Multiplexed nanomedicine for brain tumors: nanosized Hercules to tame our Lernaean Hydra inside?
2017; Future Medicine; Volume: 12; Issue: 20 Linguagem: Inglês
10.2217/nnm-2017-0260
ISSN1748-6963
AutoresWojciech K. Panek, Omar F. Khan, Dou Yu, Maciej S. Lesniak,
Tópico(s)Nanoplatforms for cancer theranostics
ResumoNanomedicineVol. 12, No. 20 EditorialFree AccessMultiplexed nanomedicine for brain tumors: nanosized Hercules to tame our Lernaean Hydra inside?Wojciech K Panek‡, Omar F Khan‡, Dou Yu & Maciej S LesniakWojciech K Panek‡ Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA, Omar F Khan‡ David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Institute for Medical Engineering & Science, Harvard MIT Division of Health Science & Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA, Dou Yu Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA & Maciej S Lesniak*Author for correspondence: Tel.: +1 312 926 1094; Fax: +1 312 695 3294; E-mail Address: maciej.lesniak@northwestern.edu Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USAPublished Online:3 Oct 2017https://doi.org/10.2217/nnm-2017-0260AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: GBMnanoparticlenanomedicinebrain tumorsiRNAconvection enhanced deliveryBTIC/brain tumor initiating cellsstem cell transcription factorFirst draft submitted: 17 August 2017; Accepted for publication: 30 August 2017; Published online: 3 October 2017A vivid embodiment of human fear is the gruesome monster Lernaean Hydra from Greek and Roman mythology, which is depicted as a multiheaded serpent guarding the entry to the underworld with nightmarish regenerative powers: for every chopped off head, replacements would multiply and the surging demonic ferocity would ensue (Figure 1). Similar motifs of such hopeless terror scatter across cultures, and the Greco-Roman fable teaches that divine intervention and the incredible might of the legendary Hercules were needed to kill the beast. A remarkable parallel can be drawn with our continuing, capricious combat against one of the deadliest human diseases to date: glioblastoma (GBM). With merely 14 months of average life expectancy despite maximal combination therapy of surgical resection, radiation and chemotherapy, GBM is the Hydra inside marked by persistent therapy resistance and unstoppable recurrence. Brain tumor-initiating cells (BTICs) are analogous to the regenerative venomous Hydra heads, in that existing therapeutic stress from classic therapy modalities only emboldens the aggressive progression of the disease, driven by these adaptive cell types in GBM. An obvious question is: where is our rescuer, Hercules? The evolution of nanotechnologies offers hope to formulate a nanosized Hercules to attack BTICs at the core, the labor that inspired us to devote this editorial to elaborate the implications.Figure 1. Hercules, by John Singer Sargent (1921), depicting the epic battle with the Lernaean Hydra.Museum of Fine Arts, Boston, MA, USA. Wikimedia Commons.Evolving nano formulations of RNAi expand therapeutic potential for heterogeneous GBMRNAi via safe and efficacious delivery of siRNAs is on the rise at the clinical translation front. It can directly correct aberrant gene expressions that instigate malignant tumor growth in the CNS, which can be 'undruggable' when using small molecules and biologicals (e.g., antibodies). A variety of nanosized biomaterials have been formulated to carry out this repair mission with specific therapeutic targets identified by molecular and genetic probing of the cancer genome from patient-derived tissue samples. The formulation of nano vehicles for RNAi is critical for the clinical success. Early efforts focused on dendrimer inspired nano constructs and solid nanoparticles (NPs), followed by the biomimetic development of tumor derived exosome-based experimental therapeutics for brain delivery [1–19]. The engineering potential of cell type selectivity for these vehicles is limited. Further development of novel lipopolymeric nanoparticle (LPNP) platforms incorporates engineered polymers in the lipid bilayer outer shell, allowing for flexible cellular uptake properties [20–22]. The ability to easily modify the chemistry of the lipid NP surface was demonstrated by recent advancements [9,23]. In the latest article by Yu et al. [23], BTIC specific uptake of LPNPs was observed, which opens the opportunity to fine tune the tumor targeting selectivity of LPNPs, thereby enhancing therapeutic potency while minimizing off-targeting or healthy tissue toxicity.Multi-targeting capacity is vital for nanoRNAi formulations against patient specific GBMThe evolution of nano carriers for siRNAs started with single core solid nano constructs based on classic materials such as gold [24], iron oxide, chitosan [5,17], porous silica [8], sugar [15], solid lipids [3,4,6,9] and an array of dendrimer inspired NPs [12]. Some of these applications showed early promise in effective RNAi of key GBM growth-promoting genes: Jensen et al. demonstrated that gold NP mediated siRNA knockdown of the oncoprotein Bcl2Like12 (Bcl2L12) reduced tumor growth [24]; Costa et al. demonstrated effective GBM inhibition using anti-miR-21 oligonucleotides, a different approach for tumor promoting miR-21 silencing [4]; and Danhier et