Dual‐pH Sensitive Charge‐Reversal Polypeptide Micelles for Tumor‐Triggered Targeting Uptake and Nuclear Drug Delivery

A novel dual‐pH sensitive charge‐reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(l ‐lysine)‐block–poly(l ‐leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3‐dimethylmaleic anhydride to form β‐carboxylic amide, making the polypeptides self‐assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell‐penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH‐sensitive β‐carboxylic amides.     

Bioinspired Diselenide‐Bridged Mesoporous Silica Nanoparticles for Dual‐Responsive Protein Delivery

Controlled delivery of protein therapeutics remains a challenge. Here, the inclusion of diselenide‐bond‐containing organosilica moieties into the framework of silica to fabricate biodegradable mesoporous silica nanoparticles (MSNs) with oxidative and redox dual‐responsiveness is reported. These diselenide‐bridged MSNs can encapsulate cytotoxic RNase A into the 8–10 nm internal pores via electrostatic interaction and release the payload via a matrix‐degradation controlled mechanism upon exposure to oxidative or redox conditions. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase A‐loaded MSNs exhibit homologous targeting and immune‐invasion characteristics inherited from the source cancer cells. The efficient in vitro and in vivo anti‐cancer performance, which includes increased blood circulation time and enhanced tumor accumulation along with low toxicity, suggests that these cell‐membrane‐coated, dual‐responsive degradable MSNs represent a promising platform for the delivery of bio‐macromolecules such as protein and nucleic acid therapeutics.     

Multifunctional Mesoporous Silica Nanoparticles with Thermal‐Responsive Gatekeeper for NIR Light‐Triggered Chemo/Photothermal‐Therapy

In this work, a matrix metalloproteinase (MMP)‐triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near‐infrared (NIR) photothermal‐responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal‐cleavable gatekeeper (Azo‐CD), which can be decapped by ICG‐generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host–guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor‐triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.     

Mesoporous Silica Nanoparticles for Intracellular Controlled Drug Delivery

The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of inorganic‐based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous‐silica‐based nanocarriers with stimuli‐responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site‐specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli‐responsive mesoporous‐silica‐based systems are described.     

ROS‐Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy

The application of nanoparticles (NPs) to drug delivery has led to the development of novel nanotherapeutics for the treatment of various diseases including cancer. However, clinical use of NP‐mediated drug delivery has not always translated into improved survival of cancer patients, in part due to the suboptimal properties of NP platforms, such as premature drug leakage during preparation, storage, or blood circulation, lack of active targeting to tumor tissue and cells, and poor tissue penetration. Herein, an innovative reactive oxygen species (ROS)‐responsive polyprodrug is reported that can self‐assemble into stable NPs with high drug loading. This new NP platform is composed of the following key components: (i) polyprodrug inner core that can respond to ROS for triggered release of intact therapeutic molecules, (ii) polyethylene glycol (PEG) outer shell to prolong blood circulation; and (iii) surface‐encoded internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration. These targeted ROS‐responsive polyprodrug NPs show significant inhibition of tumor cell growth both in vitro and in vivo.     

Smart Nanovehicles Based on pH‐Triggered Disassembly of Supramolecular Peptide‐Amphiphiles for Efficient Intracellular Drug Delivery

A novel type of nanovehicle (NV) based on stimuli‐responsive supramolecular peptide‐amphiphiles (SPAs, dendritic poly (L‐lysine) non‐covalently linked poly (L‐leucine)) is developed for intracellular drug delivery. To determine the pH‐dependent mechanism, the supramolecular peptide‐amphiphile system (SPAS) is investigated at different pH conditions using a variety of physical and chemical approaches. The pH‐triggered disassembly of SPAS can be attributed to the disappearance of non‐covalent interactions within SPAs around the isoelectric point of poly (L‐leucine). SPAS is found to encapsulate guest molecules at pH 7.4 but release them at pH 6.2. In this way, SPAS is able to act as a smart NV to deliver its target to tumor cells using intracellular pH as a trigger. The DOX‐loaded NVs are approximately 150 nm in size. In vitro release profiles and confocal laser scanning microscopy (CLSM) images of HepG2 cells confirm that lower pH conditions can trigger the disassembly of NVs and so achieve pH‐dependent intracellular DOX delivery. In vitro cytotoxicity of the DOX‐loaded NVs to HepG2 cells demonstrate that the smart NVs enhance the efficacy of hydrophobic DOX. Fluorescence‐activated cell sorting (FACS) and CLSM results show that the NVs can enhance the endocytosis of DOX into HepG2 cells considerably and deliver DOX to the nuclei.     

Multitriggered Tumor‐Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation

Tumor‐responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein‐based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross‐linking and surface polyethylene glycol coupling, can be used as versatile tumor‐responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6‐encapsulated nanospheres (Ce6‐Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6‐Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6‐Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6‐Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6‐Ns and the biocompatibility of Ce6‐Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles.     

