A Dual‐Responsive Mesoporous Silica Nanoparticle for Tumor‐Triggered Targeting Drug Delivery

A novel pH‐ and redox‐ dual‐responsive tumor‐triggered targeting mesoporous silica nanoparticle (TTTMSN) is designed as a drug carrier. The peptide RGDFFFFC is anchored on the surface of mesoporous silica nanoparticles via disulfide bonds, which are redox‐responsive, as a gatekeeper as well as a tumor‐targeting ligand. PEGylated technology is employed to protect the anchored peptide ligands. The peptide and monomethoxypolyethylene glycol (MPEG) with benzoic‐imine bond, which is pH‐sensitive, are then connected via “click” chemistry to obtain TTTMSN. In vitro cell research demonstrates that the targeting property of TTTMSN is switched off in normal tissues with neutral pH condition, and switched on in tumor tissues with acidic pH condition after removing the MPEG segment by hydrolysis of benzoic‐imine bond under acidic conditions. After deshielding of the MPEG segment, the drug‐loaded nanoparticles are easily taken up by tumor cells due to the exposed peptide targeting ligand, and subsequently the redox signal glutathione in tumor cells induces rapid drug release intracellularly after the cleavage of disulfide bond. This novel intelligent TTTMSN drug delivery system has great potential for cancer therapy.     

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.     

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.     

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.     

Tumor‐Targeting Multifunctional Rattle‐Type Theranostic Nanoparticles for MRI/NIRF Bimodal Imaging and Delivery of Hydrophobic Drugs

The development of theranostic systems capable of diagnosis, therapy, and target specificity is considerably significant for accomplishing personalized medicine. Here, a multifunctional rattle‐type nanoparticle (MRTN) as an effective biological bimodal imaging and tumor‐targeting delivery system is fabricated, and an enhanced loading ability of hydrophobic anticancer drug (paclitaxel) is also realized. The rattle structure with hydrophobic Fe₃O₄ as the inner core and mesoporous silica as the shell is obtained by one‐step templates removal process, and the size of interstitial hollow space can be easily adjusted. The Fe₃O₄ core with hydrophobic poly(tert‐butyl acrylate) (PTBA) chains on the surface is not only used as a magnetic resonance imaging (MRI) agent, but contributes to improving hydrophobic drug loading amount. Transferrin (Tf) and a near‐infrared fluorescent dye (Cy 7) are successfully modified on the surface of the nanorattle to increase the ability of near‐infrared fluorescence (NIRF) imaging and tumor‐targeting specificity. In vivo studies show the selective accumulation of MRTN in tumor tissues by Tf‐receptor‐mediated endocytosis. More importantly, paclitaxel‐loaded MRTN shows sustained release character and higher cytotoxicity than the free paclitaxel. This theranostic nanoparticle as an effective MRI/NIRF bimodal imaging probe and drug delivery system shows great potential in cancer diagnosis and therapy.     

Responsive Assembly of Upconversion Nanoparticles for pH‐Activated and Near‐Infrared‐Triggered Photodynamic Therapy of Deep Tumors

Upconversion nanoparticle (UCNP)‐mediated photodynamic therapy has shown great effectiveness in increasing the tissue‐penetration depth of light to combat deep‐seated tumors. However, the inevitable phototoxicity to normal tissues resulting from the lack of tumor selectivity remains as a major challenge. Here, the development of tumor‐pH‐sensitive photodynamic nanoagents (PPNs) comprised of self‐assembled photosensitizers grafted pH‐responsive polymeric ligands and UCNPs is reported. Under neutral pH conditions, photosensitizers aggregated in the PPNs are self‐quenched; however, upon entry into a tumor microenvironment with lower pH, the PPNs not only exhibit enhanced tumor‐cell internalization due to charge reversal but also are further disassembled into well‐dispersed nanoparticles in the endo/lysosomes of tumor cells, enabling the efficient activation of photosensitizers. The results demonstrate the attractive properties of both UCNP‐mediated deep‐tissue penetration of light and high therapeutic selectivity in vitro and in vivo.     

