Transforming Nanomedicines From Lab Scale Production to Novel Clinical Modality.

The use of nanoparticles as anticancer drug carriers has been studied for over 50 years. These nanoparticles that can carry drugs are now termed "nanomedicines". Since the approval of the first FDA "nanodrug", DOXIL in 1995, tremendous efforts have been made to develop hundreds of nanomedicines based on different materials. The development of drug nanocarriers (NCs) for cancer therapy is especially challenging and requires multidisciplinary approach. Not only is the translation from a lab scale production of the NCs to clinical scale a challenge, but tumor biology and its unique physiology also possess challenges that need to be overcome with cleverer approaches. Yet, with all the efforts made to develop new strategies to deliver drugs (including small molecules and biologics) for cancer therapy, the number of new NCs that are reaching clinical trials is extremely low. Here we discuss the reasons most of the NCs loaded with anticancer drugs are not likely to reach the clinic and emphasize the importance of understanding tumor physiology and heterogeneity, the use of predictive animal models, and the importance of sharing data as key denominators for potential successful translation of NCs from a bench scale into clinical modality for cancer care.

[1]  Joshy George,et al.  Whole–genome characterization of chemoresistant ovarian cancer , 2015, Nature.

[2]  T. Honda,et al.  Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D 1 as an Anti-Inflammatory Target , 2022 .

[3]  Wolfgang A. Weber,et al.  Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging , 2007, Proceedings of the National Academy of Sciences.

[4]  D. Peer,et al.  RNAi-based nanomedicines for targeted personalized therapy. , 2012, Advanced drug delivery reviews.

[5]  Dan Peer,et al.  Omics-based nanomedicine: the future of personalized oncology. , 2014, Cancer letters.

[6]  O. Nilsson,et al.  Detection of metastatic colon cancer cells in sentinel nodes by flow cytometry. , 2008, Journal of immunological methods.

[7]  R. Sun,et al.  Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm , 2008, Proceedings of the National Academy of Sciences.

[8]  Patrick Soon-Shiong,et al.  Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status , 2008, Anti-cancer drugs.

[9]  H. Mellstedt,et al.  Epithelial cell adhesion molecule expression (CD326) in cancer: a short review. , 2012, Cancer treatment reviews.

[10]  T. Ono,et al.  Augmented EPR effect by photo-triggered tumor vascular treatment improved therapeutic efficacy of liposomal paclitaxel in mice bearing tumors with low permeable vasculature. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[11]  P. Low,et al.  Fast release of lipophilic agents from circulating PEG-PDLLA micelles revealed by in vivo forster resonance energy transfer imaging. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[12]  T. Mészáros,et al.  Features of complement activation-related pseudoallergy to liposomes with different surface charge and PEGylation: comparison of the porcine and rat responses. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[13]  J. Lieberman,et al.  Special delivery: targeted therapy with small RNAs , 2011, Gene Therapy.

[14]  D. Peer,et al.  Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target , 2008, Science.

[15]  M. Socinski,et al.  Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  S. P. Moulik,et al.  Solution behavior of normal and reverse triblock copolymers (pluronic L44 and 10R5) individually and in binary mixture. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[17]  V. Torchilin Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery , 2014, Nature Reviews Drug Discovery.

[18]  Nathan M Belliveau,et al.  Microfluidic Synthesis of Highly Potent Limit-size Lipid Nanoparticles for In Vivo Delivery of siRNA , 2012, Molecular therapy. Nucleic acids.

[19]  A. Mandal,et al.  Resveratrol stabilized gold nanoparticles enable surface loading of doxorubicin and anticancer activity. , 2014, Colloids and surfaces. B, Biointerfaces.

[20]  Qiang Zhang,et al.  A Novel Paclitaxel Microemulsion Containing a Reduced Amount of Cremophor EL: Pharmacokinetics, Biodistribution, and In Vivo Antitumor Efficacy and Safety , 2011, Journal of biomedicine & biotechnology.

[21]  J. Lieberman,et al.  Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies , 2015, Proceedings of the National Academy of Sciences.

[22]  John C Kraft,et al.  Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. , 2014, Journal of pharmaceutical sciences.

[23]  Dan Peer,et al.  A daunting task: manipulating leukocyte function with RNAi , 2013, Immunological reviews.

[24]  S Thayumanavan,et al.  Noncovalent encapsulation stabilities in supramolecular nanoassemblies. , 2010, Journal of the American Chemical Society.

[25]  Hatem Fessi,et al.  Preparation, Characterization and Applications of Liposomes: State of the Art , 2012 .

[26]  Dan Peer,et al.  Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles. , 2014, Nanoscale.

[27]  S. Fu,et al.  Preclinical humanized mouse model with ectopic ovarian tissues , 2014, Experimental and therapeutic medicine.

[28]  S. Wise Nanocarriers as an emerging platform for cancer therapy , 2007 .

[29]  J. Majoral,et al.  Advances in combination therapies based on nanoparticles for efficacious cancer treatment: an analytical report. , 2015, Biomacromolecules.

[30]  A. PrietoGarcía,et al.  Immunoglobulin E-mediated severe anaphylaxis to paclitaxel. , 2010 .

[31]  T. Ishida,et al.  Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin. , 2014, Biological & pharmaceutical bulletin.

[32]  S. Goldberg,et al.  Therapeutic Efficacy of Combining PEGylated Liposomal Doxorubicin and Radiofrequency (RF) Ablation: Comparison between Slow-Drug-Releasing, Non-Thermosensitive and Fast-Drug-Releasing, Thermosensitive Nano-Liposomes , 2014, PloS one.

[33]  C. Sander,et al.  Evaluating cell lines as tumour models by comparison of genomic profiles , 2013, Nature Communications.

