Xiongwei Deng

Degradable hyaluronic acid/protamine sulfate interpolyelectrolyte complexes as miRNA-delivery nanocapsules for triple-negative breast cancer therapy.

Metastatic relapse is a leading cause of cancer-associated death and one of the major obstacles for effective therapy against triple-negative breast cancer. To address this problem, a miRNA-delivering nanocapsule technology based on hyaluronic acid (HA)/protamine sulfate (PS) interpolyelectrolyte complexes (HP-IPECs) is developed for efficient encapsulation and intracellular delivery microRNA-34a (miR-34a), which is a potent endogenous tumor suppressor of breast cancer. The nanocapsules are successfully generated through a self-assembly approach mediated by an electrostatic interaction. In vitro and in vivo experiments illustrate that miR-34a can be efficiently encapsulated into HP-IPECs and delivered into breast cancer cells or breast cancer tissues. Nanocomplex-assisted delivery of miR-34a induces cell apoptosis and suppresses migration, proliferation, and tumor growth of breast cancer cells via targeting CD44 and a Notch-1-signaling pathway. The obtained results suggest that HP-IPECs have a great potential as a biodegradable vector for microRNA-based therapy against triple-negative breast cancer.

Smart micelle@polydopamine core–shell nanoparticles for highly effective chemo–photothermal combination therapy

In this investigation, we have designed and synthesized a novel core-shell polymer nanoparticle system for highly effective chemo-photothermal combination therapy. A nanoscale DSPE-PEG micelle encapsulating doxorubicin (Dox-M) was designed as a core, and then modified by a polydopamine (PDA) shell for photothermal therapy and bortezomib (Btz) administration (Dox-M@PDA-Btz). The facile conjugation of Btz to the catechol-containing PDA shell can form a reversible pH-sensitive boronic acid-catechol conjugate to create a stimuli-responsive drug carrier system. As expected, the micelle@PDA core-shell nanoparticles exhibited satisfactory photothermal efficiency, which has potential for thermal ablation of malignant tissues. In addition, on account of the PDA modification, both Dox and Btz release processes were pH-dependent and NIR-dependent. Both in vitro and in vivo studies illustrated that the Dox-M@PDA-Btz nanoparticles coupled with laser irradiation could enhance the cytotoxicity, and thus combinational therapy efficacy was achieved when integrating Dox, Btz, and PDA into a single nanoplatform. Altogether, our current study indicated that the micelle@polydopamine core-shell nanoparticles could be applied for NIR/pH-responsive sustained-release and synergized chemo-photothermal therapy for breast cancer.

Mesoporous Silica Coated Polydopamine Functionalized Reduced Graphene Oxide for Synergistic Targeted Chemo-Photothermal Therapy

The integration of different therapies into a single nanoplatform has shown great promise for synergistic tumor treatment. Herein, mesoporous silica (MS) coated polydopamine functionalized reduced graphene oxide (pRGO) further modified with hyaluronic acid (HA) (pRGO@MS-HA) has been utilized as a versatile nanoplatform for synergistic targeted chemo-photothermal therapy against cancer. A facile and green chemical method is adopted for the simultaneous reduction and noncovalent functionalization of graphene oxide (GO) by using mussel inspired dopamine (DA) to enhance biocompatibility and the photothermal effect. Then, it was coated with mesoporous silica (MS) (pRGO@MS) to enhance doxorubicin (DOX) loading and be further modified with the targeting moieties hyaluronic acid (HA). The pH-dependent and near-infrared (NIR) laser irradiation-triggered DOX release from pRGO@MS(DOX)-HA is observed, which could enhance the chemo-photothermal therapy effect. In vitro experimental results confirm that pRGO@MS(DOX)-HA exhibits good dispersibility, excellent photothermal property, remarkable tumor cell killing efficiency, and specificity to target tumor cells. In vivo antitumor experiments further demonstrated that pRGO@MS(DOX)-HA could exhibit an excellent synergistic antitumor efficacy, which is much more distinct than any monotherapy. This work presents a novel nanoplatform which could load chemotherapy drugs with high efficiency and be used as light-mediated photothermal cancer therapy agent.

Tumor Acidity-Induced Sheddable Polyethylenimine-Poly(trimethylene carbonate)/DNA/Polyethylene Glycol-2,3-Dimethylmaleicanhydride Ternary Complex for Efficient and Safe Gene Delivery.

Amphiphilic PEI derivatives/DNA complexes are widely used for DNA delivery, but they are unstable in vivo and have cytotoxicity due to the excess cationic charge. PEGylation of cationic complexes can improve sterical stability and biocompatibility. However, PEGylation significantly inhibits cellular uptake and endosomal escape. In this work, sheddable ternary complexes were developed by coating a tumor acidity-sensitive β-carboxylic amide functionalized PEG layer on the binary complexes of amphiphilic cationic polyethylenimine-poly(trimethylene carbonate) nanoparticles/DNA (PEI-PTMC/DNA). Such sheddable ternary complexes markedly reduced their nonspecific interactions with serum protein in the bloodstream and obtained minimal cytotoxicity due to the protection of the PEG shell. At the tumor site, the PEG layer was deshielded by responding to the tumor acidic microenvironment and the positively charged complexes re-exposed that had higher affinity with negatively charged cell membranes. Meanwhile the positively charged complexes facilitated endosomal escape. Accordingly, this delivery system improved the biocompatibility of gene-loaded complexes and enhanced the gene transfection efficiency. Such PEGylated complexes with the ability to deshield the PEG layer at the target tissues hold great promise for efficient and safe gene delivery in vivo.

