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Nanoparticles have been extensively explored as effective means to deliver chemotherapeutic agents or photosensitizers for chemotherapy or photodynamic therapy (PDT) against cancer. In the present work, pheophorbide A (PheoA), a hydrophobic photosensitizer, was conjugated via a redox-sensitive disulfide linkage to alginate (PheoA-ALG). Anticancer agent, doxorubicin (DOX), was also loaded within the PheoA-ALG nanoparticles (DOX/PheoA-ALG NPs) and used as drug carriers for combinational antitumor treatment. The DOX/PheoA-ALG NPs were spherical in shape with a uniform diameter of approximately 210 nm. Redox-responsive drug releasing properties were shown by the DOX/PheoA-ALG NPs, with an accelerated amount of DOX and PheoA release observed in the presence of a high glutathione level (10 mM). Cellular uptake results showed that DOX/PheoA-ALG NPs were readily taken up by B16 tumor cells (murine melanoma) and enhanced DOX and PheoA uptake were detectable in the DOX/PheoA-ALG NPs-treated B16 cells in comparison to carrier free drugs. DOX/PheoA-ALG NPs also elicited intracellular ROS generation, which leads to enhanced toxicity in B16 cells. In vivo studies using B16 tumor-bearing mice further demonstrated that DOX/PheoA-ALG NPs were preferentially accumulated in tumor tissues, resulting in substantial inhibition of B16 tumor growth by chemotherapy and photodynamic therapy, which is also attributable to DOX/PheoA-ALG NP-elicited increase of serum INF-λ levels. Our results demonstrate a major potential of DOX/PheoA-ALG NPs for combinational cancer therapy.

Nanoparticles (NPs)-based adjuvants are attracting much attention in the development of vaccines. Previously, we reported a type of guanidyl-decorated polymeric NPs used as antigen delivery carriers for the first time. However, its un-degradability may restrict potential clinical translation. More importantly, the specific cellular pathway by which dendritic cells (DCs) endocytosed these NPs and the relationship among guanidyl with the antigen cross-presentation, cytokine secretion, and lymph node targeting still remain unclear. Here, we show NPs assembled by biodegradable methoxyl poly(ethylene glycol)-block-poly(ε-caprolactone)-graft-poly(2-(guanidyl) ethyl methacrylate) (mPEG-b-PCL-g-PGEM, PECG) copolymers can robustly activate DCs and promote their maturation; additionally antigen cross-presentation was improved both in vitro and in vivo. Significantly, our results also demonstrate the increase of surface guanidyl on nanoparticles modulates the depot effect and lymph node drainage of PECG NPs-based adjuvants, as well as immune responses, by regulating the secretion of cytokines including IFN-γ and TNF-α. Our study provides insights into the action of guanidyl-decorated nanoscale adjuvants and new adjuvants for vaccines containing protein antigens. We anticipate the strategy of guanidyl decoration to be a starting point for the development of more exciting immunoadjuvants.

Targeted delivery and controlled release of nitric oxide (NO) locoregionally are in high demand and challenging in cancer treatment. Herein, we report an example of galactose receptor targeted, pH-responsive and self-assembled nanoparticle-based delivery of the NO prodrug O2-(2,4-dinitrophenyl) 1-[4-(propargyloxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (alkynyl-JSK), which was chemically conjugated to an amphiphilic block copolymer through a click reaction for the first time. The assembled NO prodrug nanoparticles show high NO capacity (the content of the NO prodrug in the copolymer, ∼23.4% (w/w)), good stability and a sustained NO release pattern with unique glutathione/glutathione S-transferase (GSH/GST) activated NO-releasing kinetics. Such NO-loaded nanoparticles exhibit superior cytotoxicity to HepG2 cells. More importantly, in combination with doxorubicin (DOX) chemotherapy a significant synergistic therapeutic effect was achieved, due to its excellent galactose receptor-targeting capability, rapid acid-triggered DOX release and sustained NO release. Our findings indicate that these multifunctional nanoparticles can serve as an efficient NO and chemotherapeutic agent delivery platform, holding great promise in cancer combinatorial treatment.

The key to developing more nanocarriers for the delivery of drugs in clinical applications is to consider the route of the carrier from the administration site to the target tissue and to look for a simple design to complete this whole journey. We synthesized the amphiphilic copolymer cRGDfK–poly(ethylene glycol)-b-poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate) (cRGD–PETM) to construct multifunctional micelles. These micelles combined enhanced drug-loading efficiency with tumor-targeting properties, visual detection and controllable intracellular drug release, resulting in an improved chemotherapeutic effect in vivo. Doxorubicin (DOX) was encapsulated within the cRGD–PETM micelles as a model drug (termed as cRGD–PETM/DOX Ms). The size and morphology of the micelles were characterized systematically. As a result of the hydrophobic interaction and the π–π conjugation between the DOX molecules and the PTTMA copolymers, the cRGD–PETM/DOX Ms showed an excellent drug-loading capacity. The results of in vitro drug-release studies indicated that the cumulative release of DOX from cRGD–PETM/DOX Ms at pH 5.0 was twice that at pH 7.4. The results of fluorescent microscopic analysis showed that the cRGD–PETM/DOX Ms could be internalized by 4T1 and HepG2 cells via receptor-mediated endocytosis with rapid intracellular drug release, which resulted in increased cytotoxicity compared with free DOX. Ex vivo imaging studies showed that the cRGD–PETM/DOX Ms improved the accumulation and retention of the drug in tumor tissues. Studies of the in vivo anticancer effects showed that the cRGD–PETM/DOX Ms had a significantly higher therapeutic efficacy with lower side-effects than free DOX and PETM/DOX Ms. These results show that the multifunctional cRGD–PETM/DOX Ms have great potential as vehicles for the delivery of hydrophobic anticancer drugs.