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A multifunctional nanoplatform based on mesoporous silica nanoparticles (MSNs) was developed for combinational tumor therapy. Doxorubicin (DOX) was chosen as an antitumor drug and loaded into mesopores of MSNs via physical absorption. Then, a tumor-targeted fusion peptide conjugated with 2,3-dimethylmaleic anhydride (DTCPP) and a therapeutic peptide conjugated with 2,3-dimethylmaleic anhydride (DTPP) were introduced to the surface of MSNs as super-pH-sensitive nanovalves through disulfide linkages. The BSA adsorption assay confirmed the charge-reversal property of MSN-ss-DTPP&DTCPP nanoparticles at slightly acidic condition (pH 6.8) and superior stability in physiological environment (pH 7.4). According to the drug release research, both glutathione (GSH) and acidic condition are required for the accelerated drug release from DOX@MSN-ss-DTPP&DTCPP nanoparticles. Moreover, in vitro studies demonstrated the significantly reinforced tumor cellular uptake efficiency and mitochondrial disruption ability of DOX@MSN-ss-DTPP&DTCPP nanoparticles in tumor environment, in which DOX@MSN-ss-DTPP&DTCPP nanoparticles exhibited the preferred cytotoxicity toward αvβ3-positive human cervical carcinoma (HeLa) cells. We believe that the multifunctional dual-stimuli-sensitive MSN could provide an effective strategy for combinational tumor therapy.

The morphology of nanomedicines has a large influence on the anticancer efficiency of therapeutic agents in biological systems. In this study, camptothecin (CPT)-based nanodrugs with helical and spherical shapes were simply built without the need of any additional carriers. Self-deliverable spherical nanodrug represented a therapeutic advantage over the helical one, which was uncovered from the in vitro toxicity assay. Confocal imaging study indicated that the better outcome of spherical nanodrug was ascribed to the faster cellular uptake. With the aid of sonication treatment, helical nanodrugs with different lengths (HD-1, HD-2, HD-3, HD-4) were created. In comparing with the longest HD-1, the drug release kinetics indicated that the shortest HD-4 exhibited a 20% elevation in cumulative drug release at the first 10 h. The internalized drug amount of HD-4 was three-fold higher than that of HD-1 after the cultivation with 4T1 cells for 2 h. These results demonstrated that the anticancer efficacy of helical nanodrugs was inversely proportional to their lengths. The strategy demonstrated here presents great promise for the preparation of nanodrugs with suitable morphology for cancer therapy.

Incorporation of poly(dopamine) (PDA) into the native oligopeptide hydrogel has been demonstrated to decrease the critical gel concentration (CGC), improve the rigidity of formed hybrid hydrogel, and especially endow the hydrogel with efficient free radical scavenging ability.

Synergistic therapy involving two or more therapeutic agents with different anticancer mechanisms represents a promising approach to eradicate chemotherapy-refractory cancers. However, the preparation of a synergistic therapy platform generally involves complicated procedures to encapsulate different therapeutic agents and thereby increases the purification difficulty. In this work, we reported a simple but robust strategy to prepare a highly controllable drug delivery system (DDS) for synergistic cancer therapy. To construct this robust DDS, mesoporous silica nanoparticles (MSNs) were employed as a nanoplatform to encapsulate anticancer drug doxorubicin (DOX). After using a tumor-targeting cellular membrane-penetrating peptide (TCPP) and a mitochondria-targeting therapeutic peptide (TPP) to seal the surface pores via disulfide bonds, these newly developed MSNs can target cancer cells, penetrate cell membrane and rapidly release anticancer drug and mitochondria-targeted peptide in cytoplasm, inducing a remarkable synergistic anticancer effect. The new design concept reported here will promote the development of targeted and smart DDSs for synergistic cancer therapy.

To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica-coated gold nanorod for high-performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS4). The mesoporous silica shell is modified with β-cyclodextrin (β-CD) gatekeeper via redox-cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long-circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β-CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS4 for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near-infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high-performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.

To overcome drug resistance, efficient cancer therapeutic strategies using a combination of small-molecule drugs and macromolecule drugs is highly desired. However, because of their significant differences in molecular weight and size, it is difficult to load them simultaneously in one vector and to release them individually. Here, a biodegradable organosilica-based core-shell-structured nanocapsule was designed and used as a dual stimuli-responsive drug vector to solve this problem. Biodegradable organosilica shell coated outside the macromolecule model drug "core" would be disrupted by high glutathione (GSH) levels inside tumor cells, resulting in the escape of the entrapped drugs. Small-molecule drugs capping on the surface of the organosilica shell via pH-responsive imine bonds can be cut and released in the acidic lysosomal environment. Transmission electron microscopy has shown that the framework of the organosilica shell was dissolved and degraded after 8 h incubation with 5 mM GSH. Confocal imaging confirmed that small-molecule and macromolecular drugs were individually released from the nanoparticles because of the pH or redox-triggered degradation under the tumor microenvironment and thus led to the strong fluorescence recovery in the cytoplasm. As expected, these biodegradable organosilica nanoparticles could not release drugs into normal cells but could specifically release them into tumor cells owing to their tumor-triggered targeting capability. This system will serve as an efficient shuttle for multidrug delivery and also provide a potential strategy to overcome drug resistance.