al. also showed combined benefits of TMZ/chemo with chitosan based nano RNAi against Galectin and EGFR [5]. However, the most exciting potential of the latest multiplexed nano RNAi therapy against BTIC is the ability to customize the therapeutic targeting based on patient tissue features and the capacity to co-deliver synergistic multi-targeting siRNAs. Using a flexible LPNP nano carrier system, Yu et al. demonstrated sustained therapeutic benefit by incorporating four distinct siRNA constructs directed at four key master transcription factors, namely SOX2, OLIG2, SALL2 and POU3F2, in tumor growth driving BTICs [23]. The implication of this new advancement is that a variety of multiplexed RNAi therapy schemes are now possible based on an individual patient's tumor genetic profile, and efficacious personalized therapeutic outcomes are achievable even with increased evidence of intratumoral heterogeneity and post-therapy tumor metabolic adaptation. Given that diverse genetic drivers are continuously uncovered based on GBM BTIC characterization [25–27], therapeutic strategies targeting a singular genetic/epigenetic abnormality in GBM are insufficient to subdue the 'multiheaded monster'.Essential considerations for chemical engineering designs of nanoRNAi systemsThe journey towards efficacious nanomedicine for complex GBM starts with careful considerations of the nano construct design. For any nanoscale carrier delivering a therapeutic payload, form follows function. Drugs that are extremely hydrophobic are difficult to administer due to their low solubility and concomitant low bioavailability. For such payloads, a solid lipid NP or carbon nanotube construction can be advantageous. Their insoluble cores can partition the drug, and an outer hydrophilic layer, at times built using a surfactant, is used to promote cell membrane permeability. By contrast, RNAs, including siRNAs, are soluble and polyanionic. However, solubility does not mean greater bioavailability for RNA; the immune system responds to foreign RNAs as pathogenic, readily degrading them. Nucleotide chemical modifications can help prevent an immune response and degradation. Modified RNA can thus be attached to the surface of solid NPs. For example, gold particles with modified surface chemistries can enable covalent or electrostatic attachment. Charged materials do have trade-offs though, as materials with permanent charges can be more readily opsonized or toxic. Forgoing the NP paradigm and directly conjugating modified RNA to targeting moieties is another potential solution, though endosomal escape after uptake can potentially be compromised. Thus, the form of the nanoscale delivery carrier must solve these many RNA-specific challenges.Advantages of lipopolymeric nanoRNAi formulationsLPNPs are a promising solution. Flexible chemical synthesis means charge can be controlled. Ionizable materials, such as those containing amines, are temporarily switched to a cationic state to condense the polyanionic RNA and then returned to a neutral state. Thus, toxicity challenges caused by permanent charges are avoided. The ionizable feature is also leveraged for endosomal escape post-uptake through the proton sponge effect. Additionally, polymers can efficiently condense the RNA which, when combined with RNA chemical modification, can further prevent payload exposure and degradation. Moreover, ionizable amphiphilic polymers such as lipid polymers are both amenable to RNA payloads and NP self-assembly in aqueous environments, which obviates the need for organic solvents during production. Furthermore, NP stability can be influenced by the choice of polymer and lipid molecular weight. Even diameter can be affected, which directly impacts uptake in different tissues. Conversely, because polymer molecular weights can potentially alter the performance and characteristics of lipid polymeric NPs, their polydispersity must be carefully monitored and controlled during at-scale production.Engineering considerations for brain delivery of lipopolymeric nanoRNAi formulationsFor RNAi therapy in the brain, LPNPs offer an excellent balance of payload specificity, membrane permeability and toxicity, which can significantly boost their therapeutic index. Additionally, in terms of parenteral administration, direct injection further circumvents the challenge of crossing the blood–brain barrier after systemic delivery, which greatly focuses the therapy. However, with the large magnitude of lipid-polymer combinations possible by virtue of flexible, modular chemistry and extensive material screens may reveal new formulations that can traverse the barrier. Ionizable lipid polymeric NPs also contain and shield their RNA payloads, further avoiding localized charge-related material-induced effects and immune reactions in the brain. Another feature of lipid polymeric NPs is the RNA payload capacity. With higher ratios of RNA:lipid polymer, NPs can carry many copies of a siRNA or a multitude of different siRNAs. This type of multiplexing is tremendously advantageous because complex therapies requiring the silencing of multiple genes become possible. Moreover, one is not limited to equimolar mixes in siRNA in multiplexes. This means payloads can be proportioned to match the prevalence and