Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus “synchronizing” the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy.

Background: Lung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment. Methods: The redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model. Results: This HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 mu g mL(-1). Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol (R), PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX. Conclusion: The results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy.

Tumor-associated fibroblasts (TAFs), the most important stromal cells of the tumor microenvironment (TME), have been found to support tumorigenesis and tumor metastasis in a variety of ways, including paracrine, direct contact with cells, immune regulation and extracellular matrix remolding. Therefore, TAFs in the TME have been an optimal target for cancer therapy. In this review, the TAFs targeted therapies are summarized to provide the new strategy for tumor treatments based on the analysis of the location and specific biological phenotypes of TAFs in tumors.

Currently, the most prominent barrier to the success of orally delivered paclitaxel (PTX) is the extremely limited bioavailability of delivered therapeutic. In light of this issue, an amphiphilic sulfhydrylated N-deoxycholic acid-N,O-hydroxyethyl chitosan (TGA-DHC) was synthesized to improve the oral bioavailability of PTX. First, TGA-DHC demonstrated substantial loading of PTX into the inner hydrophobic core. A desirable enhancement in the bioavailability of PTX by TGA-DHC was verified by pharmacokinetic studies on rats against Taxol and non-sulfhydrylated DHC micelles. Moreover, cellular uptake studies revealed significant accumulation of TGA-DHC micelles encapsulating PTX or rhodamine-123 into Caco-2 cells via clathrin/caveolae-mediated endocytosis and inhibition of P-gp efflux of substrates. The results of the Caco-2 transport study further confirmed the mechanistic basis of TGA-DHC efficacy; which was attributed to permeabilized tight junctions, clathrin-mediated transcytosis across the endothelium, and inhibition of P-gp. Finally, in vitro mucoadhesion investigations on freshly excised rat intestine intuitively confirmed increased intestinal retention of drug-loaded TGA-DHC through thiol-mediated mucoadhesion. TGA-DHC has demonstrated the capability to overcome what is perhaps the most prominent barrier to oral PTX efficacy, low bioavailability, and serves as a prominent platform for oral delivery of P-gp substrates.

Since its approval by the FDA, Abraxane™ has been established as a clinical standard of paclitaxel (PTX)-based therapy against a variety of cancers. Despite success, Abraxane™ is still limited by suboptimal biodistribution, unfavorable pharmacokinetics and chronic toxicities from chloroform used during preparation. Accordingly, a PTX-loaded nanosuspension based on human serum albumin (HSA) with PEG modifiers (PTX-PEG-HSA) has been developed to optimize the in-vivo biodistribution, pharmacokinetics and safety of PTX over traditional PTX-HSA nanosuspensions prepared using the accepted method for Abraxane™. Results of in-vivo pharmacokinetic (PK) studies indicated PTX-PEG-HSA achieved prolonged blood circulation, illustrated by an 8.8-fold and 4.8-fold increase in area-under-the-curve (AUC) of PTX over Taxol® and PTX-HSA, while the mean residence time (MRT) of PTX in PTX-PEG-HSA was increased by 3.2-fold and 1.5-fold, respectively. HSA mediated active targeting further suppressed non-specific distribution of PTX to normal tissues, which permitted enhanced antitumor efficacy in S180 mice over Taxol® and PTX-HSA. Safety of intravenously administered PTX-PEG-HSA was confirmed through lower hemolytic activity, a 2.2-fold and 1.2-fold increase in LD50 (113.4 mg/kg) over Taxol® and PTX-HSA alongside the absence of local venous irritation. Studies herein suggest the therapeutic and clinical applicability of PTX-PEG-HSA for tumor specific therapy.

Co-delivery systems capable of transporting hydrophobic chemotherapeutics and hydrophilic siRNA to the same cell population with simultaneous burst release of both drugs to maximize synergistic anticancer efficacy remains elusive. In this light, a multifunctional nanoparticle (HA-PSR) consisting of a redox-sensitive core and detachable crosslinked hyaluronic acid (HA) shell was developed. Octyl modified PEI containing disulfide linkages (PSR) were synthesized as the core materials for co-encapsulation of chemotherapeutics and siRNA, while a HAase-sensitive thiolated HA (HA-SH) was collaboratively assembled to the anionic shell for CD44-mediated active targeting along with enhanced and detachable protection for drug loaded inner cores. Resultantly, HA de-protected redox-sensitive inner cores achieved co-burst release of both cargoes when triggered by glutathione (GSH) rich environments in cytoplasm. Results of in-vivo and in-vitro testing indicated successful co-encapsulation of hydrophobic drugs and hydrophilic siRNA with adjustable ratios. Selective delivery to CD44 overexpressing tumors was achieved through passive and active targeting, followed by HAase-triggered HA de-shielding and GSH-triggered burst release of both cargos. Rapid intracellular trafficking maximized synergistic cytotoxicities of chemotherapeutics and siRNA for remarkable tumor inhibition in a xenograft animal tumor model. Consequently, the HA-PSR nanoparticle holds great potential for combined chemotherapeutics/siRNA treatment in cancer with maximized synergistic antitumor efficacy.