Nano-Polypharmacy to Treat Tumors: Coencapsulation of Drug Combinations Using Nanoparticle Technology
Authors: Frank Alexis
Journal: Molecular Therapy (2014)

Complex pathologies such as cancer involve multiple molecular and genomic pathways. Combinatorial drug therapies have proven viable in that they catalyze the inhibition of multiple pathways or multiple connection points of a single pathway.1Borisy AA Elliott PJ Hurst NW Lee MS Lehar J Price ER et al.Systematic discovery of multicomponent therapeutics.Proc Natl Acad Sci USA. 2003; 100: 7977-7982Crossref PubMed Scopus (489) Google Scholar,2Al-Lazikani B Banerji U Workman P Combinatorial drug therapy for cancer in the post-genomic era.Nat Biotechnol. 2012; 30: 679-692Crossref PubMed Scopus (692) Google Scholar,3Shah PS Schaffer DV Gene therapy takes a cue from HAART: combinatorial antiviral therapeutics reach the clinic.Sci Transl Med. 2010; 2: 36ps30Crossref PubMed Scopus (2) Google Scholar,4Aliabadi HM Mahdipoor P Uludag H Response of drug sensitive and resistant breast cancer cells to combinatorial siRNA therapy.Mol Ther. 2013; 21: S82-S83Google Scholar,5Jia J Zhu F Ma X Cao Z Li Y Chen YZ Mechanisms of drug combinations: interaction and network perspectives.Nat Rev Drug Discov. 2009; 8: 111-128Crossref PubMed Scopus (658) Google Scholar,6Keith CT Borisy AA Stockwell BR Multicomponent therapeutics for networked systems.Nat Rev Drug Discov. 2005; 4: 71-78Crossref PubMed Scopus (631) Google Scholar,7Dancey JE Chen HX Strategies for optimizing combinations of molecularly targeted anticancer agents.Nat Rev Drug Discov. 2006; 5: 649-659Crossref PubMed Scopus (303) Google Scholar The benefits of using multiple drugs are supported by clinical data showing synergistic effects that are superior to the sum of the therapeutic effects of each drug, and conventional drug regimens include at least two drugs administered together or in sequence. The study reported by Blanco et al. in this issue addresses the synergistic targeting of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway by delivering both paclitaxel and rapamycin through nanoparticle (NP) incorporation.8Blanco E Sangai T Wu S Hsiao A Ruiz-Esparza GU Gonzalez-Delgado CA et al.Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway.Mol Ther. 2014; 22: 1310-1319Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar The results demonstrate the therapeutic superiority of delivering rapamycin and paclitaxel coencapsulated into a single NP formulation (nano-polypharmacy) over concomitant administration of separate NP formulations loaded with each drug individually. The results also demonstrate the critical importance of maintaining a particular drug ratio in the tumor so as to maximize the therapeutic efficacy. The activation of the PI3K/Akt/mTOR signaling pathway has been reported for numerous cancers, particularly pancreatic, ovarian, glioblastoma, and breast cancer.9Faivre S Kroemer G Raymond E Current development of mTOR inhibitors as anticancer agents.Nat Rev Drug Discov. 2006; 5: 671-688Crossref PubMed Scopus (850) Google Scholar Rapamycin and its derivatives (temsirolimus, everolimus, and AP23573) are established inhibitors of mTOR as oral or intravenous formulations. Currently 20 clinical trials are under way to test either rapamycin or its derivatives for cancer therapy in combination with at least one other chemotherapeutic drug. Paclitaxel and docetaxel are taxane drugs used for chemotherapy because of their ability to stabilize microtubules, thus interfering with the normal breakdown of microtubules during mitosis. Approximately 2,000 clinical trials are currently testing paclitaxel for cancer therapy. As reported in this issue, Blanco and colleagues tested NP formulations coencapsulating rapamycin and paclitaxel to inhibit several downstream targets of mTOR.8Blanco E Sangai T Wu S Hsiao A Ruiz-Esparza GU Gonzalez-Delgado CA et al.Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway.Mol Ther. 2014; 22: 1310-1319Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Nanomedicine is a multidisciplinary field that uses nanotechnology for diagnosis, therapy, and other medical applications.10Alexis F Rhee JW Richie JP Radovic-Moreno AF Langer R Farokhzad OC New frontiers in nanotechnology for cancer treatment.Urol Oncol. 