duration of the target genes and gene products. Multiplexing may be useful in some screening applications as well. The multifunctional potential of the LPNP platform remains to be explored. Theoretically, the LPNP construct can be further customized for cell type selectivity given the differences in uptake dynamics observed for different brain cell types. Moreover, the cargo content can also include imaging reagents such as magnetic nanocore or quantum dots for in vivo and ex vivo biodistribution analysis after administration. Thus, the multimodal integration of functionality in LPNPs offers versatility and feasibility for clinical translation and real-time assessment in patients.Clinical prospects of nanomedicine for GBMClinical applications of nanomedicine for malignant brain tumors are rising. Several sophisticated nano formulations of RNAi or combination therapies are at the early clinical trial phases after promising preclinical proof of concept (Clinicaltrials.gov: NCT02766699, NCT01906385, NCT03020017, NCT00944801, NCT02340156, NCT02820454, NCT00470613 and NCT02022644) [28,29]. Although all current clinical trials focus on select therapeutic targets, it is yet to be seen whether multitargeting nano therapeutic strategies will translate and deliver superior antitumor efficacy. Beyond target selection, and despite the early indications of positive safety profiles for some of the nano therapeutics, there are additional factors of divergence between the various strategies that can potentially contribute to differences in therapeutic efficacy. The most important is the delivery route. Systemic delivery is a preferred route for experimental nanomedicine, because of the ostensible advantages of repeatability, minimal invasiveness and the supposedly unique blood–brain barrier penetrance capacity of most nano carriers. However, there is still a deep chasm between these perceived benefits and the actual ability to accumulate sufficient therapeutic dose at tumor sites after systemic injections to render meaningful therapeutic efficacy. With the demonstration of dose-dependent therapeutic benefits in experimental rodent models of GBM, Yu et al. confirmed recent evidence of intratumoral convection enhanced delivery (CED) using a subcutaneously implanted osmotic pump (Alzet™, Durect Corp., CA, USA). With increasing clinical interests for direct intratumoral delivery of GBM therapeutics via CED [30–35], this direction forgoes some of the perceptions of systemic delivery benefits and substitutes them with the potentially efficacious local accumulation of antitumor therapeutics. Clinical evaluation of CED based nano therapeutics for GBM is underway (NCT02022644). The potential for combinatorial clinical application with standard care (surgery, temozolomide and radiation) has yet to be tested and could be even greater than the multiplexed nanoRNAi alone. However, intratumoral delivery of nano therapeutics is an evolving strategy that requires continued technological innovations to reduce complications associated with the surgical implantation of catheters or other medical devices. Significant amelioration of the pain and inconvenience associated with the surgical implantation is needed for clinical translation.Challenges ahead for advancements in nanomedicine against GBMThe putative therapeutic potential of LPNP systems in rodent models of patient derived xenograft GBM has been demonstrated. Now, several engineering feats must be conquered to expedite clinical translation and expand the CNS applications of multiplexed LPNP therapies to other neurological disorders: The molecular mechanisms of LPNP uptake and endosomal escape need to be identified in order to enhance therapeutic efficacy of the LPNP system via engineering customization; brain delivery strategies and distribution plan must be refined to ensure full therapeutic coverage of the original and recurring GBM mass; methodologies must be established for dynamic sampling and therapeutic candidate adjustments based on tumor phenotype and genotype shift in response to therapy; enable therapeutic targeting of other brain tumor cellular compositions, such as immune cells and microenvironment, etc., to comprehensively purge the tumor promoting elements; the incorporation of more sophisticated genome engineering tools such as Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) technology; and enable non-invasive telemetry through, for example, live imaging modalities. 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Neuro Oncol. 17(Suppl. 2), ii3–ii8 (2015).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByThe Frontiers of Neurosurgery13 July 2019 Vol. 12, No. 20 Follow us on social media for the latest updates Metrics History Published online 3 October 2017 Published in print October 2017 Information© 2017 Future Medicine LtdKeywordsGBMnanoparticlenanomedicinebrain tumorsiRNAconvection enhanced deliveryBTIC/brain tumor initiating cellsstem cell transcription factorFinancial & competing interests disclosureThis work was supported by NIH R35CA197725 (MS Lesniak), Burroughs Wellcome Collaborative Travel Grant (D Yu), the Elsa U. Pardee Foundation Grant (D Yu). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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