˙OH are the primary reactive species in the photocatalytic process. The strong interfacial interaction between TiO2 and IDT-COOH is in favour of rapid charge transfer, which leads to enhanced photocatalytic performance. This work offers a feasible method to fabricate TiO2-based photocatalytic agents with a wide visible light response and improved exciton dissociation.

Kinetic analysis of highly effective triplex formation between a small molecule-peptide nucleic acid conjugate probe and the influenza A virus RNA promoter region at neutral pH.

In order to overcome the pH limitations of triplex-forming peptide nucleic acid (PNA) in binding to double-stranded RNA (dsRNA), we have recently proposed a new design of triplex-forming PNA-based fluorogenic probes that work at neutral pH for sensing the panhandle structure of the influenza A virus (IAV) RNA promoter region. Our strategy is based on the conjugation of a small molecule (DPQ) capable of selectively binding to the internal loop structure with the triplex-forming forced intercalation of thiazole orange (tFIT) probe with natural PNA nucleobases. In this work, the triplex formation of tFIT-DPQ conjugate probes with IAV target RNA at neutral pH was examined by means of a stopped-flow technique UV melting and fluorescence titration experiments. The obtained results revealed that (i) the conjugation strategy is responsible for the observed strong binding affinity due to a very fast association rate constant and a slow dissociation rate constant; (ii) the binding follows a pattern of the DPQ unit binding first to the internal loop region, followed by the tFIT unit binding to the complementary dsRNA region. Our results emphasize the importance of both the tFIT and the DPQ components of the conjugate probe design and revealed an association mechanism for the tFIT-DPQ probe-dsRNA triplex formation towards the IAV RNA at neutral pH.

Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of hepatic LDL receptors (LDLRs). Current therapeutic approaches use antibodies that disrupt PCSK9 binding to LDLR to reduce circulating LDL-C concentrations or siRNA that reduces PCSK9 synthesis and thereby levels in circulation. Recent reports describe small molecules that, like therapeutic antibodies, interfere with PCSK9 binding to LDLR. We report an alternative approach to decrease circulating PCSK9 levels by accelerating PCSK9 clearance and degradation using heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding invitro and accelerated PCSK9 clearance invivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation.

Emerging Target-Directed Approaches for the Treatment and Diagnosis of Microbial Infections.

With the rising levels of drug resistance, developing efficient antimicrobial therapies has become a priority. A promising strategy is the conjugation of antibiotics with relevant moieties that can potentiate their activity by target-directing. The conjugation of siderophores with antibiotics allows them to act as Trojan horses by hijacking the microorganisms' highly developed iron transport systems and using them to carry the antibiotic into the cell. Through the analysis of relevant examples of the past decade, this Perspective aims to reveal the potential of siderophore-antibiotic Trojan horses for the treatment of infections and the role of siderophores in diagnostic techniques. Other conjugated molecules will be the subject of discussion, namely those involving vitamin B12, carbohydrates, and amino acids, as well as conjugated compounds targeting protein degradation and β-lactamase activated prodrugs.

Surface modifying MIL-125(Ti) by devisable poly(amino) conjugate molecule to significantly enhance its visible light photo-degradation properties

A novel core/shell nanocomposite was successfully synthesized through surface coating MIL-125(Ti) with a poly(amino) conjugate molecule (4′,4‴,4⁗′,4⁗‴-(ethene-1,1,2,2-tetrayl)tetrakis([1,1′-biphenyl]-4-amine)) by the facile one-step solvothermal method for improving the photocatalytic properties under visible light. The nanocomposite was detailed characterized through TEM, SEM, XRD, FT-IR, BET, EDS and XPS. Photoelectrochemical characterizations showed that the nanocomposites exhibited lower band gap as well as excellent migration and separation efficiency of photo-generated charges compared with the original MIL-125(Ti). The optimized nanocomposite (TNMT-2) exhibited an excellent photo-degradation effect for a representative organic contaminant tetracycline hydrochloride and the total tetracycline hydrochloride removal efficiency can reach 96.5 % under visible light illumination, and higher removal efficiency was received in practical water treatment. In addition, TNMT-2 nanocomposite showed great reusability, stability, and applicability. Furthermore, the photo-degradation mechanism and the photo-degradation pathways of tetracycline hydrochloride were investigated. The relationship between the photocatalytic properties of the nanocomposite and the structure of the organic molecular were explored, and electron-donating groups as well as large π–π conjugate structure were the two most important factors. This study indicates that by designing the molecular structures, the photocatalytic properties of Ti-based MOFs can be easily regulated and TNMT-2 nanocomposite is an effective visible light catalyst for organic pollutants with great applicable potential.

