Intratumoral Fate of Functional Nanoparticles in Response to Microenvironment Factor: Implications on Cancer Diagnosis and Therapy
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Advanced Drug Delivery Reviews 143 (2019) 37–67 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Intratumoral fate of functional nanoparticles in response to microenvironment factor: Implications on cancer diagnosis and therapy Jinrong Peng a,1,QianYangb,1,KunShia, Yao Xiao a,XiaweiWeia,⁎, Zhiyong Qian a,⁎ a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041,Sichuan,PRChina b School of Pharmacy, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu 610500, Sichuan, PR China article info abstract Article history: The extraordinary growth and progression of tumor require enormous nutrient and energy. Unregulated behav- Received 29 October 2018 iors of cancer cell progressing and persistently change of tumor microenvironment (TME) which acts as the soil Received in revised form 4 June 2019 for cancer growth and metastasis are the ubiquitous features. The tumor microenvironment exhibits some Accepted 24 June 2019 unique features which differ with the normal tissues. While the nanoparticles get through the blood vessel leak- Available online 2 July 2019 age, they encounter immediately and interact directly with these microenvironment factors. These factors may Keywords: inhibit the diffusion of nanoparticles from penetrating through the tumor, or induce the dissociation of nanopar- Functional nanoparticles ticles. Different nanoparticles encountered with different intratumoral microenvironment factors end up in dif- Intratumoral fate ferent way. Therefore, in this review, we first briefly introduced the formations, distributions, features of some Tumor microenvironment intratumoral microenvironment, and their effects on the tumor progression. They include extracellular matrix Cancer diagnosis (ECM), matrix metalloproteinases (MMPs), acidic/hypoxia environment, redox environment, and tumor associ- Cancer therapy ated macrophages (TAMs). We then exemplified how these factors interact with nanoparticles and emphasized the potentials and challenges of nanoparticle-based strategies facing in enhancing intratumoral penetration and tumor microenvironment remodeling. We hope to give a simple understanding of the interaction between these microenvironment factors and the nanoparticles, thus, favors the designing and constructing of more ideal func- tional nanoparticles. © 2019 Elsevier B.V. All rights reserved. Contents 1. Introduction............................................................... 38 2. Bigpictureoftumormicroenvironmentfactors............................................... 39 3. Extracellularmatrix(ECM)andECM-nanoparticleinteractions........................................ 41 3.1. Formationandfeatures....................................................... 41 3.1.1. LocationofECM...................................................... 41 3.1.2. ThecomponentsandcompositionsofECM.......................................... 41 3.1.3. DysregulationofECMandout-of-balanceofECMhomeostasisintumor.............................41 3.2. FateofnanoparticleinECM..................................................... 43 3.3. Implicationsonnanomedicine-basedcancerdiagnosisandtherapy................................... 44 4. Metalloproteinases(enzymes)andMMP-responsivenanoparticles...................................... 45 4.1. MMPs (enzymes): basic structure and classifications......................................... 45 4.2. FunctionsandexpressionsofMMPs................................................. 46 4.2.1. Basicfunctions...................................................... 46 4.2.2. Secretionorexpression................................................... 46 4.2.3. EffectsofMMPsontumorprogressionandinvasion...................................... 46 4.3. CleavagesequencesforMMPs.................................................... 47 4.4. MMPsresponsivenanomedicines:nowandfuture.......................................... 48 ⁎ Corresponding authors. E-mail addresses: [email protected] (X. Wei), [email protected] (Z. Qian). 1 These authors did equal contributions to this work. https://doi.org/10.1016/j.addr.2019.06.007 0169-409X/© 2019 Elsevier B.V. All rights reserved. 