Editorial pubs.acs.org/molecularpharmaceutics
Drug Delivery and Reversal of MDR (siP62) and/or PSMB5 (β5) expressing plasmid DNA (pβ5) for overcoming cisplatin-resistant ovarian cancer. Knockdown of P62 expression and upregulation of β5 expression could enhance the oxidative stress related cytotoxicity and sensitize the cells to cisplatin. The synthetic dsRNA analogue polyinosinic-polycytidylic acid (poly(I:C)) was utilized for combination therapy. Wagner et al. synthesized a set of molecularly precise oligo(ethanamino)amides comprising PEG conjugated methotrexate ligands. The poly(I:C) polyplexes of the polyglutamylated methotrexate variants showed higher cellular uptake and synergistic combined cytotoxicity in folate receptor positive KB cells. Wang et al. exploited a therapeutic strategy for non-small-cell lung carcinoma (NSCLC) based on the interaction between downregulation of GATA binding protein 2 (GATA2) and the KRAS mutation. The siRNA targeting to GATA2 (siGATA2) was delivered by the cationic lipid-assisted polymeric nanoparticles (NPsiGATA2). NPsiGATA2 did not affect the KRAS wildtype cells, but significantly inhibited tumor growth in the KRAS mutant A549 NSCLC xenograft model via systemic delivery. Roy and Li et al. developed the PEGylated carboxymethylcellulose conjugate of docetaxel, exhibiting a 6.5 times lower IC50 compared to native docetaxel in the highly Pgp expressing EMT6/AR1 murine breast cancer cells, and 90% of inhibition rate of tumor growth was observed in the animal model. Chow et al. reported a nanodiamond−mitoxantrone complex that favorably improved intracellular drug retention and enhanced the cytotoxicity in the mitoxantrone-resistant MDA-MB-231luc-D3H2LN breast cancer cell line. In the work of BlancoPrieto et al., the edelfosine-loading lipid nanoparticles did not increase intracellular drug accumulation, which however still efficiently killed the resistant K-562 leukemia cells due to the different subcellular drug distribution, yielding different effects on subcellular machinery. There are two studies focusing on mitochondria-targeting drug delivery for evading MDR. Kelley et al. found that a shift of the cell death mechanism from necrosis to a controlled apoptotic pathway could be achieved by tuning the alkylating activity of chlorambucil (mt-Cbl) via chemical modification. The modified mt-Cbl compounds bypassed MDR by rapidly accumulating in mitochondria and inducing cell death directly. Lavasanifar et al. investigated the conjugation of DOX with a lipophilic triphenylphosphonium (TPP) that was featured by its mitochondria-membrane selectivity. The mitochondria-targeting TPP-DOX showed enhanced cytotoxicity in MDA-MB435/DOX cells, with the increased levels of caspase 3 and PARP. Gottesman’s group identified a thiosemicarbazone termed NSC73306 with selective cytotoxicity toward P-gp-expressing cells, and demonstrated that its uptake was dependent on copper transporter 1 (CTR1), and inhibited by cisplatin, a
Multidrug resistance (MDR) is the paramount obstacle for successful chemotherapy, and the leading cause of cancerrelated deaths worldwide, accounting for treatment failure in over 90% of patients with metastatic cancer.1 The mechanisms of MDR involve a broad range of factors, such as the elevating efflux of intracellular drugs; drug activation and inactivation; DNA-damage repair; DNA methylation; and dysfunction of apoptosis.2 Advanced drug delivery techniques have been applied to reverse MDR, and achieved prospective progress. In particular, bionanotechnology plays an increased important role in combating MDR cancer. Nanoparticles are able to not only improve the biodistribution of chemotherapeutic drugs and their intracellular fate but also actively circumvent the drug efflux. In this special issue, the majority of the articles (14 out of 21) focus on nanotechnology-based drug delivery, providing a glimpse into the current major research interest in reversal of MDR. Interestingly, 8 out of 15 research articles apply combinational therapy, half of which (4 articles) involve RNA biologic drugs. The combination of two chemotherapeutic agents with different mechanisms often yields synergistic effects due to simultaneous action on various anticancer pathways. Liu et al. developed the core-matched nanoemulsions functionalized by vitamin E (VE) and tocopherol polyethylene glycol succinate (TPGS) for codelivery of hydrophobic and hydrophilic drugs, paclitaxel, and 5-fluoroucacil to overcome PTX resistance in a MDR KB-8-5 carcinoma cell line. They concluded that the inhibition of ATPase activity by VE and