Nucleus-targeted Drug Delivery Research Articles

Adaptive Size Evolution of an MOFs-in-MOF Nanovehicle for Enhanced Nucleus-Targeted Tumor Chemotherapy.

A metal-organic frameworks (MOFs)-in-MOF nanovehicle (160 nm), which was constructed with newly prepared ultrasmall Cu(I)Cu(II)-BTC MOFs (UCMs, 2.95 nm) loaded with doxorubicin (DOX) and a nuclear localization signal (NLS) peptide as multicores (UCMDNs) and ZIF-8 as the shell MOF, was proposed to cross layers of biological barriers with adaptive size evolution capacity for achieving efficient nucleus-targeted drug delivery. It first enhanced tumor tissue penetration through its larger nanosize effect. Then the acidic tumor environment made the ZIF-8 shell degrade, releasing small-sized UCMDNs to enter into the cell and into the nucleus under the guidance of NLS. Furthermore, due to the distinct surface structural characteristics of UCMs, UCMDNs remained stable in the cytoplasm and collapsed in the nucleus due to the DOX-DNA interaction to deliver DOX precisely. It showed superior performance in the nucleus-directed delivery of DOX (delivery efficiency up to 56.7%) and a high tumor growth inhibition rate (96.4%), offering promising prospects in tumor chemotherapy.

Design of red-emitting 1D zinc coordination polymer for targeted drug delivery to nucleus

Cell nucleus is considered as the ultimate target for various therapeutic agents in numerous disease treatments. Nucleus-targeted drug delivery systems are more effective in cancer chemotherapy, as over 75% of the commonly used chemotherapeutic drugs in clinic are acting on cell nucleus. Herein a novel 1D semiconducting zinc coordination polymer (Zn-QCDM) was designed with a reduced bandgap of 1.91 eV and bright red fluorescence. Because of the strong π-π stacking and Zn-O coordination with unpaired bases on RNA, the Zn-QCDM shows selective targeting of nucleoli with the selectivity over 40%. After loading camptothecin (CPT), a typical chemotherapeutic drug, the Zn-QCDM can effectively deliver the drug to nucleus, thereby significantly enhances the therapeutic effect. The inhibition rate of the Zn-QCDM loaded with CPT reaches 74% in mouse breast 4T1 tumor treatments, which is 29% higher than that of pristine CPT. This progress provides a paradigm in design of structure-precise drug carrier with clear targeting property as well as mechanism interpretation.

Nuclear Delivery of Nanoparticle-Based Drug Delivery Systems by Nuclear Localization Signals.

Nanomedicine 2.0 refers to the next generation of nanotechnology-based medical therapies and diagnostic tools. This field focuses on the development of more sophisticated and precise nanoparticles (NPs) for targeted drug delivery, imaging, and sensing. It has been established that the nuclear delivery of NP-loaded drugs can increase their therapeutic efficacy. To effectively direct the NPs to the nucleus, the attachment of nuclear localization signals (NLSs) to NPs has been employed in many applications. In this review, we will provide an overview of the structure of nuclear pore complexes (NPCs) and the classic nuclear import mechanism. Additionally, we will explore various nanoparticles, including their synthesis, functionalization, drug loading and release mechanisms, nuclear targeting strategies, and potential applications. Finally, we will highlight the challenges associated with developing nucleus-targeted nanoparticle-based drug delivery systems (NDDSs) and provide insights into the future of NDDSs.

Research progress in nucleus-targeted tumor therapy.

The nucleus is considered the most important organelle in the cell as it plays a central role in controlling cell reproduction, metabolism, and the cell cycle. The successful delivery of drugs into the nucleus can achieve excellent therapeutic effects, which reveals the potential of nucleus-targeted therapy in precision medicine. However, the transportation of therapeutics into the nucleus remains a significant challenge due to various biological barriers. Herein, we summarize the recent progress in the nucleus-targeted drug delivery system (NDDS). The structures of the nucleus and nuclear envelope are first described in order to understand the mechanisms by which drugs cross the nuclear envelope. Then, various drug delivery strategies based on the mechanisms and their applications are discussed. Finally, the challenges and solutions in the field of nucleus-targeted drug delivery are raised for developing a more efficient NDDS and promoting its clinical transformation.