38 J. Peng et al. / Advanced Drug Delivery Reviews 143 (2019) 37–67 5. TumoracidityandpH-responsivenanomaterialsfortumordiagnosisandtherapy................................49 5.1. Formationanddistributionoftumoracidity..............................................49 5.2. pH-responsiveunitsfortheconstructionofpH-responsivenanocarriers.................................51 5.3. pH-responsivenanomaterialsfortumordiagnosisandtherapy.....................................51 5.3.1. Preciseandactivatedtumordiagnosis............................................51 5.3.2. Preciseandactivatedtumortherapy.............................................53 5.3.3. pH-responsivenanotheranostics...............................................56 5.4. Beyondthefateofdissociationoftheintratumoralnanoparticlesinacidicenvironment..........................56 6. Redoxenvironment............................................................57 6.1. Componentsandfeatures......................................................57 6.2. GSHresponsiveunitsandROSresponsiveunits............................................57 6.2.1. GSH-responsiveunits....................................................58 6.2.2. ROS-responsivenanomaterials................................................58 6.3. Constructionsandapplicationsofredoxresponsivenanomedicines...................................58 6.3.1. GSH-responsivenanocarriers................................................58 6.3.2. ROS-sensitivenanomaterials................................................58 6.3.3. NanomaterialsforimprovingROS-generationinantitumortherapy...............................59 7. Tumor-associatedmacrophages(TAMs)...................................................60 7.1. FormationofTAMs.........................................................60 7.2. FunctionsofTAMs.........................................................60 7.3. InvivofateofnanoparticleswhilefacingwithTAMs..........................................60 8. Localdeliveryandtheintratumoralfateofnanoparticles...........................................61 9. Perspectivesandchallenges........................................................62 Acknowledgements..............................................................63 References...................................................................63 1. Introduction solid tumor was estimated as only 0.7% of an injected dose of nanopar- ticles [15]. With active tumor-targeting ligand modification, the median It has been N20 years since the first nanoparticle drug – Doxil had delivery efficiency is just increased to 0.9%. And the number of the nano- been approved by the U.S. Food & Drug Administration (FDA) at 1990s particles directly interacted with cancer cells is as low as 0.0014% [16]. when had pasted N30 years from the first paper on liposomes published Although some drug developers point out that the free drug molecules in mid-1960s. During this period, which ranges more than half century, accumulate with efficiencies are just one-tenth to one one-hundredth either the scale of clinical translational nanomedicines or the research the median efficiencies of the nanoparticle-based formulations depth of the biological and multi-disciplinary basic theory of (nanomedicines) and the debates about the controversial low delivery nanomedicine has been greatly developed. It has been reported that efficiency is still ongoing, the uncovered intratumoral biological barriers N700 open or active clinical trials have been undergoing (search results actually indicate a bumpy road while the nanoparticles enter into the from ClinicalTrials.gov). Meanwhile, in fundamental research fields, the tumor tissues to directly interact with cancer cells. uncovering of enhanced permeability and retention (EPR) effect and its The extraordinary growth of tumor requires enormous nutrient and prevailing have promoted the development nanosystems [1,2], al- energy. Unregulated behaviors of cancer cell progressing and persis- though its extent and homogeneity as well as susceptibility still need tently change of tumor microenvironment (TME) which acts as the to be further validated [3]; the heterogeneity of cancer which mainly soil for cancer growth and metastasis are the ubiquitous features [17]. accounted for the poor therapeutic outcome of chemotherapy or immu- It forces the cancer to alter their metabolic behaviors and adapt to the notherapy, etc. has also been identified [4,5]; rethinking and further de- upregulated glucose metabolism which promoting the cancer cells velopment of tumor microenvironment (TME) have provided more transforming to more invasive subtype [18]. The expanding neoplastic biological information on its effect on nanomedicine-based tumor ther- mass and disorganized tumor vasculature lead to the formation of phys- apy [6,7]; active tumor-targeting has been rendered and proved to be a iological environment of tumor microenvironment with ubiquitous more efficient strategy for nanomedicine accumulation in tumor site; features. then, “protein corona” has been identified as the “prime culprit” caused After the nanoparticles get through the endothelial cell layer by EPR the failure of active tumor-targeting [8,9], while the active tumor effect or transcytosis, they will firstly encounter the