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Nanoparticle drug delivery system improves the therapeutic efficacy of a drug; however, achieving sustained release from nanoparticles is challenging, owing to the increase of surface area and pronounced burst release. In this study, by incorporating an organogel of 12-hydroxystearic acid (12-HSA) into lipid-bilayers, a gel-liposomal formulation was developed to sustain drug release over time. The lipid-bilayer-coated nanogels (LBCNs) with a particle size of approximately 200 nm and with a core-shell structure had an entrapment efficiency of up to 80% for paclitaxel. LBCNs could continually release both hydrophobic and water-soluble drugs over time. Interestingly, the incorporation of organogel enhanced the cellular uptake of liposomes significantly and, accordingly, enabled improved cytotoxicity of chemotherapy agent against the cancer cells. In conclusion, by formulating the organogel into the lipid bilayers, gel-liposomes were developed, allowing for sustained drug release, improved internalization and the resultant enhancement of cytotoxicity of chemotherapy agent to cancer cells., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Treatment of metastatic cancer continues to be a huge challenge worldwide. Notably, drug nanocrystals (Ns) in nanosuspensions clearly belong to a type of nanoparticle. Therefore, a question arose as to whether these drug particles can also be applied as carriers for drug delivery. Here, we design a novel paclitaxel (PTX) nanocrystal stabilized with complexes of matrix metalloproteinase (MMP)-sensitive β-casein/marimastat (MATT) for co-delivering MATT and PTX and combined therapy of metastatic breast cancer. The prepared Ns (200 nm) with a drug-loading of >50% were potent in treatment of metastatic cancer, which markedly inhibited MMP expression and activity and greatly blocked the lung metastasis and angiogenesis. In conclusion, employing protein-drug complexes as stabilizers, Ns with dual payloads are developed and are a promising strategy for co-delivery. Furthermore, the developed Ns can target the tumor microenvironment and cancer cells and, as a result, enable efficient treatment for breast metastatic cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, invasion, and metastasis. Therefore, a therapy that combines chemotherapeutic drugs with a TME modulator could be a promising route for cancer treatment. This paper reports a nanoplatform self-assembled from a hyaluronic acid (HA)-paclitaxel (PTX) (HA-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the TME and cancer cells. Interestingly, the prodrug HA-PTX can self-assemble on both positively and negatively charged liposomes, forming hybrid nanoparticles (HNPs, 100 nm). Triggered by mild hyperthermia, HA-PTX/MATT-LTSLs HNPs rapidly release their payloads into the extracellular environment, and the released HA-PTX quickly enters 4T1 cells through a CD44-HA affinity. The HNPs possess promoted tumor accumulation (1.6-fold), exhibit deep tumor penetration, and significantly inhibit the tumor growth (10-fold), metastasis (100%), and angiogenesis (10-fold). Importantly, by targeting the TME and maintaining its integrity via inhibiting the expression and activity of matrix metalloproteinases (>5-fold), blocking the fibroblast activation by downregulating the TGF-β1 expression (5-fold) and suppressing the degradation of extracellular matrix, the HNPs allow for significant metastasis inhibition. Overall, these findings indicate that a prodrug of an HA-hydrophobic-active compound and liposomes can be self-assembled into a smart nanoplatform for the dual targeting of the TME and tumor cells and efficient combined treatment; additionally, the co-delivery of MATT and HA-PTX with the HNPs is a promising approach for the treatment of metastatic cancer. This study creates opportunities for fabricating multifunctional nanodevices and offers an efficient strategy for disease therapy.

In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A prodrug-based nanosystem obtained by formulating prodrug and nanotechnology into a system is one of the most promising strategies to enhance drug delivery for disease treatment. Herein, we report a new nanosystem based on HA-PTX conjugates (HA-PTX Ns), which penetrated across cell membranes into cytosol, thus enhancing paclitaxel (PTX) delivery. HA-PTX Ns were successfully obtained based on HA-PTX, and their average particle size was approximately 200 nm. Importantly, unlike other prodrug-based nanosystems, HA-PTX Ns obtained cellular entry without entrapment within the lysosomal-endosomal system by using pathways including clathrin-mediated endocytosis, microtubule-associated internalization, macropinocytosis and cholesterol-dependence. Due to significant accumulation in tumors, HA-PTX Ns had more than a 4-fold decrease in tumor volume on day 14 in contrast with PTX alone. In conclusion, HA-PTX Ns could enter cells, bypass the lysosomal-endosomal system and improve PTX delivery., (Copyright © 2015. Published by Elsevier B.V.)