Adhesive AuNP tape-mediated hierarchical assembly of multicenter DNA nanocomplexes for tumor cell nucleus-targeted staged drug delivery in vivo

Developing DNA nanostructures as delivery vectors into organelles is a key technical barrier because of their innate poor pharmacokinetic properties. Herein, we propose a unique concept for high precision cancer therapy by using small gold nanoparticles (AuNPs) as adhesive nano-tapes to fold a long string of aptamer-attached tetrahedral DNA pearls (Apt-Nano-Tetra) into a spherical multicenter DNA nanostructure that can serve as a nucleus-targeted drug delivery carrier (Apt-ADMC) with a 75～85 times enhanced doxorubicin (Dox)-loading capacity. After specifically entering target tumor cells, Dox-Apt-ADMC is disassembled into individual AuNPs surrounded by short Apt-Nano-Tetra, finally reaching cell nucleus and causing cell apoptosis. Even if Dox-Apt-ADMC is treated with fetal bovine serum for 12 h, the drug delivery ability is not compromised, contributing to high functional stability in circulation system. As such, the systemically-administrated Dox-Apt-ADMC shows 7 times enhanced tumor accumulation and almost 100% inhibits tumor growth without detectable systemic toxicity.

Multifunctional nanoplatforms as cascade-responsive drug-delivery carriers for effective synergistic chemo-photodynamic cancer treatment

Synergistic chemo-photodynamic therapy has garnered attention in the field of cancer treatment. Here, a pH cascade-responsive micellar nanoplatform with nucleus-targeted ability, for effective synergistic chemo-photodynamic cancer treatment, was fabricated. In this micellar nanoplatform, 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin (Por), a photodynamic therapy (PDT) agent was utilized for carrying the novel anticancer drug GNA002 to construct a hydrophobic core, and cyclic RGD peptide (cRGD)-modified polyethylene glycol (PEG) (cRGD-PEG) connected the cell-penetrating peptide hexaarginine (R6) through a pH-responsive hydrazone bond (cRGD-PEG-N = CH-R6) to serve as a hydrophilic shell for increasing blood circulation time. After passively accumulating in tumor sites, the self-assembled GNA002-loaded nanoparticles were actively internalized into cancer cells via the cRGD ligands. Once phagocytosed by lysosomes, the acidity-triggered detachment of the cRGD-PEG shell led to the formation of R6-coated secondary nanoparticles and subsequent R6-mediated nucleus-targeted drug delivery. Combined with GNA002-induced nucleus-specific chemotherapy, reactive oxygen species produced by Por under 532-nm laser irradiation achieved a potent synergistic chemo-photodynamic cancer treatment. Moreover, our in vitro and in vivo anticancer investigations revealed high cancer-suppression efficacy of this ideal multifunctional nanoplatform, indicating that it could be a promising candidate for synergistic anticancer therapy.

Nucleic Acid Aptamers as a Potential Nucleus Targeted Drug Delivery System.

Nucleus targeted drug delivery provides several opportunities for the treatment of fatal diseases such as cancer. However, the complex nucleocytoplasmic barriers pose significant challenges for delivering a drug directly and efficiently into the nucleus. Aptamers representing singlestranded DNA and RNA qualify as next-generation highly advanced and personalized medicinal agents that successfully inhibit the expression of certain proteins; possess extraordinary gene-expression for manoeuvring the diseased cell's fate with negligible toxicity. In addition, the precisely directed aptamers to the site of action present a tremendous potential to reach the nucleus by escaping the ensuing barriers to exhibit a better drug activity and gene expression. This review epigrammatically highlights the significance of targeted drug delivery and presents a comprehensive description of the principal barriers faced by the nucleus targeted drug delivery paradigm and ensuing complexities thereof. Eventually, the progress of nucleus targeting with nucleic acid aptamers and success achieved so far have also been reviewed. Systematic literature search was conducted of research published to date in the field of nucleic acid aptamers. The review specifically points out the contribution of individual aptamers as the nucleustargeting agent rather than aptamers in conjugated form.

Direct Nucleus-Targeted Drug Delivery Using Cascade pHe /Photo Dual-Sensitive Polymeric Nanocarrier for Cancer Therapy.