TPGS contributed to the reversal of MDR. Wu et al. demonstrated that simultaneous delivery of the synergistic drugs doxorubicin (DOX) and mitomycin C (MMC) by the polymer−lipid hybrid nanoparticles (PLN) could reverse MDR in EMT6/AR1 cells. In non-immunocompromised mouse models, PLN presented increased efficacy and reduced cardiotoxicity compared to the PEGylated liposomal DOX. Huang and Li et al. developed the polymeric micelles based on poly(ethylene-glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) for DOX and lapatinib, in which lapatinib was used as an adjuvant for DOX treatment, showing improved outcomes in an animal model with resistant breast tumor. Codelivery of nucleic acid drugs along with chemotherapeutics has been often employed to restore the apoptosis-inducing signal pathways and sensitize MDR cells. There are four studies involving the combination of gene therapy and chemotherapy by codelivering siRNA, shRNA, DNA, or dsRNA analogue with chemo drugs. Harashima et al. developed the multifunctional envelope-type nanodevice containing YSK05 as a vector of polo-like kinase 1-siRNA and DOX. They found downregulation of cyclin B1 mRNA and a measurable delay in growth of OS-RC-2 tumor. Shen and Li et al. reported the Pluronic P85-polyethylenimine/TPGS complex nanoparticles with incorporation of iRGD−TPGS conjugate used to codeliver PTX and survivin-shRNA for MDR lung cancer treatment. Ramesh et al. used the multifunctional nanoparticles containing cisplatin and P62/SQSTM1 siRNA © 2014 American Chemical Society
Special Issue: Drug Delivery and Reversal of MDR Published: August 4, 2014 2493
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Molecular Pharmaceutics
Editorial
substrate of CTR1. The study suggests the connection among P-gp, CTR1, and NSC73306. Salinomycin (Sali) is selectively toxic to cancer stem cells (CSCs) that are linked with tumor MDR. Chen et al. synthesized the amphiphilic iTEP−Sali by conjugation of the hydrophobic Sali to a hydrophilic, immune-tolerant, elastin-like polypeptide (iTEP). The self-assembly iTEP-Sali nanoparticles could encapsulate free Sali with two additives (N,Ndimethylhexylamine and α-tocopherol) for killing CSC. Last but not least, we include six reviews in this issue, providing insights into various technologies for MDR reversal. Kabanov et al. described a simple yet effective approach by using amphiphilic block copolymers (e.g., Pluronic), for overcoming MDR. Wender et al. developed a general strategy involving cell-penetrating peptide−drug conjugates. The conjugation not only increased cellular uptake but also improved the solubility of parent drugs. The conjugates are not subject to drug efflux due to the increased size. Shi et al. focused on the recent developments of the inorganic nanoparticle-based drug delivery systems to circumvent MDR by codelivery of anticancer drug with therapeutic genes, chemosensitizers, or diagnostic agents. The applications of RNA have been discussed in two reviews. Amiji et al. outlined the principles and mechanisms based on RNA interference and the barriers against its clinical translation. Li and Mahato discussed the roles of miRNAs in the development of resistant prostate cancers and their involvement in various drug resistant mechanisms. They summarized the strategies for treating resistant prostate cancers by targeting specific miRNAs. Panzarini and Dini provided a review about the relationship between MDR reversal and nanomaterials or autophagy, which suggested a pivotal role of autophagy modulation induced by nanomaterials in counteracting MDR. In conclusion, studies on overcoming MDR through drug delivery strategies have recently become state-of-the-art in cancer therapy. It is expected that the rapidly growing understanding between drug delivery and MDR reversal will promote the clinical translation and benefit MDR cancer therapy.
Yongzhuo Huang,* Guest Editor Yaping Li,* Guest Editor
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Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China
AUTHOR INFORMATION
Corresponding Authors
*(Y.H.) Tel: +86-21-20231000 ext 1401. E-mail: yzhuang@ simm.ac.cn. *(Y.L.) Tel: +86-21-20231000 ext 1515. E-mail:
[email protected]. cn. Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Wilson, T. R.; Johnston, P. G.; Longley, D. B. Anti-apoptotic mechanisms of drug resistance in cancer. Curr. Cancer Drug Targets 2009, 9, 307−19. (2) Wilson, T. R.; Longley, D. B.; Johnston, P. G. Chemoresistance in solid tumours. Ann. Oncol. 2006, 17 (Suppl. 10), x315−24.
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