Self-assembled ternary hybrid nanodrugs for overcoming tumor resistance and metastasis.

Traditional chemotherapy exhibits a certain therapeutic effect toward malignant cancer, but easily induce tumor multidrug resistance (MDR), thereby resulting in the progress of tumor recurrence or metastasis. In this work, we deigned ternary hybrid nanodrugs (PEI/DOX@CXB-NPs) to simultaneously combat against tumor MDR and metastasis. In vitro results demonstrate this hybrid nanodrugs could efficiently increase cellular uptake at pH 6.8 by the charge reversal, break lysosomal sequestration by the proton sponge effect and trigger drugs release by intracellular GSH, eventually leading to higher drugs accumulation and cell-killing in drug-sensitive/resistant cells. In vivo evaluation revealed that this nanodrugs could significantly inhibit MDR tumor growth and simultaneously prevent A549 tumor liver/lung metastasis owing to the specifically drugs accumulation. Mechanism studies further verified that hybrid nanodrugs were capable of down-regulating the expression of MDR or metastasis-associated proteins, lead to the enhanced anti-MDR and anti-metastasis effect. As a result, the multiple combination strategy provided an option for effective cancer treatment, which could be potentially extended to other therapeutic agents or further use in clinical test.

pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages for enhanced MDR reversal and chemotherapy.

TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance (MDR) and as an anticancer agent for synergistic antitumor effects. However, the comparatively high critical micelle concentration (CMC), low drug loading (DL) and poor tumor target limit its further clinical application. To overcome these drawbacks, the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials, ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material. The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin (DOX)-loaded micelles at neutral aqueous solutions. The micelles exhibited the lower CMC (8.2 × 10-5 mg/ml), higher DL (10.8%) and long-term storage and circulation stability, and showed enhanced cellular uptake, apoptosis, cytotoxicity, and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH (5.0), MDR reversal of TPGS, and synergistic effect of DOX and TPGS. Therefore, the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.

Dynamic precise dual-drug-backboned nano-prodrugs for selective chemotherapy.

To achieve an ideal drug delivery platform with precise composition and high tumor selectivity, the PEGylated dual-drug backboned prodrug was synthesized via the copolymerization between diamine monomer of ortho ester and cisplatin- demethylcantharidin conjugate (Pt(IV)-1), and then terminated by mPEG550-active ester. The amphipathic prodrug could self-assemble into nano-prodrugs, which endowed the precise structure and high drug loading. Moreover, the nano-prodrugs exhibited physicochemical stability at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change for selective tumor accumulation and enhanced cellular internalization at tumoral extracellular pH (6.8), and efficient drug release for synergetic apoptosis and cytotoxicity at tumoral intracellular pH (5.0)/glutathione. Thus, the precise dual-drug backboned nano-prodrugs with detachable PEGylation, dynamic size change and efficient drug release could be potentially translated for clinically selective cancer treatment. STATEMENT OF SIGNIFICANCE: Few nanomedicines have been clinically used for cancer treatment and little progress has been made in the last decades due to the unprecise composition and unsatisfactory tumor selectivity. Herein, the PEGylated dual-drug backboned nano-prodrugs were successfully constructed by rational design and endowed the defined structure, precise drug ratio, extraordinary high drug loading and reduction/pH dual sensitivity. The nano-prodrugs further exhibited the stable storage and blood circulation through PEGylation and low critical micelle concentration, enhanced tumor accumulation and cellular uptake via extracellular DePEGylation and dynamic size translation, and synergetic cytotoxicity via intracellular efficient drug release, respectively. This study can open a new avenue for easy industrial manufacture and quality control, and highly selective chemotherapy appealing for clinical translation. .

Self-assembled 5-fluorouracil-cinnamaldehyde nanodrugs for greatly improved chemotherapy in vivo.

The preferred cancer treatment is to achieve a high therapeutic effect as well as reduce side effects. In this study, we developed carrier-free nano drugs based on 5-fluorouracil (5FU) and cinnamaldehyde (CA) to meet the above goals. Two model drugs were spliced by acetal linkage and ester bond, which could self-assemble into nano drug particles (5FU-CA NPs) with a size of ∼170 nm. In vitro cell experiments showed 5FU-CA NPs were efficiently internalized by HepG2 cells. They then quickly exerted dual drug activities by the cleavage of acetal and ester bond, resulting in enhanced cell-killing efficacy and apoptosis. Synergistic mechanisms were achieved via the anti-metabolic effects mediated by 5FU-COOH and the oxidative damage induced by CA. In vivo anti-tumor evaluation further indicated that 5FU-CA NPs had higher tumor growth inhibition than 5FU-COOH/CA mixture (5FU-COOH + CA) and exhibited lower systemic toxicity under the same reducing dose of each drug. Overall, this is a successful synergistic anti-tumor attempt through rational self-assembly of drugs with different mechanisms and it can be extrapolated to other agents.

pH-sensitive deoxycholic acid dimer for improving doxorubicin delivery and antitumor activity in vivso.

To develop simple and effective nano-drug delivery systems remains a major challenge in cancer treatment. Herein, we synthesized an ortho ester-linked deoxycholic acid dimer (DCA-OE), which could effectively self-assemble with doxorubicin (DOX) to form stable nanoparticles (DCA-OE/DOX NPs) by a single emulsion method. DCA-based nanoparticles had a desirable size (∼200 nm), morphology (spherical shape), and high drug encapsulation (drug loading content of ∼18.0 %, drug loading efficiency of ∼77.6 %). DCA-OE could improve the stability and solubility of DOX in physiological environment, while pH-sensitive ortho ester linkage endowed the ability to release DOX quickly in cancer cells. In vitro cytotoxicity and apoptosis verified drug-loaded dimer nanoparticles had similar toxicity with free DOX. Besides, these particles could efficiently accumulate and penetrate into human liver carcinoma cell line (HepG2) multicellular spheroids, thus resulting in enhanced antitumor effect. In vivo tests further exhibited that DCA-OE/DOX NPs had lower systemic toxicity and higher tumor inhibition effect, and its tumor inhibition rate was 84.1 %, which was far more than free DOX (49.3 %). Therefore, the strategy to link functional small molecules with ortho ester has great potentials in specific delivery of anticancer drugs.