NIR‐Induced Disintegration of CuS‐Loaded Nanogels for Improved Tumor Penetration and Enhanced Anticancer Therapy

Nanocarrier‐based cancer therapy suffers from poor tumor penetration and unsatisfied therapeutical efficacy, as its vascular extravasation efficiency is often compromised by the intrinsic physiological heterogeneity in tumor tissues. In this work, novel near infrared (NIR)‐responsive CuS‐loaded nanogels are prepared to deliver anticarcinogen into the tumor. These hybrid polymeric nanogels possess high photothermal conversion efficiency, and are able to load a large amount of antitumor drug (e.g., doxorubicin [DOX]). More importantly, the thermal heat could induce self‐destruction of the big‐size framework of hybrid nanogels into small nanoparticles, which greatly facilitates tumor penetration to release DOX deep inside the tumor, as validated by photoacoustic (PA) imaging which exhibits 26.3 times enhancement at the interior region compared to signals of groups without laser irradiation. Such structural alteration, combined with strong photothermal and chemotherapy effects, leads to remarkable inhibition of tumor growth in mice. As a result, this NIR‐induced disintegration of CuS‐loaded nanogels provides a novel drug delivery strategy and might open a new window for clinical cancer treatment.     

Novel nanogels as drug delivery systems for poorly soluble anticancer drugs

Two types of novel nanogels were prepared using shell cross-linking of Pluronic F127 micelles with polyethylenimine (PEI) (F127/PEI nanogel), and penetrating network of poly(butylcyanoacrylate) (PBCA) in Pluronic F127 micelles (F127/PBCA nanogel). Poorly soluble anticancer drug, paclitaxel (PTX) and 10-hydroxycamptothecin (HCPT), were used as model drugs and incorporated into nanogels. The results obtained from FT-IR spectroscopy confirmed that the drugs were molecularly dispersed in the nanogels. DLS measurements demonstrated that the nanogel size distribution was narrow with average diameter less than 200 nm. TEM images indicated that the nanogels were spherical in shape and had smooth surfaces. The drug-loaded nanogels showed sustained release profiles compared with the free drugs as revealed by in vitro release experiments. Cytotoxicity tests showed that the cytotoxicity of drug-loaded nanogels against cancer cell in vitro was much higher than that of the free drug. The data demonstrate that these novel nanogels improved stability towards dilution, increased solubility and showed better cellular uptake by cells compared with free drug.     

Liposomes‐Camouflaged Redox‐Responsive Nanogels to Resolve the Dilemma between Extracellular Stability and Intracellular Drug Release

Liposomes have shown great promises for pharmaceutical applications, but still suffer from the poor storage stability, undesirable drug leakage, and uncontrolled drug release. Herein, liposomes‐camouflaged redox‐responsive nanogels platform (denoted as “R‐lipogels”) is prepared to integrate the desirable features of sensitive nanogels into liposomes to circumvent their intrinsic issues. The results indicate that drug‐loaded R‐lipogels with controlled size and high stability not only can achieve a very high doxorubicin (DOX)‐loading capacity (12.9%) and encapsulation efficiency (97.3%) by ammonium sulfate gradient method and very low premature leakage at physiological condition, but also can quickly release DOX in the reducing microenvironment of tumor cells, resulting in effective growth inhibition of tumor cells. In summary, the strategy given here provides a facile approach to develop liposomes–nanogels hybrid system with combined beneficial features of stealthy liposomes and responsive nanogels, which potentially resolves the dilemma between systemic stability and intracellular rapid drug release.     

A Paclitaxel Prodrug Activatable by Irradiation in a Hypoxic Microenvironment

The innate hypoxic microenvironment of most solid tumors has a major influence on tumor growth, invasiveness, and distant metastasis. Here, a hypoxia-activated self-immolative prodrug of paclitaxel (PTX₂-Azo) was synthesized and encapsulated by a peptide copolymer decorated with the photosensitizer chlorin e6 (Ce6) to prepare light-boosted PTX nanoparticle (Ce6/PTX₂-Azo NP). In this nanoparticle, PTX₂-Azo prevents premature drug leakage and realizes specific release in hypoxic tumor microenvironment and the photosensitizer Ce6 not only efficiently generates singlet oxygen under light irradiation but also acts as a positive amplifier to promote the release of PTX. The combination of photodynamic therapy (PDT) and chemotherapy results in excellent antitumor efficacy, demonstrating the great potential for synergistic cancer therapy.     

