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.     

A New Co‐P Nanocomposite with Ultrahigh Relaxivity for In Vivo Magnetic Resonance Imaging‐Guided Tumor Eradication by Chemo/Photothermal Synergistic Therapy

Design of new nanoagents that intrinsically have both diagnostic imaging and therapeutic capabilities is highly desirable for personalized medicine. In this work, a novel nanotheranostic agent is fabricated based on polydopamine (PDA)‐functionalized Co‐P nanocomposites (Co‐P@PDA) for magnetic resonance imaging (MRI)‐guided combined photothermal therapy and chemotherapy. The ultrahigh relaxivity of 224.61 mm ^?1 s^?1 can enable Co‐P@PDA to be applied as an excellent contrast agent for MRI in vitro and in vivo, providing essential and comprehensive information for tumor clinical diagnosis. Moreover, Co‐P@PDA exhibit excellent photothermal performance owing to the strong near‐infrared (NIR) absorbance of both Co‐P nanocomposite and PDA. Highly effective ablation of tumors is achieved in a murine tumor model because the NIR laser not only induces photothermal effects but also triggers the chemotherapeutic drug on‐demand release, which endows the Co‐P@PDA with high curative effects but little toxicity and few side effects. These findings demonstrate that Co‐P@PDA are promising agents for highly effective and precise antitumor treatment and warrant exploration as novel theranostic nanoagents with good potential for future clinical translation.     

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.     

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.     

Recent Advances in Upconversion Nanoparticles‐Based Multifunctional Nanocomposites for Combined Cancer Therapy

Lanthanide‐doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous‐wave near‐infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue‐penetration ability and high signal‐to‐noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging‐guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co‐delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti‐cancer effects, reduces individual drug‐related toxicity and suppresses multi‐drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs‐based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs‐based composites. The future prospects and challenges in this emerging field will be also discussed.     

1D Coordination Polymer Nanofibers for Low‐Temperature Photothermal Therapy

Near‐infrared (NIR)‐light‐triggered photothermal therapy (PTT) usually requires hyperthermia to >50 °C for effective tumor ablation, which can potentially induce inflammatory disease and heating damage of normal organs nearby, while tumor lesions without sufficient heating (e.g., the internal part) may survive after treatment. Achieving effective tumor killing under relatively low temperatures is thus critical toward successful clinical use of PTT. Herein, we design a simple strategy to fabricate poly(ethylene glycol) (PEG)‐modified one‐dimensional nanoscale coordination polymers (1D‐NCPs) with intrinsic biodegradability, large surface area, pH‐responsive behaviors, and versatile theranostic functions. With NCPs consisting of Mn2+/indocyanine green (ICG) as the example, Mn‐ICG@pHis‐PEG display efficient pH‐responsive tumor retention after systemic administration and then load Gambogic acid (GA), a natural inhibitor of heat‐shock protein 90 (Hsp90) that plays an essential role for cells to resist heating‐induced damage. Such Mn‐ICG@pHis‐PEG/GA under a mild NIR‐triggered heating is able to induce effective apoptosis of tumor cells, realizing low‐temperature PTT (~43 °C) with excellent tumor destruction efficacy. This work not only develops a facile approach to fabricate PEGylated 1D‐NCPs with tumor‐specific pH responsiveness and theranostic functionalities, but also presents a unique low‐temperature PTT strategy to kill cancer in a highly effective and minimally invasive manner.     

Enhanced Photothermal Therapy through the In Situ Activation of a Temperature and Redox Dual‐Sensitive Nanoreservoir of Triptolide

Photothermal therapy (PTT) has attracted tremendous attention due to its noninvasiveness and localized treatment advantages. However, heat shock proteins (HSPs) associated self‐preservation mechanisms bestow cancer cells thermoresistance to protect them from the damage of PTT. To minimize the thermoresistance of cancer cells and improve the efficacy of PTT, an integrated on‐demand nanoplatform composed of a photothermal conversion core (gold nanorod, GNR), a cargo of a HSPs inhibitor (triptolide, TPL), a mesoporous silica based nanoreservoir, and a photothermal and redox di‐responsive polymer shell is developed. The nanoplatform can be enriched in the tumor site, and internalized into cancer cells, releasing the encapsulated TPL under the trigger of intracellular elevated glutathione and near‐infrared laser irradiation. Ultimately, the liberated TPL could diminish thermoresistance of cancer cells by antagonizing the PTT induced heat shock response via multiple mechanisms to maximize the PTT effect for cancer treatment.     

Protein‐Based Artificial Nanosystems in Cancer Therapy

Proteins, like actors, play different roles in specific applications. In the past decade, significant achievements have been made in protein‐engineered biomedicine for cancer therapy. Certain proteins such as human serum albumin, working as carriers for drug/photosensitizer delivery, have entered clinical use due to their long half‐life, biocompatibility, biodegradability, and inherent nonimmunogenicity. Proteins with catalytic abilities are promising as adjuvant agents for other therapeutic modalities or as anticancer drugs themselves. These catalytic proteins are usually defined as enzymes with high biological activity and substrate specificity. However, clinical applications of these kinds of proteins remain rare due to protease‐induced denaturation and weak cellular permeability. Based on the characteristics of different proteins, tailor‐made protein‐based nanosystems could make up for their individual deficiencies. Therefore, elaborately designed protein‐based nanosystems, where proteins serve as drug carriers, adjuvant agents, or therapeutic drugs to make full use of their intrinsic advantages in cancer therapy, are reviewed. Up‐to‐date progress on research in the field of protein‐based nanomedicine is provided.     

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.