Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.
Although great success has been obtained in the clinic, the current immune checkpoint inhibitors still face two challenging problems: low response rate and immune-related adverse effects (irAEs). Here we report the combination of immunogenic chemotherapy and locally expressed PD-L1 trap fusion protein for efficacious and safe cancer immunotherapy. We demonstrate that oxaliplatin (OxP) boosts anti-PD-L1 mAb therapy against murine colorectal cancer. By design of a PD-L1 trap and loading its coding plasmid DNA into a lipid-protamine-DNA nanoparticle, PD-L1 trap is produced transiently and locally in the tumor microenvironment, and synergizes with OxP for tumor inhibition. Significantly, unlike the combination of OxP and anti-PD-L1 mAb, the combination of OxP and PD-L1 trap does not induce obvious Th17 cells accumulation in the spleen, indicating better tolerance and lower tendency to irAEs. The reports here may highlight the potential of applying PD-L1 inhibitor, especially locally expressed PD-L1 trap, in cancer therapy following OxP-based chemotherapy.
Achievement of potent immunoresponses against self/tumor antigens and effective therapeutic outcome against advanced tumors remain major challenges in cancer immunotherapy. The specificity and efficiency of two nanoparticle-based delivery systems, lipid-calcium-phosphate (LCP) nanoparticle (NP) and liposome-protamine-hyaluronic acid (LPH) NP, provide us an opportunity to address both challenges. A mannose-modified LCP NP delivered both tumor antigen (Trp 2 peptide) and adjuvant (CpG oligonucleotide) to the dendritic cells and elicited a potent, systemic immune response regardless of the existence or the stage of tumors in the host. This vaccine was less effective, however, against later stage B16F10 melanoma in a subcutaneous syngeneic model. Mechanistic follow-up studies suggest that elevated levels of immune-suppressive cytokines within the tumor microenvironment, such as TGF-β, might be responsible. We strategically augment the efficacy of LCP vaccine on an advanced tumor by silencing TGF-β in tumor cells. The delivery of siRNA using LPH NP resulted in about 50% knockdown of TGF-β in the late stage tumor microenvironment. TGF-β down-regulation boosted the vaccine efficacy and inhibited tumor growth by 52% compared with vaccine treatment alone, as a result of increased levels of tumor infiltrating CD8+ T cells and decreased level of regulatory T cells. Combination of systemic induction of antigen-specific immune response with LCP vaccine and targeted modification of tumor microenvironment with LPH NP offers a flexible and powerful platform for both mechanism study and immunotherapeutic strategy development.
Selective gene expression in tumors via responsive dissociation of polyplexes triggered by intracellular signals is demonstrated. An esterase-responsive charge-reversal polymer mediates selective gene expression in the cancer cells high in esterases over fibroblasts low in esterase activity. Its gene therapy with the TRAIL suicide gene effectively induces apoptosis of HeLa cells but does not activate fibroblasts to secrete WNT16B, enabling potent cancer gene therapy with few side effects.
Drug resistance is a major challenge to the effective treatment of cancer. We have developed two nanoparticle formulations, cationic liposome-polycation-DNA (LPD) and anionic liposome-polycation-DNA (LPD-II), for systemic co-delivery of doxorubicin (Dox) and a therapeutic small interfering RNA (siRNA) to multiple drug resistance (MDR) tumors. In this study, we have provided four strategies to overcome drug resistance. First, we formed the LPD nanoparticles with a guanidinium-containing cationic lipid, i.e. N,N-distearyl-N-methyl-N-2-(N-arginyl) aminoethyl ammonium chloride, which can induce reactive oxygen species, down-regulate MDR transporter expression, and increase Dox uptake. Second, to block angiogenesis and increase drug penetration, we have further formulated LPD nanoparticles to co-deliver vascular endothelial growth factor siRNA and Dox. An enhanced Dox uptake and a therapeutic effect were observed when combined with vascular endothelial growth factor siRNA in the nanoparticles. Third, to avoid P-glycoprotein-mediated drug efflux, we further designed another delivery vehicle, LPD-II, which showed much higher entrapment efficiency of Dox than LPD. Finally, we delivered a therapeutic siRNA to inhibit MDR transporter. We demonstrated the first evidence of c-Myc siRNA delivered by the LPD-II nanoparticles down-regulating MDR expression and increasing Dox uptake in vivo. Three daily intravenous injections of therapeutic siRNA and Dox (1.2 mg/kg) co-formulated in either LPD or LPD-II nanoparticles showed a significant improvement in tumor growth inhibition. This study highlights a potential clinical use for the multifunctional nanoparticles with an effective delivery property and a function to overcome drug resistance in cancer. The activity and the toxicity of LPDand LPD-II-mediated therapy are compared.The occurrence of drug resistance is a main impediment to the success of cancer chemotherapy. Cancer cells develop different ways to be resistant to chemotherapy drugs. Overexpression of drug transporter proteins, such as P-glycoprotein (P-gp) 2 plays a key role in regulating drug resistance. Development of strategies to down-regulate the expression of P-gp or inhibit P-gp function has been the major subject of cancer research. For example, one of the strategies to overcome MDR is to use carriers like nanoparticles to avoid P-gp-mediated drug efflux. Only the drug presenting in the cell membrane can be effluxed out of the cancer cell. The drug delivered by nanoparticles is internalized in the cytoplasm or the lysosome and not pumped out by P-gp (1). Dox-loaded liposomes are able to overcome MDR by increasing Dox uptake in the nuclei and extending retention in the nuclei of the MDR cells (2, 3). Small interfering RNA (siRNA) is a promising novel approach of cancer therapy. It offers a new strategy to downregulate the targeted oncogene for therapeutic intervention. Systemically delivering siRNA to tumors remains a major hurdle in cancer gene therapy (4, 5). Major problems of siRNA delivery include poor cellula...
The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, we report a novel prodrug-based nanoplatform self-assembled by the disulfide bond linked conjugates of PTX and oleic acid (OA) for rapid and differential release of PTX in tumor cells. This redox-responsive prodrug-nanosystem demonstrates multiple therapeutic advantages, including one-step facile fabrication, high drug-loading efficiency (56%, w/w), on-demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug-nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.
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