[34]  Z. Duan,et al.  Biodistribution and Pharmacokinetic Analysis of Paclitaxel and Ceramide Administered in Multifunctional Polymer-Blend Nanoparticles in Drug Resistant Breast Cancer Model , 2008, Molecular pharmaceutics.

[35]  S. P. Moulik,et al.  Interaction of Cetyltrimethylammonium Bromide with Sodium Dodecyl-Sulfate in Electrolyte and Nonelectrolyte Environments , 1982 .

[36]  Joonyoung Park,et al.  Nanoparticle characterization: state of the art, challenges, and emerging technologies. , 2013, Molecular pharmaceutics.

[37]  G. Koning,et al.  Cetuximab-oxaliplatin-liposomes for epidermal growth factor receptor targeted chemotherapy of colorectal cancer. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[38]  H. Hirano,et al.  Wogonin, a Plant Flavone, Potentiates Etoposide‐Induced Apoptosis in Cancer Cells , 2007, Annals of the New York Academy of Sciences.

[39]  R. Kamm,et al.  Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function , 2012, Proceedings of the National Academy of Sciences.

[40]  Andreas Kjær,et al.  Positron Emission Tomography Based Elucidation of the Enhanced Permeability and Retention Effect in Dogs with Cancer Using Copper-64 Liposomes. , 2015, ACS nano.

[41]  Dan Peer,et al.  Nanotoxicity and the importance of being earnest. , 2012, Advanced drug delivery reviews.

[42]  Y. Yeo,et al.  Beyond the imaging: limitations of cellular uptake study in the evaluation of nanoparticles. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[43]  Karen C Liu,et al.  Extracellular stability of nanoparticulate drug carriers , 2014, Archives of pharmacal research.

[44]  P. Couvreur,et al.  Lipid prodrug nanocarriers in cancer therapy. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[45]  Khalil Arshak,et al.  Review on State-of-the-art in Polymer Based pH Sensors , 2007, Sensors.

[46]  V. Torchilin,et al.  Current trends in the use of liposomes for tumor targeting. , 2013, Nanomedicine.

[47]  Markku Miettinen,et al.  KIT (CD117): A Review on Expression in Normal and Neoplastic Tissues, and Mutations and Their Clinicopathologic Correlation , 2005, Applied immunohistochemistry & molecular morphology : AIMM.

[48]  Dan Peer,et al.  Toxicity profiling of several common RNAi-based nanomedicines: a comparative study , 2013, Drug Delivery and Translational Research.

[49]  S. Panigrahi,et al.  Two-dimensional surface properties of an antimicrobial hydantoin at the air-water interface: an experimental and theoretical study. , 2010, Colloids and surfaces. B, Biointerfaces.

[50]  N. Artzi,et al.  RNAi nanomaterials targeting immune cells as an anti-tumor therapy: the missing link in cancer treatment? , 2016 .

[51]  Y. Barenholz,et al.  Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles: a porcine model. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[52]  Dan Peer,et al.  Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles. , 2015, ACS nano.

[53]  Matthew T. Basel,et al.  Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs , 2012, BioResearch open access.

[54]  Ze-yong Li,et al.  One-pot construction of functional mesoporous silica nanoparticles for the tumor-acidity-activated synergistic chemotherapy of glioblastoma. , 2013, ACS applied materials & interfaces.

[55]  L. Mayer,et al.  Nanoscale particulate systems for multidrug delivery: towards improved combination chemotherapy. , 2014, Therapeutic delivery.

[56]  Manish Kohli,et al.  Nanoparticles for combination drug therapy. , 2013, ACS nano.

[57]  V. Poroikov,et al.  Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3 , 2018, International journal of molecular sciences.

[58]  D. Peer Immunotoxicity derived from manipulating leukocytes with lipid-based nanoparticles. , 2012, Advanced drug delivery reviews.

[59]  Liangfang Zhang,et al.  Nanoparticle-assisted combination therapies for effective cancer treatment. , 2010, Therapeutic delivery.

[60]  G. Muehllehner,et al.  Positron emission tomography , 2006, Physics in medicine and biology.

[61]  Alexander V Kabanov,et al.  Can nanomedicines kill cancer stem cells? , 2013, Advanced drug delivery reviews.

[62]  Dan Peer,et al.  Localized RNAi therapeutics of chemoresistant grade IV glioma using hyaluronan-grafted lipid-based nanoparticles. , 2015, ACS nano.

[63]  D. Peer,et al.  Tumor-targeted hyaluronan nanoliposomes increase the antitumor activity of liposomal Doxorubicin in syngeneic and human xenograft mouse tumor models. , 2004, Neoplasia.

[64]  Dan Peer,et al.  Modulation of drug resistance in ovarian adenocarcinoma using chemotherapy entrapped in hyaluronan-grafted nanoparticle clusters. , 2014, ACS nano.

[65]  W. Jane,et al.  Peptide-Mediated Liposomal Doxorubicin Enhances Drug Delivery Efficiency and Therapeutic Efficacy in Animal Models , 2013, PloS one.

[66]  Fengping Tan,et al.  Dual-targeting nanocarrier system based on thermosensitive liposomes and gold nanorods for cancer thermo-chemotherapy. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[67]  H. Maeda Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting , 2012, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[68]  Liandong Deng,et al.  Sustained release of PTX-incorporated nanoparticles synergized by burst release of DOX⋅HCl from thermosensitive modified PEG/PCL hydrogel to improve anti-tumor efficiency. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[69]  Didier Gourier,et al.  Nanoprobes with near-infrared persistent luminescence for in vivo imaging , 2007, Proceedings of the National Academy of Sciences.