Iridium photosensitizer constructed liposomes with hypoxia-activated prodrug to destrust hepatocellular carcinoma

Hypoxic tumor microenvironment is a major challenge for photodynamic therapy(PDT). To overcome this problem, PDT combined hypoxia-activated chemotherapy is a promising strategy for hypoxic cancer therapy. Herein, a multifunctional liposome(AQ4N-Ir1-sorafenib-liposome) is prepared by encapsulating a hypoxia-activated prodrug AQ4N, a photosensitizer iridium(III) complex and hepatocellular carcinoma(HCC) targeting drug sorafenib, for synergistic therapy of HCC. Ir1-mediated PDT upon irradiation ind...     

Copper-thioguanine metallodrug with self-reinforcing circular catalysis for activatable MRI imaging and amplifying specificity of cancer therapy

For chemotherapy, drug delivery systems often suffer from the inefficient drug loading capability, which usually cause systems toxicity and extra burden to excrete carrier itself. Moreover, the cancer therapeutic efficacy is also greatly limited by the specificity of tumor microenvironment for reactive oxygen species(ROS) based cancer therapeutic strategy(e.g., chemodynamic therapy). Herein, we have developed metal-drug coordination nanoplatform that can not only be responsive to tumor microenvironment but also modulate it, so as to achieve efficient treatment of cancer. Excitingly, by employing small molecule drug(6-thioguanine) as ligand copper ions, we achieve a high drug loading rate(60.1%) and 100% of utilization of metal-drug coordination nanoplatform(Cu-TG). Interestingly, Cu-TG possessed high-efficiently horseradish peroxidase-like, glutathione peroxidase-like and catalase-like activity. Under the tumor microenvironment, Cu-TG exhibited the self-reinforcing circular catalysis that is able to amplify the cellular oxidative stress, inducing notable cancer cellular apoptosis. Moreover, Cu-TG could be activated with glutathione(GSH) and facilitated for GSH triggered 6-TG release, higher selective therapeutic effect toward cancer cells, and GSH activated T_1 weight-magnetic resonance imaging. Based on the above properties, Cu-TG exhibited magnetic resonance imaging(MRI) guiding, efficient and synergistic combination of chemodynamic and chemotherapy with self-reinforcing therapeutic outcomes in vivo.     

Combined nanosuspensions from two natural active ingredients for cancer therapy with reduced side effects

Tumor drug resistance and systemic side effects of chemotherapeutic drugs are the main reasons for the failure of cancer treatment. In recent years, it was found that some natural active ingredients can reverse MDR and regulate body immunity to enhance the efficacy and reduce toxicity of chemotherapeutic drugs. In this paper, a new nanosuspensions, HCPT and QUR hybrid nanosuspensions (HQ-NPs), was prepared by the microprecipitation-high pressure homogenization method to reverse tumor drug resistance, reduce toxicity, and increase therapeutic efficacy. The in vitro investigation results showed that HQ-NPs had a unique shape (particle size was about 216.3 ± 5.9 nm), changed crystalline, and different dissolution rates compared with HCPT-NPs and QUR-NPs, which is attributed to the strong intermolecular forces between HCPT and QUR as indicated by the results of the molecule dock. It was verified that the HQ-NPs could double the retention of HCPT in cells and enhance the cytotoxicity to A549/PTX cells in vitro tests compared with HCPT-NPs. We also found that HQ-NPs can significantly enhance the accumulation of HCPT in tumor sites, improve the antitumor activity of HCPT, and protect the immune organs and other normal tissues (P < 0.01), compared with HCPT-NPs. Therefore, hybrid nanosuspensions can offer promising potential as the drug delivery system for HCPT and QUR to increase the therapeutic efficacy and reduce the toxicity of HCPT.     