The clinical outcomes of conventional mono-chemotherapy of cancers are usually far from satisfactory due to some issues such as tumor heterogeneity and resistance to chemotherapeutic drugs. With the increasing knowledge of molecular signal pathways and pathological mechanisms involved in the initiation and progression of cancers, collaborative strategies have been elaborated to optimize therapeutic outcomes. This review surveys the most recent advances in combination therapy including combination chemotherapy, chemotherapy plus gene therapy, chemotherapy plus phototherapy, as well as chemotherapy plus immunotherapy. Additionally, chemotherapy-involved multiple therapy that merges various therapeutic modalities is also presented. We try to elicit the rationales of applying these combinational formulations for cancer chemotherapy, which might provide new guidelines for high-performance cancer treatments.

A versatile gold nanoparticle-based multifunctional nanocomposite AuNP@CD-AD-DOX/RGD was constructed flexibly via host-guest interaction for targeted cancer chemotherapy. The pH-sensitive anticancer prodrug AD-Hyd-DOX and the cancer-targeted peptide AD-PEG8-GRGDS were modified on the surface of AuNP@CD simultaneously, which endowed the resultant nanocomposite with the capability to selectively eliminate cancer cells. In vitro studies indicated that the AuNP@CD-AD-DOX/RGD nanocomposite was preferentially uptaken by cancer cells via receptor-mediated endocytosis. Subsequently, anticancer drug DOX was released rapidly upon the intracellular trigger of the acid microenvirenment of endo/lysosomes, inducing apoptosis in cancer cells. As the ideal drug nanocarrier, the multifunctional gold nanoparticles with the active targeting and controllable intracellular release ability hold the great potential in cancer therapy.

In this paper, an activable cell-penetrating peptide (CR8G3PK6, ACPP) with a shielding group of 2,3-dimethylmaleic anhydride (DMA) was conjugated with antitumor drug doxorubicin (DOX) to construct a novel prodrug (DOX-ACPP-DMA) for tumor targeted drug delivery. The shielding group of DMA linked to the primary amines of K6 through the amide bond was used to block the cell-penetrating function of the polycationic CPP (R8) through intramolecular electrostatic attraction at physiological pH 7.4. At tumor extracellular pH 6.8, the hydrolysis of DMA led to charge reversal, activating the pristine function of CPP for improved cellular uptake by tumor cells. Confocal laser scanning microscopy (CLSM) and flow cytometry studies revealed that the cellular uptake of DOX-ACPP-DMA was significantly enhanced after acid-triggered activation in both HeLa and COS7 cells. After cell internalization, the overexpressed intracellular proteases would further trigger drug release in cells. Both in vitro and in vivo investigations showed that the peptidic prodrug exhibited significant tumor growth inhibition and demonstrated great potential for tumor therapy.

Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an "off-on" drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.

A new multi-functional amphiphilic fusion (MFAF) peptide comprised of a multi-functional fusion peptide sequence (GFLGR8GDS) and a hydrophobic polycaprolactone (PCL) tail was designed and prepared. In aqueous solution, through the strong hydrophobic interaction among the PCL tails, this MFAF peptide can self-assemble into core–shell micelles at a low concentration with the anti-tumor drug doxorubicin (DOX) loaded in the core and the multi-functional fusion peptide sequence located on the shell. When incubating the DOX-loaded micelles with tumor and normal cells, the micelles can use the RGD and membrane-penetrating peptide (eight continuous arginine residues, R8) sequences to target tumor cells and penetrate cell membranes. Subsequently, cathepsin B, an enzyme over-expressed in late endosomes and lysosomes of tumor cells that can specifically hydrolyze the GFLG sequence, can break the micellar structure and lead to a rapid release and escape of loaded DOX from endosomes, resulting in the apoptosis of tumor cells. The MFAF peptide presents great potential as a new drug delivery platform for targeted cancer chemotherapy.

Introducing drugs into gene delivery systems to fabricate co-delivery systems for synergy therapy has become a promising strategy for tumor therapy. In this study, a dual responsive co-delivery system RHD/p53 was fabricated to enhance the antitumor efficacy with a low dose of doxorubicin (DOX). The reducible branched cationic polypeptide (RBCP), which was cross-linked via the thiol groups of two three-armed cationic peptides (CRR)2KRRC and (CHH)2KHHC, was designated as RH. Then, DOX was immobilized on RH via pH-sensitive hydrazone bonds to obtain RHD. The positively charged RHD could compress p53 plasmid to form RHD/p53 complexes. After RHD/p53 complexes accumulated in tumor sites, the ability of cell penetrating by cationic peptide (CRR)2KRRC would facilitate the cellular internalization of complexes. Then, the complexes would be trapped in endosome, and the cleavage of hydrazone bonds in the intracellular acidic endosome could lead to pH-induced release of DOX. Additionally, the ability of protonation by (CHH)2KHHC could promote the escape of complexes from endosome to cytoplasm. Due to the cleavage of disulfide bonds triggered by the high-content GSH in cytoplasm, the complexes would be degraded and released p53 for co-therapy to improve antitumor efficacy. Both in vitro and in vivo studies indicated that dual responsive co-delivery system RHD/p53 could enhance antitumor efficacy, which provides a useful strategy for co-delivery of different therapeutic agents in tumor treatment.