A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer-drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer-PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23,000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer-PTX prodrug system is promising in tumor therapy.

Tumor-targeted drug delivery and microenvironment-responsive drug release are attractive strategies in cancer treatment. Our previous study demonstrated that redox-sensitive micelles based on hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates exhibited excellent drug-loading capacities (34.1%) for paclitaxel (PTX) and rapid drug release in response to reducing agent, glutathione. In the present study, the physicochemical and biological properties of PTX-loaded HA-ss-DOCA (PTX-HA-ss-DOCA) micelles were investigated further. The micelles have an average size of about 120 nm and a zeta potential of about -36 mV. Transmission electron microscopy and wide-angle X-ray diffraction analysis demonstrated redox-sensitive degradation of micelles in the presence of glutathione. Moreover, the encapsulated payload was effectively released from HA-ss-DOCA micelles into cytoplasm and then rapidly transported into nuclei. In vitro cytotoxicity and cell apoptosis assay further revealed that HA significantly improved the tumor-specific drug delivery of HA-ss-DOCA micelles via receptor-mediated endocytosis, while efficient intracellular drug release and transportation lead to marked inhibition of tumor cell growth, as compared to Taxol(®) and insensitive micelles. More importantly, PTX-HA-ss-DOCA micelles demonstrated superior in vivo antitumor activity compared with Taxol(®) and insensitive control, and decreased systemic toxicity. Herein we present data which provide valuable insight into the design and development of tumor-specific drug delivery systems., (Copyright © 2015. Published by Elsevier B.V.)

To obtain efficient therapeutics, drug release into the cytosol is required because drug targets are often located in the cytosol or have active sites that require intracellular machinery in the cytosolic compartment. However, typical nanocarriers gain cellular entry by endocytic mechanisms, confining the internalized nanocarriers to the endosomal-lysosomal system, thus resulting in the rapid destruction of active drugs without release into the cytosol. Herein, hybrid nanoparticles (HNs) with a core-shell structure, which was based on nanoemulsion-templates stabilized by both β-lactoglobulin (β-LG) and lecithin, were developed. Additionally, its formation mechanism and structure were also studied. Importantly, the HNs could directly penetrate the cell membrane and enter the cytosol, without entrapment within the endosomal-lysosomal system via the lipid raft-like pathway, thus enhancing its antitumor activities. We therefore concluded that HNs are promising targeting delivery systems for drugs, especially for pharmaceutical proteins and gene-targeting drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

An amphiphilic carboxymethyl chitosan-quercetin (CQ) conjugate was designed and synthesized for oral delivery of paclitaxel (PTX) to improve its oral bioavailability by increasing its water solubility and bypassing the P-gp drug efflux pumps. CQ conjugate had low critical micelle concentration (55.14 μg/mL), and could self assemble in aqueous condition to form polymeric micelles (PMs). PTX-loaded CQ PMs displayed a particle size of 185.8 ± 4.6 nm and polydispersity index (PDI) of 0.134 ± 0.056. The drug-loading content (DL) and entrapment efficiency (EE) were 33.62 ± 1.34% and 85.63 ± 1.26%, respectively. Moreover, PTX-loaded CQ PMs displayed similar sustained-release profile in simulated gastrointestinal fluids (pH 1.2/pH 6.8) and PBS (pH 7.4). In situ intestinal absorption experiment showed that PTX-loaded CQ PMs significantly improved the effective permeability of PTX as compared to verapamil (P < 0.01). Likewise, PTX-loaded CQ PMs significantly enhanced the oral bioavailability of PTX, resulting in strong antitumor efficacy against tumor xenograft models with better safety profile as compared to Taxol(®) and Taxol(®) with verapamil. Overall, the results implicate that CQ PMs are promising vehicles for the oral delivery of water-insoluble anticancer drugs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)