The cell nucleus-targeted delivery of therapeutic agents plays a critical role in cancer therapy, since the biological target of many anticancer therapeutics is the cell nucleus. However, multiple physiological barriers limit the delivery efficiency of free drugs, resulting in unsatisfactory therapeutic effects. Herein, thioketal crosslinked polyphosphoester-based nanoparticles with a tumor acidity (pHe )-sensitive transactivator of transcription (TAT) peptide (DA-masked TAT-decorating reactive oxygen species (ROS)-sensitive Ce6/DOX-loaded hyperbranched nanoparticles (D TRCD)) are explored for cascade nucleus-targeted drug delivery. Following administration, D TRCD experiences prolonged circulation by masking the targeting effect of its TAT peptide and then achieves enhanced tumor cell uptake and improved translocation into the perinuclear region by reactivating the TAT targeting capability in tumor tissue. Subsequently, ROS generated by D TRCD under 660 nm laser not only disrupts the nuclear membrane to allow entry into the nuclei but also triggers intracellular release of the payload in the nuclei. As evidenced by in vivo experiments, such pHe /photo dual-sensitive polymeric nanocarriers offer remarkable therapeutic effects, efficiently suppressing tumor growth. This multistage cascade nucleus-targeted drug delivery concept provides new avenues to develop nucleus-targeted drug delivery systems.

Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy

Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy.

Fluorescent Carbon Quantum Dots with Intrinsic Nucleolus-Targeting Capability for Nucleolus Imaging and Enhanced Cytosolic and Nuclear Drug Delivery.

Nucleolus tracking and nucleus-targeted photodynamic therapy are attracting increasing attention due to the importance of nucleolus and the sensitivity of nucleus to various therapeutic stimuli. Herein, a new class of multifunctional fluorescent carbon quantum dots (or carbon dots, CDs) synthesized via the one-pot hydrothermal reaction of m-phenylenediamine and l-cysteine was reported to effectively target nucleolus. The as-prepared CDs possess superior properties, such as low-cost and facile synthesis, good water dispersibility, various surface groups for further modifications, prominent photostability, excellent compatibility, and rapid/convenient/wash-free staining procedures. Besides, as compared with SYTO RNASelect (a commonly used commercial dye for nucleolus imaging) that can only image nucleolus in fixed cells, the CDs can realize high-quality nucleolus imaging in not only fixed cells but also living cells, allowing the real-time tracking of nucleolus-related biological behaviors. Furthermore, after conjugating with protoporphyrin IX (PpIX), a commonly used photosensitizer, the resultant CD-PpIX nanomissiles showed remarkably increased cellular uptake and nucleus-targeting properties and achieved greatly enhanced phototherapeutic efficiency because the nuclei show poor tolerance to reactive oxygen species produced during the photodynamic therapy. The in vivo experiments revealed that the negatively charged CD-PpIX nanomissiles could rapidly and specifically target a tumor site after intravenous injection and cause efficient tumor ablation with no toxic side effects after laser irradiation. It is believed that the present CD-based nanosystem will hold great potential in nucleolus imaging and nucleus-targeted drug delivery and cancer therapy.

Caged Molecular Glues as Photoactivatable Tags for Nuclear Translocation of Guests in Living Cells.

We developed dendritic caged molecular glues (CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple guanidinium ion (Gu+) pendants are protected by an anionic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Negatively charged CagedGlue-R hardly binds to anionic biomolecules because of their electrostatic repulsion. However, upon exposure of CagedGlue-R to UV light or near-infrared (NIR) light, the BANVOC groups of CagedGlue-R are rapidly detached to yield an uncaged molecular glue (UncagedGlue-R) that carries multiple Gu+ pendants. Because Gu+ forms a salt bridge with PO4-, UncagedGlue-R tightly adheres to anionic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formation. When tagged with CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the CagedGlue-R tag is photochemically uncaged to form UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiation with light.

Facilely synthesized pH-responsive fluorescent polymer dots entrapping doped and coupled doxorubicin for nucleus-targeted chemotherapy