Synthesis and characterization of folic acid‐modified carboxymethyl chitosan‐ursolic acid targeted nano‐drug carrier for the delivery of ursolic acid and 10‐hydroxycamptothecin

Carboxymethyl chitosan (CMCS), as a water‐soluble, biocompatible, and biodegradable polymer, is an excellent carrier for a sustained drug delivery system. In this study, a amphiphilic carboxymethyl chitosan‐ursolic acid nano‐drug carrier modified by folic acid (FPCU) were prepared, and then the nano‐drug carrier wrapped another anticancer drug 10‐hydroxycamptothecin were self‐assembled into nanoparticles (FPCU/HCPT NPs). The FPCU/HCPT NPs had a suitable size, high drug loading efficiency of ursolic acid (6.4%) and 10‐hydroxycamptothecin (14.1%). The drug release study in vitro indicated that the nanoparticles have obviously sustained effect and pH sensitive behaviors, the drug release amount was higher at pH 5.5 than at pH 7.4. in vitro and in vivo study showed that the nanoparticles displayed a high antitumor efficiency to tumor cells compared with free drug. The nano delivery system as a carrier for ursolic acid (UA) and 10‐hydroxycamptothecin (HCPT) has good application prospects in cancer treatment.     

Construction of a biotin-targeting drug delivery system and its near-infrared theranostic fluorescent probe for real-time image-guided therapy of lung cancer

The therapy of non-small lung cancer(NSCLC) is limited by wide metastasis and chemotherapy resistance, herein, we present a new cancer-targeting prodrug PBG with the integration of real-time fluorescence visualization. The potent anticancer drug Gefitinib conjugates a biotin recognition ligand yielding the prodrug PBG via a GSH-activatable disulfide bond linker. Once coupling a near-infrared azo-BODIPY fluorophore into the molecular structure of PBG, we obtain its fluorescent theranostic TBG. Th...     

Two-dimensional LDH nanodisks modified with hyaluronidase enable enhanced tumor penetration and augmented chemotherapy

The condensed tumor extracellular matrix(ECM) consisting of cross-linked hyaluronic acid(HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase(HAase)-modified layered double hydroxide(LDH) nanoplatform loaded with anticancer drug doxorubicin(DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.     

A tumor mRNA-dependent gold nanoparticle-molecular beacon carrier for controlled drug release and intracellular imaging

We demonstrate a tumor mRNA-dependent drug carrier for controlled release of doxorubicin (Dox) and intracellular imaging based on gold nanoparticle-molecular beacon. Fluorescent Dox is released effectively and induces apoptosis in breast cancer cells but not in normal cells. Significantly, the release of Dox is correlated positively with the quantities of tumor mRNA, which is according to various stages of tumor progression, and so can decrease effectively side effects of Dox.     

A highly X-ray sensitive iridium prodrug for visualized tumor radiochemotherapy

Concomitant treatment of radiotherapy and chemotherapy is widely used in cancer therapy. The search for highly efficient radiochemotherapy drugs for tumor targeting therapy under image-guiding is of considerable interest. Herein we report an Ir-based prodrug Ir-NB with high sensitization efficiency for in vivo tumor microenvironment responsive cancer-targeted bioimaging radiochemotherapy. To the best of our knowledge, the sensitivity enhancement ratio (SER) of the Ir-NB prodrug is the highest among those reported for radiotherapy metal complex drugs. From detailed action mechanism study, we provide evidence that the prodrug is effectively suppresses the tumor growth through inducing mitochondrial dysfunction, and eventually amplifies the apoptotic signal pathway. This study provides an approach for the development of cancer theranostic agents for tumor radiotherapy.

A highly X-ray sensitive molecular prodrug, Ir-NB, was reported for visualized tumor radiochemotherapy. To our knowledge, the sensitivity enhancement ratio of the prodrug is the highest among the reported radiotherapy metal complexes drugs.     

A GSH-depleted platinum(IV) prodrug triggers ferroptotic cell death in breast cancer

Cisplatin is the first-line drug for treatment of various solid tumors including breast cancer due to the broad anti-tumor spectrum and strong anti-tumor effect. However, serious side effects and long-term medication of reduced sensitivity by high GSH in tumor cells have severely restricted its further clinical application. Herein, a GSH-depleted Pt(IV) prodrug (Platin B) based on cisplatin and 4-carboxylphenylboronic acid pinacol ester was prepared to solve the problems. As an excellent GSH scavenger, 4-carboxylphenylboronic acid pinacol ester could be activated by intracellular redox reactions to release quinone methide, thereby amplifying oxidative stress and leading to breast cancer ferroptosis therapy. Interestingly, the consumption of GSH can also reduce cisplatin inactivation, enhance the sensitivity of tumor cells to cisplatin and efficiently induce apoptosis/ferroptosis. This work highlights the use of GSH scavenger for triggering ferroptotic cell death in breast cancer.     

Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor

Photodynamic therapy (PDT) has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death (ICD) effects. However, the strategy is limited in the innate hypoxic tumor microenvironment. There are two key elements for the realization of enhanced PDT: specific cellular uptake and release of the photosensitizer in the tumor, and a sufficient amount of oxygen to ensure photodynamic efficiency. Herein, self-oxygenated biomimetic nanoparticles (CS@M NPs) co-assembled by photosensitizer prodrug (Ce6-S-S-LA) and squalene (SQ) were engineered. In the treatment of triple negative breast cancer (TNBC), the oxygen carried by SQ can be converted to reactive oxygen species (ROS). Meanwhile, glutathione (GSH) consumption during transformation from Ce6-S-S-LA to chlorin e6 (Ce6) avoided the depletion of ROS. The co-assembled (CS NPs) were encapsulated by homologous tumor cell membrane to improve the tumor targeting. The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin (CRT) and high mobility group protein B1 (HMGB1), and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha (HIF-1α)-CD39-CD73-adenosine a2a receptor (A2AR) pathway, which not only promoted the maturation of dendritic cells (DC) and the presentation of tumor specific antigens, but also induced effective immune infiltration of tumors. Overall, the integrated nanoplatform implements the concept of multiple advantages of tumor targeting, reactive drug release, and synergistic photodynamic therapy-immunotherapy, which can achieve nearly 90% tumor suppression rate in orthotopic TNBC models.     

Intracellular enzyme-activatable prodrug for real-time monitoring of chlorambucil delivery and imaging

Carboxylesterase, a necessary enzyme in various mammalian cells, has been employed in various biological applications. Herein, we designed and synthesized a novel carboxylesterase-based prodrug, which can realize simultaneous drug-release imaging and cancer chemotherapy. This prodrug comprises three parts:coumarin as the fluorophore and the cleavable architecture, chlorambucil as the anticancer drug, and acetyl group as the enzyme-responsive unit. The presence of carboxylesterase leads to the activation of coumarin fluorescence, and this fluorescence serves as the reporting signal for assessing the enzyme level and drug release. Moreover, the prodrug was incorporated in liposome for monitoring drug release and chemotherapeutic effect in living cells. Upon internalization by HeLa cells, the prodrug can release chlorambucil and exhibit high cytotoxicity. This approach may provide some helpful insights for enhancing therapeutic effect and tracking the release of prodrug.     

Multi‐Stimuli‐Responsive Polymeric Prodrug for Enhanced Cancer Treatment

Accomplishing efficient delivery of a nanomedicine to the tumor site will encounter two contradictions as follows: 1) a contradiction between prolonged circulation time and endocytosis by cancer cells; 2) a dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. While developing a nanomedicine which can solve the above two contradictions simultaneously is still a challenge, here, a multi‐stimuli‐responsive polymeric prodrug (PLys‐co‐(PLys‐DA)‐co‐(PLys‐SS‐PTX))‐b‐PLGLAG‐mPEG (P‐PEP‐SS‐PTX‐DA) is synthesized which is multi‐sensitive to overexpressed matrix metalloproteinase‐2 (MMP‐2), low pH, and high concentration of glutathione in tumors. The P‐PEP‐SS‐PTX‐DA can be dePEGylated and reversed from negative at normal physiological pH to positive charge at tumor extracellular microenvironment; in this way, it can solve the contradiction between prolonged circulation time and endocytosis by cancer cells. Owing to the high reductive conditions in cancer cells, P‐PEP‐SS‐PTX‐DA is ruptured to release paclitaxel (PTX) intracellular efficiently; therefore, it can resolve the dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. These indicate that the multi‐stimuli‐responsive polymeric prodrug has potential application prospects in drug delivery and cancer therapy.     