2008; 26: 74-85Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar,11Sprintz M Nanotechnology for advanced therapy and diagnosis.Biomed Microdevices. 2004; 6: 101-103Crossref PubMed Scopus (9) Google Scholar,12Wang X Yang L Chen ZG Shin DM Application of nanotechnology in cancer therapy and imaging.CA Cancer J Clin. 2008; 58: 97-110Crossref PubMed Scopus (548) Google Scholar,13Davis SS Biomedical applications of nanotechnology—implications for drug targeting and gene therapy.Trends Biotechnol. 1997; 15: 217-224Abstract Full Text PDF PubMed Scopus (377) Google Scholar,14Farokhzad OC Nanotechnology for drug delivery: the perfect partnership.Expert Opin Drug Deliv. 2008; 5: 927-929Crossref PubMed Scopus (59) Google Scholar,15Alexis F Pridgen E Molnar LK Farokhzad OC Factors affecting the clearance and biodistribution of polymeric nanoparticles.Mol Pharm. 2008; 5: 505-515Crossref PubMed Scopus (2739) Google Scholar,16Peer D Karp JM Hong S Farokhzad OC Margalit R Langer R Nanocarriers as an emerging platform for cancer therapy.Nat Nanotechnol. 2007; 2: 751-760Crossref PubMed Scopus (6916) Google Scholar Although the National Nanotechnology Initiative defines the nanoscale as having an upper size limit of 100 nm (http://www.nano.gov/about-nni/glossary), NPs as large as 150 nm are currently in clinical trials of drugs including small molecules, peptides, proteins, and nucleic acids. The breakthrough potential of NPs has resulted in several US Food and Drug Administration (FDA)-approved, first-generation, nontargeted drug delivery systems.17Alexis F Pridgen E Langer R Farokhzad O Nanoparticle technologies for cancer therapy.in: Schäfer-Korting M Drug Delivery (Handbook of Experimental Pharmacology. 197. Springer, Berlin, Germany2010: 55-86Google Scholar,18Davis ME Chen Z Shin DM Nanoparticle therapeutics: an emerging treatment modality for cancer.Nat Rev Drug Discov. 2008; 7: 771-782Crossref PubMed Scopus (3541) Google Scholar,19Ferrari M Cancer nanotechnology: opportunities and challenges.Nat Rev Cancer. 2005; 5: 161-171Crossref PubMed Scopus (3832) Google Scholar Previous reports have demonstrated greater accumulation of NPs in tumors than in liver and spleen, owing to the NPs' size and shape, which can significantly affect their biodistribution and circulation time.15Alexis F Pridgen E Molnar LK Farokhzad OC Factors affecting the clearance and biodistribution of polymeric nanoparticles.Mol Pharm. 2008; 5: 505-515Crossref PubMed Scopus (2739) Google Scholar,20Petros RA DeSimone JM Strategies in the design of nanoparticles for therapeutic applications.Nat Rev Drug Discov. 2010; 9: 615-627Crossref PubMed Scopus (2876) Google Scholar Compared with free drugs, there are several advantages of using NP drug delivery systems to deliver a single drug: (i) patients can tolerate higher maximum doses without additional side effects, (ii) greater bioavailability and solubility, and (iii) a larger dose of therapeutic drug reaches the tumor. The hydrodynamic diameter of the poly(ethylene glycol)-poly(ε-caprolactone) NP used by Blanco et al. is approximately 10 nm, which is sufficiently large to avoid easy filtration and excretion by the kidney but small enough that it can exploit the vascular defects associated with the enhanced permeability and retention effect in tumors.8Blanco E Sangai T Wu S Hsiao A Ruiz-Esparza GU Gonzalez-Delgado CA et al.Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway.Mol Ther. 2014; 22: 1310-1319Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Therefore, it is expected that the polymeric micelles will circulate for a prolonged period, accumulate into the tumor, internalize into cancer cells through nonspecific endocytosis due to rapid cellular division, and release paclitaxel and rapamycin for a prolonged period of time. Indeed, the authors demonstrate that both drugs are released through diffusion for 24 hours and without a burst release. The authors further show that the ratio of drugs coencapsulated into polymeric micelles can be maintained by varying the feed-drug proportion during the preparation of the NP formulations. This is critical because the precision of the drug dose can ultimately determine its therapeutic efficacy. Blanco et al. next tested the hypothesis that a precise ratio of rapamycin to paclitaxel is required to achieve a synergistic efficacy on breast cancer cell lines.8Blanco E Sangai T Wu S Hsiao A Ruiz-Esparza GU Gonzalez-Delgado CA et al.Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway.Mol Ther. 2014; 22: 1310-1319Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar They found that NPs loaded with a single drug are less cytotoxic than NPs loaded with the drug combination. These in vitro results demonstrate both the need to maintain a precise ratio of rapamycin to paclitaxel in NP formulations and the enhanced cytotoxicity of encapsulating both drugs into a single NP formulation. The authors next report data showing that coencapsulation of the drugs in the NP formulation is critical to maintaining a beneficial drug ratio in the tumor. The rapamycin-to-paclitaxel ratio (~3:1) was maintained 48 hours after administration and was established as the synergistic ratio in vitro. Importantly, coadministration of NPs loaded with rapamycin and NPs loaded with paclitaxel did not maintain this drug ratio in the tumor for 48 hours. Although the total concentration of rapamycin and paclitaxel was higher in tumors of animals treated with concomitant administration of drug-loaded NPs than the concentration of both drugs from the nano-polypharmacy formulation, the appropriate drug ratio was not maintained. The differential delivery of drug to the tumor when coadministering NP drug formulations is perhaps due to the differential pharmacokinetics of NPs loaded with rapamycin versus paclitaxel. Panagi et al.21Panagi Z Beletsi A Evangelatos G Livaniou E Ithakissios DS Avgoustakis K Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGA–mPEG nanoparticles.Int J Pharmaceutics. 2001; 221: 143-152Crossref PubMed Scopus (206) Google Scholar have demonstrated that the administration dose of poly (lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs significantly affects their biodistribution. Because the ratio of the drugs is maintained during the coadministration of the drug-loaded NPs, the dose of each NP formulation differs and may affect the accumulation of each NP drug-loaded formulation into the tumor. There was significantly greater tumor regression by the nano-polypharmacy formulation than with the mixture of NP formulations loaded with rapamycin and paclitaxel. In addition, there was significantly greater tumor regression for nano-polypharmacy formulations delivering a rapamycin-to-paclitaxel ratio of 3:1 than with a ratio of 2:1, as predicted by the in vitro results. Further pharmacological studies are expected to be of use in determining cytotoxicity in healthy organs—one of the main challenges associated with free-drug combination treatments. NPs delivering drug combinations could also help to overcome challenges associated with drug resistance. High levels of p-Akt in breast cancer patients treated with tamoxifen are associated with reduced survival time. Additional studies using cell lines resistant to rapamycin could provide a better understanding of the potential of nano-polypharmacy to overcome drug resistance. It is possible that the drug combination ratio for cell sensitivity and cell resistance may differ—a possibility that will support personalized therapy using nano-polypharmacy formulations.22Chiang A Million RP Personalized medicine in oncology: next generation.Nat Rev Drug Discov. 2011; 10: 895-896Crossref PubMed Scopus (18) Google Scholar,23Schilsky RL Personalized medicine in oncology: the future is now.Nat Rev Drug Discov. 2010; 9: 363-366Crossref PubMed Scopus (239) Google Scholar It is unclear, however, whether nano-polypharmacy will be useful for drug combinations that do not require a very precise drug ratio concentration for synergistic efficacy. Although coencapsulation of drugs into nanomaterials is expected to progress from preclinical to clinical studies, regulatory issues must also be addressed. However, it is not expected that regulatory challenges will be significantly greater than for single-drug delivery nanomaterials,24Desai N Challenges in development of nanoparticle-based therapeutics.AAPS J. 2012; 14: 282-295Crossref PubMed Scopus (538) Google Scholar,25Zolnik BS Sadrieh N Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs.Adv Drug Deliv Rev. 2009; 61: 422-427Crossref PubMed Scopus (101) Google Scholar in that the review process is similar to that for other nanomaterials except that combination products are regulated by the Office of Combination Products at the FDA.