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The combination of high dose of oral lapatinib (LAPA), a HER2 tyrosine kinase inhibitor, with intravenous paclitaxel (PTX) exhibited a clinical survival advantage compared with PTX alone against HER2 positive breast cancer. However, localized delivery system with high regional drug level may greatly decrease the dose of drug, leading to higher safety and lower cost. In an attempt to imitate the fast and slow exposure of these two drugs in clinic use, we incorporated PTX nanoparticles and LAPA microparticles into a thermosensitive hydrogel (PL-gel) for peritumoral injection, using PTX-gel plus LAPA-oral (P-gel + L-oral) and so on as controls. To visually study in vitro or in vivo, PTX/DID and LAPA/DIR hybrid crystals were prepared. In vitro and in vivo studies demonstrated the fast and short-term release of PTX, as well as the slow and long-term release of LAPA from the PL-gel. The most synergistic effect was found between LAPA and PTX on the cell line overexpressing both HER2 and P-gp, and the mechanisms related to LAPA-induced inhibition on P-gp expression, more G2/M phase arrest of PTX and more uptake of PTX in tumor cells. With a dose of LAPA in PL-gel group only less than 5% of that in P-gel + L-oral group, PL-gel demonstrated significant tumor suppression similar to P-gel + L-oral group, and showed longer mice survival time. Besides, PL-gel achieved more steady LAPA accumulation in tumors and revealed significantly less toxicity compared with P-gel + L-oral group. To summarize, this localized co-delivery system with good synergistic effects between LAPA and PTX might offer a potential strategy for HER2 and P-gp positive breast cancer. [ABSTRACT FROM AUTHOR]

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the α7 nAChR-overexpressing tumors, herein, α-conotoxin ImI, a disulfide-rich toxin with highly affinity for α7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of α7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the α7 nAChR-targeted nanomedicines could deliver more specifically and faster into α7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca 2+ transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro , paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, α7 nAChR is also a promising target for anti-tumor drug delivery and in this case, α-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting α7 nAChR-overexpressing tumors. [ABSTRACT FROM AUTHOR]

As a sustained-release drug depot for localized cancer treatment, in situ thermo-sensitive hydrogel has attracted increasing interests. However, it is currently a big challenge to achieve high drug-loading, sustained and stable drug release, as well as long-term local drug retention simultaneously. We hypothesized that this goal could be accomplished by incorporating the nanocrystals (NCs) of a hydrophobic drug, such as paclitaxel (PTX) into the thermo-sensitive hydrogel (Gel). Hence, a PTX-NCs-Gel system has been constructed with thermo-sensitive Pluronic F127, using PTX-NCs and Taxol® as the controls. Besides, near infra-red agent DiR was used to prepare PTX/DiR hybrid NCs and PTX/DiR hybrid NCs-Gel as well. As a result, this hydrogel system could achieve a high drug loading of PTX up to 3mg/ml while stabilize the particle size of PTX-NCs significantly compared with PTX-NCs alone. There was no obvious interaction between PTX-NCs and F127. Obviously, PTX/DiR hybrid NCs-Gel presented better localized retention capacity and a much longer retention time in murine 4T1 tumor than PTX/DiR hybrid NCs and Cremophor/ethanol solubilized DiR in vivo. With a linear elimination, over 10% of PTX still remained inside of mouse 4T1 tumor 20days after intratumoral dosing of PTX-NCs-Gel. Importantly, PTX-NCs exhibited comparable cytotoxity against 4T1 and MCF-7 cells in vitro compared with Taxol®, which could ensure the efficacy of PTX-NCs-Gel. After intratumoral injection, PTX-NCs-Gel was found to be the most effective among all PTX formulations in the 4T1 and MCF-7 tumor-bearing mice models, with much lower system toxicity than Taxol®. In general, it is believed that the novel thermo-sensitive hydrogel system prepared in this study with PTX-NCs affords high drug-loading, sustained and stable drug release, as well as extended drug retention inside of tumor, which results in better therapy and lower toxicity. [ABSTRACT FROM AUTHOR]

Recent decades have witnessed several nanocrystal-based hydrophobic drug formulations because of their excellent performance in improving drug loading and controlling drug release as mediate drug forms in tablets or capsules. However, the intravenous administration of drug nanocrystals was usually hampered by their hydrophobic surface properties, causing short half-life time in circulation and low drug distribution in tumor. Here, we proposed to enclose nanocrystals (NC) of hydrophobic drug, such as paclitaxel (PTX) into erythrocyte membrane (EM). By a series of formulation optimizations, spherical PTX nanoparticles (PN) with the particle size of around 280 nm were successfully cloaked in erythrocyte membrane, resulting in a PTX-NP-EM (PNM) system. The PNM could achieve high drug loading of PTX (>60%) and stabilize the particle size significantly compared to PN alone. Besides, the fluorescence-labeling PNM presented better tumor cell uptake, stronger cytotoxicity, and higher drug accumulation in tumor compared to PN. Finally, the PNM was found to be the most effective against tumor growth among all PTX formulations in tumor-bearing mice models, with much lower system toxicity than control formulation. In general, the PNM system with high drug-loading as well as superior bio-distributions in vivo could be served as a promising formulation. [ABSTRACT FROM AUTHOR]

Chemotherapy post cancer surgery has important clinical significance for reducing the chance of recurrent-metastasis. However, postoperative chemotherapy efficacy is hampered by poor targeting capability and dose-limiting toxicity of chemo-drugs. Herein, we report a bio-mimetic platelet membrane-cloaked paclitaxel nanocrystal system (PPNCs), which consists of spherical paclitaxel nanocrystals (PNCs) as a high-dose drug core, polyethylene glycol-conjugated paclitaxel (PEG-PTX) as an amphiphilic molecule to adjust the surface hydrophilicity of PNCs and the shell of platelet membrane that can target surgical coagulation site. The in vitro characterization of PPNCs exhibited uniform particle size distribution, high drug loading, and good stability, which are crucial for effective drug delivery. At cell levels, PPNCs showed greater cellular uptake and higher cytotoxicity in 4T1 breast cancer cells than bare PNCs. In vivo , the nanoparticles could deliver high-dose chemo-drugs and target the coagulation site caused by surgery or vascular disrupting agents, resulting in enhanced anti-tumor efficacy and reduced systemic toxicities. In general, the PPNCs system can be served as a promising and efficient drug delivery system for postoperative chemotherapy. The bio-mimetic platelet membrane-cloaked paclitaxel nanocrystal system (PPNCs) could carry high-dose chemo-drugs and target the coagulation site caused by surgery or vascular disrupting agents, resulting in enhanced anti-tumor efficacy and reduced systemic toxicities. Unlabelled Image • The bio-mimetic PPNCs consists of three components, drug nanocrystals, pegylated paclitaxel and platelet membrane shell. • PPNCs exhibited uniform particle size distribution, high drug loading, and good stability. • PPNCs retained the expression of specific platelet membrane proteins, collagen binding capacity with little risk of thrombi. • PPNCs could target the coagulation site caused by surgery or VDA, resulting in better anti-tumor effect and improved safety. [ABSTRACT FROM AUTHOR]