Doxorubicin (Dox) functionalization methods can affect the Dox loading efficiency and release capability in nanosized drug delivery systems. Herein, different Dox-functionalized (doping, coupling, and doping and coupling) fluorescent poly(9,9-dioctylfluorene-alt-benzothiadiazole) (PFBT) polymer dots were designed and their application performance was evaluated. Polyethylene glycol-modified doxorubicin (PEG-Dox) was synthesized using a responsive hydrazone linker. PEG-DOX-doped polymer dots were self-assembled using a co-precipitation method and free PEG-Dox was further coupled on the surface of the polymer dots via an EDC-NHS coupling to prepare the PEG-Dox doped and coupled PFBT polymer dots. The hydrazone linker of PEG-Dox is responsive to the acidic environment, resulting in the doped Dox being released into the cell nucleus and the coupled Dox changes the structure of the polymer dots and accelerates the release of the doped Dox. Moreover, the coupled Dox linked via an amide bond was still on the surface of the polymer dots and retained their cytoplasmic toxicity for a synergistic effect. A high Dox carrying efficiency (weight of the loaded Dox/weight of PFBT) was achieved using the PEG-Dox doped and coupled PFBT polymer dots: 107% and 82% of Dox was released in vitro within 24 h at pH 5.5. The cytotoxicity and cell imaging were investigated in three cancer cell lines: cervical cancer cells (HeLa), lung cancer cells (NCI-H292), and glioma cells (U87-MG); the results indicate that the PEG-Dox doped and coupled PFBT polymer dots show a distinct killing efficacy and nucleus targeted capability. Moreover, in vivo tumor suppression was observed in lung tumor-bearing mice over 20 days and no weight loss and damage or inflammation of the major organs were detected using the PEG-Dox doped and coupled PFBT polymer dots.

Preparation and characterization of novel chitosan-protamine nanoparticles for nucleus-targeted anticancer drug delivery.

It is well known that most anticancer drugs commonly show high toxicity to the DNA of tumor cells and exert effects by combining with the DNA or associated enzymes in the nucleus. Most developed drugs are first delivered into the cytoplasm and then transferred to the nucleus through the membrane pores. Sometimes, the transportation of drugs from cytoplasm to nucleus is not efficient and often results in poor therapeutic effects. In this study, we developed special and novel nanoparticles (NPs) made of chitosan and protamine for targeted nuclear capture of drugs to enhance anticancer effects. The anticancer effects of nuclear targeted-delivery of drugs in NPs were also evaluated by investigating cytotoxicity, cellular uptake mechanism, and cell apoptosis on cells. Chitosan–protamine NPs were characterized by good drug entrapment, sustained release, small average particle size, low polydispersity index, and high encapsulation efficiency; and accomplished the efficient nuclear delivery of fluorouracil (5-Fu). Compared with free 5-Fu and 5-Fu-loaded chitosan NPs, treatment of A549 cells and HeLa cells with 5-Fu-loaded chitosan–protamine NPs showed the highest cytotoxicity and further induced the significant apoptosis of cells. In addition, 5-Fu-loaded chitosan–protamine NPs exhibited the best efficiency in inhibiting tumor growth than the other three formulations. 5-Fu-loaded chitosan–protamine NPs enhanced antitumor efficacy through the targeted nuclear capture of drugs and showed promising potential as a nanodelivery system for quickly locating drugs in the nucleus of cells.

PH-activated size reduction of large compound nanoparticles for in vivo nucleus-targeted drug delivery

Nucleus-targeted drug delivery is a promising strategy for anticancer therapy, but in vivo nucleus-targeted drug delivery has been challenging. Limited by the channel size of the nucleopore, vehicles that enter the nucleus via the nucleopore actively should be small and decorated with nuclear localization signal (NLS). However, the small vehicle size may promote leakage of vehicles into normal tissues, and the positively-charged NLS can lead to strong non-specific interactions in vivo. In the present study, we demonstrate an in vivo nucleus-targeted drug delivery using large compound nanoparticles with detachable PEG shell. The nanoparticles are composed of PEG-benzoic imine-oligo-l-lysine/iridium(III) metallodrug complex and formed in a kinetically-controlled fashion. Under physiological conditions (pH 7.4), the nanoparticles are large (ca. 150 nm) and protected by an inert PEG shell. When internalized into intracellular acidic endo/lysosomes of cancer cells, the nanoparticles dissociate into smaller ones (ca. 40 nm) and the PEG chains detach due to the cleavage of the benzoic imine bond at low pH. The small nanoparticles, with exposure of the oligo-l-lysine after the detachment of the PEG shield, then translocate into the nucleus via the nucleopore due to the small size and nuclear localization ability of the oligo-l-lysine. Importantly, the small particles could significantly release the contained drug into the nucleus, leading to ca. 20-fold higher cytotoxicity compared to the native drug in vitro. Further in vivo application of the nucleus-targeting nano-system in a nude-mice model showed significant tumor inhibition and remarkable life-span elongation.