Combinatorial Drug Conjugation Enables Nanoparticle Dual‐Drug Delivery

A new approach to loading multiple drugs onto the same drug‐delivery nanocarrier in a precisely controllable manner, by covalently preconjugating multiple therapeutic agents through hydrolyzable linkers to form drug conjugates, is reported. In contrast to loading individual types of drugs separately, this drug‐conjugates strategy enables the loading of multiple drugs onto the same carrier with a predefined stoichiometric ratio. The cleavable linkers allow the therapeutic activity of the individual drugs to be resumed after the drug conjugates are delivered into the target cells and unloaded from the delivery vehicle. As a proof of concept, the synthesis and characterization of paclitaxel–gemcitabine conjugates are demonstrated. The time‐dependent hydrolysis kinetics and cytotoxicity of the combinatorial drug conjugates against human pancreatic cancer cells are examined. It is shown that the synthesized drug conjugates can be readily encapsulated into a lipid‐coated polymeric drug‐delivery nanoparticle, which significantly improves the cytotoxicity of the drug conjugates as compared to the free drug conjugates.     

Redox‐Triggered Gatekeeper‐Enveloped Starlike Hollow Silica Nanoparticles for Intelligent Delivery Systems

The design and development of multifunctional carriers for drug delivery based on hollow nanoparticles (HNPs) have attracted intense interests. Ordinary spherical HNPs are demonstrated to be promising candidates. However, the application of HNPs with special morphologies has rarely been reported. HNPs with sharp horns are expected to own higher endocytosis efficiencies than spherical counterparts. In this work, novel starlike hollow silica nanoparticles (SHNPs) with different sizes are proposed as platforms for the fabrication of redox‐triggered multifunctional systems for synergy of gene therapy and chemotherapy. The CD‐PGEA gene vectors (consisting of β‐CD cores and ethanolamine‐functionalized poly(glycidyl methacrylate) (denoted BUCT‐PGEA) arms) are introduced ingeniously onto the surfaces of SHNPs with plentiful disulfide bond‐linked adamantine guests. The resulting supramolecular assemblies (SHNP‐PGEAs) possess redox‐responsive gatekeepers for loaded drugs in the cavities of SHNPs. Meanwhile, they also demonstrate excellent performances to deliver genes. The gene transfection efficiencies, controlled drug release behaviors, and synergistic antitumor effect of hollow silica‐based carriers with different morphologies are investigated in detail. Compared with ordinary spherical HNP‐based counterparts, SHNP‐PGEA carriers with six sharp horns are proven to be superior gene vectors and possess better efficacy for cellular uptake and antitumor effects. The present multifunctional carriers based on SHNPs will have promising applications in drug/gene codelivery and cancer treatment.     

Remote Light‐Responsive Nanocarriers for Controlled Drug Delivery: Advances and Perspectives

Engineering of smart photoactivated nanomaterials for targeted drug delivery systems (DDS) has recently attracted considerable research interest as light enables precise and accurate controlled release of drug molecules in specific diseased cells and/or tissues in a highly spatial and temporal manner. In general, the development of appropriate light‐triggered DDS relies on processes of photolysis, photoisomerization, photo‐cross‐linking/un‐cross‐linking, and photoreduction, which are normally sensitive to ultraviolet (UV) or visible (Vis) light irradiation. Considering the issues of poor tissue penetration and high phototoxicity of these high‐energy photons of UV/Vis light, recently nanocarriers have been developed based on light‐response to low‐energy photon irradiation, in particular for the light wavelengths located in the near infrared (NIR) range. NIR light‐triggered drug release systems are normally achieved by using two‐photon absorption and photon upconversion processes. Herein, recent advances of light‐responsive nanoplatforms for controlled drug release are reviewed, covering the mechanism of light responsive small molecules and polymers, UV and Vis light responsive nanocarriers, and NIR light responsive nanocarriers. NIR‐light triggered drug delivery by two‐photon excitation and upconversion luminescence strategies is also included. In addition, the challenges and future perspectives for the development of light triggered DDS are highlighted.     

ATP/pH Dual Responsive Nanoparticle with d‐[des‐Arg10]Kallidin Mediated Efficient In Vivo Targeting Drug Delivery

Inflammation has been reported as one significant hallmark of breast cancer in relation to tumor development, metastasis, and invasion. The bradykinin receptor 1 (B1R) is highly expressed on inflammatory breast tumor cells thus providing a promising targeting site for tumor recognition and sufficient receptor mediated endocytosis. In this study, the authors evaluate the targeting efficiency of l ‐form and d ‐form [des‐Arg¹⁰]kallidin both in vitro and in vivo. To further improve the drug delivery efficiency, the authors establish a dandelion like nanoparticle by combining the polymeric drug conjugates and aptamer complex together. The doxorubicin conjugated polymer is complexed with adenosine‐5′‐triphosphate (ATP) sensitive hybridized aptamer in self‐assembly process by intercalating into the double strand scaffolds. The acid labile conjugating bond and ATP sensitive aptamer endow the nanoparticle with dual responsiveness to intracellular milieu, thus triggering a quick drug release in tumor cells. Remarkable therapeutic effects and tuned in vivo pharmacokinetics profiles are shown by the aptamer complexed drug conjugates nanoparticle with B1R active targeting modification. Therefore the strategies of B1R targeting and ATP/pH dual‐responsiveness nanoparticle help achieve enhanced drug accumulation within tumor cells and efficient chemotherapy for breast cancer.