Biodegradable nanogels prepared by atom transfer radical polymerization as potential drug delivery carriers: synthesis, biodegradation, in vitro release, and bioconjugation

Stable biodegradable nanogels cross-linked with disulfide linkages were prepared by inverse miniemulsion atom transfer radical polymerization (ATRP). These nanogels could be used for targeted drug delivery scaffolds for biomedical applications. The nanogels had a uniformly cross-linked network, which can improve control over the release of encapsulated agents, and the nanogels biodegraded into water-soluble polymers in the presence of a biocompatible glutathione tripeptide, which is commonly found in cells. The biodegradation of nanogels can trigger the release of encapsulated molecules including rhodamine 6G, a fluorescent dye, and Doxorubicin (Dox), an anticancer drug, as well as facilitate the removal of empty vehicles. Results obtained from optical fluorescence microscope images and live/dead cytotoxicity assays of HeLa cancer cells suggested that the released Dox molecules penetrated cell membranes and therefore could suppress the growth of cancer cells. Further, OH-functionalized nanogels were prepared to demonstrate facile applicability toward bioconjugation with biotin. The number of biotin molecules in each nanogel was determined to be 142,000, and the formation of bioconjugates of nanogels with avidin was confirmed using optical fluorescence microscopy.     

GSH/ROS Dual-Responsive Supramolecular Nanoparticles Based on Pillar[6]arene and Betulinic Acid Prodrug for Chemo–Chemodynamic Combination Therapy

Chemodynamic therapy (CDT) based on intracellular Fenton reactions is attracting increasing interest in cancer treatment. A simple and novel method to regulate the tumor microenvironment for improved CDT with satisfactory effectiveness is urgently needed. Therefore, glutathione (GSH)/ROS (reactive oxygen species) dual-responsive supramolecular nanoparticles (GOx@BNPs) for chemo–chemodynamic combination therapy were constructed via host–guest complexation between water-soluble pillar[6]arene and the ferrocene-modified natural anticancer product betulinic acid (BA) prodrug, followed by encapsulation of glucose oxidase (GOx) in the nanoparticles. The novel supramolecular nanoparticles could be activated by the overexpressed GSH and ROS in the tumor microenvironment (TME), not only accelerating the dissociation of nanoparticles—and, thus, improving the BA recovery and release capability in tumors—but also showing the high-efficiency conversion of glucose into hydroxyl radicals (·OH) in succession through intracellular Fenton reactions. Investigation of antitumor activity and mechanisms revealed that the dramatic suppression of cancer cell growth induced by GOx@BNPs was derived from the elevation of ROS, decrease in ATP and mitochondrial transmembrane potential (MTP) and, finally, cell apoptosis. This work presents a novel method for the regulation of the tumor microenvironment for improved CDT, and the preparation of novel GSH/ROS dual-responsive supramolecular nanoparticles, which could exert significant cytotoxicity against cancer cells through the synergistic interaction of chemodynamic therapy, starvation therapy, and chemotherapy (CDT/ST/CT).     

Integrating of lipophilic platinum(IV) prodrug into liposomes for cancer therapy on patient-derived xenograft model

Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, cholesPt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of CholesPt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, CholesPt(IV)-Liposomes showed a small particle size (105.6 nm), the rapid release of platinum (Pt) ions, and notable apoptosis of cancer cells. In addition, according to the fluidity and safety results of animal experiments in mice, CholesPt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patient-derived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.     

Redox-responsive micelles integrating catalytic nanomedicine and selective chemotherapy for effective tumor treatment

Chemotherapy is one of the most conventional modalities for cancer therapy. However, the high multidrug resistance of tumor cells still limited the clinical application of current chemotherapy. Considering the ability of nitric oxide (NO) to modulate potent P-glycoprotein to inhibit multi-drug resistance, a synergistic methodology combining chemotherapy and sustained NO generation is an ideal way to further promote the chemotherapy. Herein, a multi-functional micelle with tumor-selective chemotherapy driven by redox-triggered doxorubicin (DOX) release and drug resistance inhibition based on intracellular NO generation was fabricated for effective tumor treatment. The micelle consists of DOX as core, arginine/glucose oxidase (Arg/GOx) as shell and redox-responsive disulfide bond as a linker, which is denoted as micelle-DOX-Arg-GOx. The Arg serves as the biological precursor of nitric oxide for inhibition of multi-drug resistance to promote chemotherapy and GOx catalyzes glucose to produce hydrogen peroxide (H₂O₂) for increasing the generation of NO. Moreover, the glucose supply could be simultaneously blocked by the catalytic process, which further enhanced therapeutic efficiency. This micelle requests a tumor-specific microenvironment (a considerable amount of GSH) to perform synergistic therapeutics including chemotherapy, starvation therapy (catalytic medicine), and gas therapy for tumor treatment, which resulted in significant cytotoxicity to tumor tissue.