A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery

Tumor cell nucleus-targeted delivery of antitumor agents is of great interest in cancer therapy, since the nucleus is one of the most frequent targets of drug action. Here we report a smart polymeric conjugate platform, which utilizes stimulus-responsive strategies to achieve multistage nuclear drug delivery upon systemic administration. The conjugates composed of a backbone based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer and detachable nucleus transport sub-units that sensitive to lysosomal enzyme. The sub-units possess a biforked structure with one end conjugated with the model drug, H1 peptide, and the other end conjugated with a novel pH-responsive targeting peptide (R8NLS) that combining the strength of cell penetrating peptide and nuclear localization sequence. The conjugates exhibited prolonged circulation time and excellent tumor homing ability. And the activation of R8NLS in acidic tumor microenvironment facilitated tissue penetration and cellular internalization. Once internalized into the cell, the sub-units were unleashed for nuclear transport through nuclear pore complex. The unique features resulted in 50-fold increase of nuclear drug accumulation relative to the original polymer–drug conjugates in vitro, and excellent in vivo nuclear drug delivery efficiency. Our report provides a strategy in systemic nuclear drug delivery by combining the microenvironment-responsive structure and detachable sub-units.

Multifunctional Nanoprobes for Cancer Cell Targeting, Imaging and Anticancer Drug Delivery

The diagnosis and treatment of cancer have been greatly improved with recent developments in bio-nanotechnology, including engineering of multifunctional probes. One of the promising nanoscale tools for cancer imaging is fluorescent quantum dots (QDs), whose small size and unique optical properties allow them to penetrate into cells and ensure highly sensitive optical diagnosis of cancer at the cellular level. Furthermore, novel multi-functional probes have been developed in which QDs are conjugated with one or several functional molecules, including targeting moieties and therapeutic agents. Here, the strategy for engineering novel nanocarriers for controlled nucleus-targeted antitumor drug delivery and real-time imaging by single- or two-photon microscopy is described. A triple multifunctional nanoprobe is being developed that consists of a nitrogen-based heterocyclic derivative, an anticancer agent interacting with a DNA in living cells; a recognized molecule serving as a vector responsible for targeted delivery of the probe into cancer cells; and photoluminescent QDs providing the imaging capability of the probe. Subsequent optimization of the multifunctional nanoprobe will offer new possibilities for cancer diagnosis and treatment.

Nucleus-Targeted Drug Delivery: Theoretical Optimization of Nanoparticles Decoration for Enhanced Intracellular Active Transport

A rational design for a nanoparticle is suggested, which will maximize its arrival efficiency from the plasma membrane to the nuclear surrounding. The design is based on grafting the particle surface with polymer spacers, each ending with a motor protein associating molecule, for example, nuclear localization signal peptide. It is theoretically shown that the spacer polymer molecular weight can be adjusted to significantly increase the effective particle processivity time. This should lead to appreciable enhancement of active transport of the nanocarrier, and consequently drug delivery, to the nucleus.

Enzyme‐Responsive Cell‐Penetrating Peptide Conjugated Mesoporous Silica Quantum Dot Nanocarriers for Controlled Release of Nucleus‐Targeted Drug Molecules and Real‐Time Intracellular Fluorescence Imaging of Tumor Cells

Here, a set of novel and personalized nanocarriers are presented for controlled nucleus-targeted antitumor drug delivery and real-time imaging of intracellular drug molecule trafficking by integrating an enzyme activatable cell penetrating peptide (CPP) with mesoporous silica coated quantum dots nanoparticles. Upon loading of antitumor drug, doxorubicin (DOX) and further exposure to proteases in tumor cell environment, the enzymatic cleavage of peptide sequence activates oligocationic TAT residues on the QDs@mSiO2 surface and direct the DOX delivery into cellular nucleus. The systematic cell imaging and cytotoxicity studies confirm that the enzyme responsive DOX-loaded CPP-QDs@mSiO2 nanoparticles can selectively release DOX in the tumor cells with high cathepsin B enzyme expression and greatly facilitate DOX accumulation in targeted nucleus, thus exhibiting enhanced antitumor activity in these cells. As contrast, there is limited nuclear-targeted drug accumulation and lower tumor cytotoxicity observed in the cells without enzyme expression. More importantly, significant antitumor DOX accumulation and higher tumor inactivation is also found in the drug resistant tumor cells with targeted enzyme expression. Such simple and specific enzyme responsive mesoporous silica-QDs nanoconjugates provide great promise for rational design of targeted drug delivery into biological system, and may thus greatly facilitate the medical theranostics in the near future.