Sequentially Site‐Specific Delivery of Apoptotic Protein and Tumor‐Suppressor Gene for Combination Cancer Therapy

Nanocarrier‐mediated codelivery of multiple anticancer drugs is a potential strategy for enhanced efficacy of combination cancer treatment by unifying differential pharmacokinetic properties and maintaining an optimal ratio of drug cargoes. However, a programmable codelivery system is highly desired to deliver different therapeutics to their specific sites of action to pursue maximized combinational effect. Herein a liposome‐based nanoassembly (p53/C‐rNC/L‐FA) is developed for intracellular site‐specific delivery of an apoptotic protein cytochrome c (CytoC) and a plasmid DNA encoding tumor‐suppressing p53 protein (p53 DNA). p53/C‐rNC/L‐FA consists of an acid‐activated fusogenic liposomal membrane shell modified with folic acid (L‐FA) and a DNA/protein complex core assembled by the p53 DNA, protamine and CytoC‐encapsulated redox‐responsive nanocapsule (C‐rNC). Intratumoral and intraendosomal acidities promote membrane fusion between liposome and biomembrane, resulting in release of the encapsulated p53/C‐rNC complex into the cytoplasm. The cytoplasmic reduction causes degradation of C‐rNC with release of CytoC that induces tumor cell apoptosis. The p53 DNA is transported into the nucleus by the aid of the cationic protamine and thus generates expression of the p53 protein that enhances apoptosis combined with CytoC. p53/C‐rNC/L‐FA is demonstrated to significantly induce tumor cell apoptosis and inhibit tumor growth in the orthotopic breast tumor mouse model.     

Pulmonary Codelivery of Doxorubicin and siRNA by pH‐Sensitive Nanoparticles for Therapy of Metastatic Lung Cancer

A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis‐aconitic anhydride (CA, a pH‐sensitive linker) to obtain PEI‐CA‐DOX conjugates. The PEI‐CA‐DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI‐CA‐DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI‐CA‐DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma‐bearing mice, the PEI‐CA‐DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long‐term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI‐CA‐DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.     

Double‐Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor‐Depth Photothermal Therapy

This study reports a double‐targeting “nanofirework” for tumor‐ignited imaging to guide effective tumor‐depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS‐HA). The HA corona provides active tumor‐targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS‐HA is specifically set within the optimal size window for passive tumor‐targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size‐dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS‐HA due to HAase‐catalyzed HA degradation, in turn activating the recovery of initially CuS‐quenched luminescence of UCNP and also driving the tumor‐depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor‐ignited explosible firework. Together with the double‐targeting functionality, the pathology‐selective tumor ignition permits precise tumor detection and imaging‐guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors.     

Near‐Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH‐/H2O2‐Responsive O2‐Evolving Synergetic Cancer Therapy

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen‐dependent photodynamic therapy (PDT), but also antitumor drug‐based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen‐dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)‐mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one‐for‐all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H₂O₂‐responsive self‐sufficiency of O₂ and near‐infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O₂ plays an important role in overcoming the chemotherapeutic drug‐resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.     

Anionic Lipid,pH‐Sensitive Liposome‐Gold Nanoparticle Hybrids for Gene Delivery – Quantitative Research of the Mechanism

Gene therapy is a potential method for treating a large range of diseases. Gene vectors are widely used in gene therapy for promoting the gene delivery efficiency to the target cells. Here, gold nanoparticles (AuNPs) coated with dimethyldioctadecylammonium bromide (DODAB)/dioleoylphosphatidylethanolamine (DOPE) are synthesized using a facile method for a new gene vector (DODAB/DOPE‐AuNPs), which possess 3‐ and 1.5‐fold higher transfection efficiency than those of DODAB‐AuNPs and a commercial transfection agent, respectively. Meanwhile, it is nontoxic with concentrations required for effective gene delivery. Imaging and quantification studies of cellular uptake reveal that DOPE increases gene copies in cells, which may be attributed to the smaller size of AuNPs/DNA complexes. The dissociation efficiency of DNA from the endocytic pathway is quantified by incubating with different buffers and investigated directly in the cells. The results suggest that DOPE increases the internalization of AuNPs/DNA complexes and promotes DNA release from early endosomes for the vector is sensitive to the anionic lipid membrane and the decreasing pH along the endocytic pathway. The new vector contains the potential to be the new alternative as gene delivery vector for biomedical applications.     

Mitochondria‐Targeting Magnetic Composite Nanoparticles for Enhanced Phototherapy of Cancer

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities in current days while the high laser power density demand and low tumor accumulation are key obstacles that have greatly restricted their development. Here, magnetic composite nanoparticles for dual‐modal PTT and PDT which have realized enhanced cancer therapeutic effect by mitochondria‐targeting are reported. Integrating PTT agent and photosensitizer together, the composite nanoparticles are able to generate heat and reactive oxygen species (ROS) simultaneously upon near infrared (NIR) laser irradiation. After surface modification of targeting ligands, the composite nanoparticles can be selectively delivered to the mitochondria, which amplify the cancer cell apoptosis induced by hyperthermia and the cytotoxic ROS. In this way, better photo therapeutic effects and much higher cytotoxicity are achieved by utilizing the composite nanoparticles than that treated with the same nanoparticles missing mitochondrial targeting unit at a low laser power density. Guided by NIR fluorescence imaging and magnetic resonance imaging, then these results are confirmed in a humanized orthotropic lung cancer model. The composite nanoparticles demonstrate high tumor accumulation and excellent tumor regression with minimal side effect upon NIR laser exposure. Therefore, the mitochondria‐targeting composite nanoparticles are expected to be an effective phototherapeutic platform in oncotherapy.     