Hybrid Prodrug Nanoparticles with Tumor Penetration and Programmed Drug Activation for Enhanced Chemoresistant Cancer Therapy

Despite nanomedicine having shown great potential for reversing cancer cell resistance, the suboptimal transport across multiple biological obstacles seriously impedes its reaching targets at an efficacious level, which remains a challenging hurdle for clinical success in resistant cancer therapy. Here, a lipid-based hybrid nanoparticle was designed to efficiently deliver the therapeutics to resistant cells and treat resistant cancer in vivo. The hybrid nanoparticles (D-NPs/tetrandrine (TET)) are composed of a pH-responsive prodrug 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-doxorubicin (DOX), an efflux inhibitor TET, and a surfactant DSPE-[methoxy (poly(ethylene glycol))-2000] (DSPE-mPEG2000), which hierarchically combatted the sequential physiological and pathological barriers of drug resistance and exhibited prolonged blood circulation, high tumor accumulation, and deep tumor parenchyma penetration. In the meantime, the programmed stepwise activation of encapsulated TET and DOX suppressed the function of resistance-related P-glycoprotein in a timely manner and facilitated the DOX sustained accommodation in tumor cells. Through systematic studies, the results show that such a nanosystem dramatically enhances drug potency and significantly overcomes the DOX resistance of breast cancer with negligible systemic toxicities. These findings provide new strategies to systemically combat chemoresistant cancers.

Targeting long non-coding RNA ASBEL with oligonucleotide antagonist for breast cancer therapy

Long non-coding RNAs (lncRNAs) are defined as a class of RNA transcripts longer than 200 nucleotides encoded by mammalian genomes that lack protein-coding potential. LncRNA ASBEL has been identified as an anti-sense transcript of BTG3 (B cell translocation gene 3) gene, which encodes an anti-proliferation protein. Remarkable down-regulation of BTG3 has been reported in triple-negative breast cancer (TNBC). In the present study, a number of single-stranded modified anti-sense DNA oligonucleotides (antago) were designed, synthesized and screened for specific lncRNA ASBEL knockdown. We showed here that anti-ASBEL antago played a significant tumor suppressive role in TNBC by effective down-regulating lncRNA ASBEL, which in turn led to increased BTG3 expression. The obtained data suggest lncRNA ASBEL as a novel therapeutic target in TNBC.

In Situ Monitoring of MicroRNA Replacement Efficacy and Accurate Imaging‐Guided Cancer Therapy through Light‐Up Inter‐Polyelectrolyte Nanocomplexes

Abstract Replacement of downregulated tumor‐suppressive microRNA (Ts‐miRNA) is recognized as an alternative approach for tumor gene therapy. However, in situ monitoring of miRNA replacement efficacy in a real‐time manner via noninvasive imaging is continually challenging. Here, glutathione (GSH)‐activated light‐up peptide‐polysaccharide‐inter‐polyelectrolyte nanocomplexes are established through self‐assembly of carboxymethyl dextran with disulfide‐bridged (“S—S”) oligoarginine peptide (S‐Arg4), in which microRNA‐34a (miR‐34a) and indocyanine green (ICG) are simultaneously embedded and the nanocomplexes are subsequently stabilized by intermolecular cross‐linking. Upon confinement within the robust nanocomplexes, the near‐infrared fluorescence (NIRF) of ICG is considerably quenched (“off”) due to the aggregation‐caused quenching effect. However, after intracellular delivery, the disulfide bond in S‐Arg4 can be cleaved by intracellular GSH, which leads to the dissociation of nanocomplexes and triggers the simultaneous release of miR‐34a and ICG. The NIRF of ICG is concomitantly activated through dequenching of the aggregated ICG. Very interestingly, a good correlation between time‐dependent increase in NIRF intensity and miR‐34a replacement efficacy is found in nanocomplexes‐treated tumor cells and tumor tissues through either intratumoral or intravenous injections. Systemic nanocomplexes‐mediated miR‐34a replacement significantly suppresses the growth of HepG‐2‐ and MDA‐MB‐231‐derived tumor xenografts, and provides a pronounced survival benefit in these animal models.

Nanodiamond-based layer-by-layer nanohybrids mediate targeted delivery of miR-34a for triple negative breast cancer therapy

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer and significantly associated with poor prognosis and high risk of recurrence. miR-34a has been identified as a potent tumor suppressor whose expression is dramatically downregulated in TNBC. Currently, rectification of miRNA abnormality serves as a novel tumor therapeutic strategy. miR-34a is thus used as powerful antitumor agent for miRNA-based therapy against TNBC. However, miRNA-based antitumor therapy is challenged by effective targeted delivery of miRNA. In the present study, nanodiamond (ND), protamine (PS) and folic acid (FA) were used to construct ND-based layer-by-layer nanohybrids through a self-assembly approach for targeted miR-34a delivery in TNBC cells and xenograft TNBC tumors. We found that the targeted delivery of miR-34a remarkably suppressed cell proliferation, migration and induced the apoptosis of TNBC cells in vitro and inhibited tumor growth in vivo via down-regulating Fra-1 expression. The data suggest a great potential of ND-based nanohybrids for targeted intratumoral delivery of miR-34a for TNBC therapy.