Doxorubicin-isoniazid conjugate regulates immune response and tumor microenvironment to enhance cancer therapy

Immune checkpoint inhibitors (ICIs) represent a new class of immunotherapy drugs, and are used to relieve immune suppression or enhance the immune response through the blockade of checkpoint ligands or receptors. ICIs have achieved great success in clinical cancer treatment. Monoamine oxidase A (MAOA) is a potent immune checkpoint of immunotherapy. Recently, it has been reported that MAOA inhibitors could enhance CD8+ T cell activity by upregulating 5-HT autocrine pathway in T cells. In this study, we synthesized doxorubicin (DOX) and isoniazid (INH, a MAOA inhibitor) conjugates through a pH sensitive hydrazone bond. Results of the in vivo studies showed that DOX-INH could effectively enhance the activity of CD8+ T cells and perform a synergistic anti-tumor effect with PD-L1 small molecular inhibitor (BMS202). In addition, in an orthotopic 4T1 breast cancer model, it was demonstrated that DOX-INH could inhibit the epithelial-mesenchymal transition process by blocking Shh, IL-6, and TGF-β signaling pathways, thereby inhibiting the growth and metastasis of breast cancer. Thus, a simple and effective small molecule conjugate produced by the combination of a chemotherapy drug and a MAOA inhibitor shows broad prospect in cancer therapy.

Environmentally affable and highly efficient donor material based on cyclopentadithiophene (CPDT) framework for remarkable organic solar cells

The quantum chemical exploration of highly conjugated D-π-A type molecules based on cyclopentadithiophene (CPDT) core is anticipated to recommend novel organic materials for efficient organic solar cells (OSCs). Five new conjugated molecules (C1–C5) were designed by drafting of reference CR through thiophene bridged end caped acceptors and their geometric, as well as optoelectronic properties, were investigated at MPW1PW91/6-31G (d,p) functional. All the newly tailored chromophores (C1–C5) proclaimed lower energy gap values (ranging from 1.95 to 2.19 eV) than the reference CR (3.18 eV). TD-DFT calculations of all the newly designed molecules revealed higher λmax in the range 500–514 nm than the reference CR (483.2 nm) in dichloromethane solvent. Lower excitation energies (1.79–1.94 eV) and higher dipole moment (4.84–18.37 D) for all the drafted compounds (C1–C5) than reference CR were observed which proclaimed efficient charge transfer. Simulations of global reactivity parameters like hardness, chemical potential, softness and electrophilicity manifested all these molecules (C1–C5) to be reactive and thermally stable. The small values of reorganization energies for electron and hole exhibited high electron-hole mobilities and low charge recombination. The power conversion efficiency (PCE) parameters were simulated by scaling the HOMO of designed molecules acting as a donor with LUMO of PC61BM acceptor. All the designed molecules (C1–C5) demonstrated high open circuit voltage (0.67–0.92 V) than the reference (0.49 V) which is favorable for enhancement of PCE. Also, the higher values of fill factor (FF) ranging from 0.8417 to 0.8677 for newly designed chromophores increased the PCE than reference CR (0.8015). The results demonstrated the suitability of these donor molecules designed by deliberated technique, opening a new path for the development of donor's contributors to OSCs and may prove efficient materials for fabrication of future OSCs.

Effective cell penetration of negatively‐charged proline‐rich SAP(E) peptides with cysteine mutation

AbstractMost of cell penetrating peptides (CPPs) are rich in positively‐charged amino acids but the cationic property may provoke possible problems in practical applications. In this study, we carefully substituted the hydrophobic amino acids in the SAP(E) sequence, a rare example of negatively‐charged proline‐rich CPP, with cysteine for enhancement of cell penetrating activity as well as reversible conjugation of cargo molecules. Most substituents showed almost negligible cell penetrating activity, but a cysteine substituent on the 7th valine (SAP(E)‐7C) showed more improved cell penetrating activity than SAP(E). When treated to cells, the negatively‐charged SAP(E)‐7C exhibited much lower degree of co‐localization with acidic endosomes or lysosomes compared to positively‐charged TAT. SAP(E)‐7C could significantly enhance the PTX efficacy on MDA‐MB‐231 cells by non‐covalent complexation with PTX. As a proof‐of‐concept for covalent conjugation of cargo drugs, mercaptoethanol, a model drug, was conjugated to the cysteine residue of SAP(E)‐7C via a disulfide bond, and the glutathione‐dependent release from the conjugate was confirmed. The negatively‐charged SAP(E)‐7C with a cysteine handle can be a useful molecular module for the development of CPP‐based drug delivery carrier.