Dual‐Peak Absorbing Semiconducting Copolymer Nanoparticles for First and Second Near‐Infrared Window Photothermal Therapy: A Comparative Study

Near‐infrared (NIR) light is widely used for noninvasive optical diagnosis and phototherapy. However, current research focuses on the first NIR window (NIR‐I, 650–950 nm), while the second NIR window (NIR‐II, 1000–1700 nm) is far less exploited. The development of the first organic photothermal nanoagent (SPN_I‐II) with dual‐peak absorption in both NIR windows and its utilization in photothermal therapy (PTT) are reported herein. Such a nanoagent comprises a semiconducting copolymer with two distinct segments that respectively and identically absorb NIR light at 808 and 1064 nm. With the photothermal conversion efficiency of 43.4% at 1064 nm generally higher than other inorganic nanomaterials, SPN_I‐II enables superior deep‐tissue heating at 1064 nm over that at 808 nm at their respective safety limits. Model deep‐tissue cancer PTT at a tissue depth of 5 mm validates the enhanced antitumor effect of SPN_I‐II when shifting laser irradiation from the NIR‐I to the NIR‐II window. The good biodistribution and facile synthesis of SPN_I‐II also allow it to be doped with an NIR dye for fluorescence‐imaging‐guided NIR‐II PTT through systemic administration. Thus, this study paves the way for the development of new polymeric nanomaterials to advance phototherapy.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

Tumor pH‐Responsive Albumin/Polyaniline Assemblies for Amplified Photoacoustic Imaging and Augmented Photothermal Therapy

Tumor‐microenvironment‐responsive theranostics have great potential for precision diagnosis and effective treatment of cancer. Polyaniline (PANI) is the first reported pH‐responsive organic photothermal agent and is widely used as a theranostic agent. However, tumor pH‐responsive PANI‐based theranostic agents are not explored, mainly because the conversion from the emeraldine base (EB) to emeraldine salt (ES) state of PANI requires pH < 4, which is lower than tumor acidic microenvironment. Herein, a tumor pH‐responsive PANI‐based theranostic agent is designed and prepared for amplified photoacoustic imaging guided augmented photothermal therapy (PTT), through intermolecular acid–base reactions between carboxyl groups of bovine serum albumin (BSA) and imine moieties of PANI. The albumin/PANI assemblies (BSA–PANI) can convert from the EB to ES state at pH < 7, accompanied by the absorbance redshift from visible to near‐infrared region. Both in vitro and in vivo results demonstrate that tumor acidic microenvironment can trigger both the photoacoustic imaging (PAI) signal amplification and the PTT efficacy enhancement of BSA–PANI assemblies. This work not only highlights that BSA–PANI assemblies overcome the limitation of low‐pH protonation, but also provides a facile assembly strategy for a tumor pH‐responsive PANI‐based nanoplatform for cancer theranostics.     

Development of Dual‐Pore Coexisting Branched Silica Nanoparticles for Efficient Gene–Chemo Cancer Therapy

Various strategies for combination therapy to overcome current limitations in cancer therapy have been actively investigated. Among them, simultaneous delivery of multiple drugs is a subject of high interest due to anticipated synergistic effect, but there have been difficulties in designing and developing effective nanomaterials for this purpose. In this work, dual‐pore coexisting hybrid porous silica nanoparticles are developed through Volmer–Weber growth pathway for efficient co‐delivery of gene and anticancer drug. Based on the different pore sizes (2–3 and 40–45 nm) and surface modifications of the core and branch domains, loading and controlled release of gene and drug are achieved by appropriate strategies for each environment. With excellent loading capacity and low cytotoxicity of the present platform, the combinational cancer therapy is successfully demonstrated against human cervical cancer cell line. Through a series of quantitative analyses, the excellent gene–chemo combinational therapeutic efficiency is successfully demonstrated. It is expected that the present nanoparticle will be applicable to various biomedical fields that require co‐delivery of small molecule and nucleic acid.