New Treatment Options in Metastatic Pancreatic Cancer

Simple Summary The poor prognosis of pancreatic cancer (PC) is associated with several factors, such as diagnosis at an advanced stage, early distant metastases, and remarkable resistance to most conventional treatment options. The pathogenesis of PC seems to be significantly more complicated than originally assumed. To develop effective treatment schemes prolonging patient survival, a multidirectional approach encompassing different aspects of the cancer is needed. Particular directions have been established; however, further studies bringing them all together and connecting the strengths of each therapy are needed. This review aims to provide an overview of new or emerging therapeutic strategies for the more effective management of metastatic PC. Abstract Pancreatic cancer (PC) is the seventh leading cause of cancer death across the world. Poor prognosis of PC is associated with several factors, such as diagnosis at an advanced stage, early distant metastases, and remarkable resistance to most conventional treatment options. The pathogenesis of PC seems to be significantly more complicated than originally assumed, and findings in other solid tumours cannot be extrapolated to this malignancy. To develop effective treatment schemes prolonging patient survival, a multidirectional approach encompassing different aspects of the cancer is needed. Particular directions have been established; however, further studies bringing them all together and connecting the strengths of each therapy are needed. This review summarises the current literature and provides an overview of new or emerging therapeutic strategies for the more effective management of metastatic PC.

[1]  P. Hausner,et al.  BRAF-driven pancreatic cancer: prevalence, molecular features and therapeutic opportunities. , 2022, Molecular cancer research : MCR.

[2]  D. Sohal,et al.  Pancreatic Adenocarcinoma Management. , 2022, JCO oncology practice.

[3]  M. Fujishiro,et al.  The Role of the Microbiome in Pancreatic Cancer , 2022, Cancers.

[4]  A. Nasierowska-Guttmejer,et al.  Diabetes Mellitus and Pancreatic Ductal Adenocarcinoma—Prevalence, Clinicopathological Variables, and Clinical Outcomes , 2022, Cancers.

[5]  Sotorasib Tackles KRASG12C-Mutated Pancreatic Cancer. , 2022, Cancer discovery.

[6]  P. Stafford,et al.  Molecular characterization of KRAS wild type tumors in patients with pancreatic adenocarcinoma. , 2022, Clinical cancer research : an official journal of the American Association for Cancer Research.

[7]  Yusheng Ye,et al.  Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial. , 2022, The Lancet. Oncology.

[8]  T. Burns,et al.  First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety , 2022, Journal of Clinical Oncology.

[9]  V. Ganju,et al.  Exceptional Response to Olaparib and Pembrolizumab for Pancreatic Adenocarcinoma With Germline BRCA1 Mutation and High Tumor Mutation Burden: Case Report and Literature Review , 2022, JCO precision oncology.

[10]  S. Batra,et al.  Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies , 2022, Theranostics.

[11]  Hepato-Pancreato-Biliary Malignancies: Diagnosis and Treatment in the 21st Century , 2022 .

[12]  B. Goh,et al.  Taxol: Mechanisms of action against cancer, an update with current research , 2022, Paclitaxel.

[13]  Hezhe Lu,et al.  TGF-β Signaling and Resistance to Cancer Therapy , 2021, Frontiers in Cell and Developmental Biology.

[14]  A. Azmi,et al.  KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond. , 2021, Cancer treatment reviews.

[15]  D. Sleeman,et al.  Cobimetinib Plus Gemcitabine: An Active Combination in KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients in Previously Treated and Failed Multiple Chemotherapies , 2021, Journal of pancreatic cancer.

[16]  J. Berlin,et al.  Randomized Phase II Study of PARP Inhibitor ABT-888 (Veliparib) with Modified FOLFIRI versus FOLFIRI as Second-line Treatment of Metastatic Pancreatic Cancer: SWOG S1513 , 2021, Clinical Cancer Research.

[17]  E. O’Reilly,et al.  Pancreatic Cancer: A Review. , 2021, JAMA.

[18]  A. Azmi,et al.  Targeting KRAS in pancreatic cancer: new drugs on the horizon , 2021, Cancer and Metastasis Reviews.

[19]  Nguyen H. Tran,et al.  The role of microbiome in pancreatic cancer , 2021, Cancer and Metastasis Reviews.

[20]  Ming-Yuan Chen,et al.  The role of the bacterial microbiome in the treatment of cancer , 2021, BMC cancer.

[21]  J. Doloff,et al.  Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity. , 2021, Advanced drug delivery reviews.

[22]  P. Philip,et al.  BRCA mutations in pancreatic cancer and progress in their targeting , 2021, Expert opinion on therapeutic targets.

[23]  L. You,et al.  Advances in the epidemiology of pancreatic cancer: Trends, risk factors, screening, and prognosis. , 2021, Cancer letters.

[24]  K. Bensalah,et al.  Sunitinib Alone or After Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Is There Still a Role for Cytoreductive Nephrectomy? , 2021, European urology.

[25]  G. Peoples,et al.  Near Complete Pathologic Response to PD-1 Inhibitor and Radiotherapy in a Patient with Locally Advanced Pancreatic Ductal Adenocarcinoma , 2021, OncoTargets and therapy.

[26]  A. Klein Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors , 2021, Nature Reviews Gastroenterology & Hepatology.

[27]  Ji Luo KRAS mutation in pancreatic cancer. , 2021, Seminars in oncology.

[28]  Michelle A. Anderson,et al.  Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer , 2021, Clinical Cancer Research.

[29]  P. Philip,et al.  Randomized phase II trial of olaparib + pembrolizumab versus olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2+) mutations: SWOG S2001. , 2021 .

[30]  Joon-Oh Park,et al.  Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. , 2021 .

[31]  Edward J. Kim,et al.  Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma , 2021, Investigational New Drugs.

[32]  K. Almhanna,et al.  Pancreatic cancer and immune checkpoint inhibitors-still a long way to go. , 2021, Translational gastroenterology and hepatology.

[33]  H. McLeod,et al.  Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in KRAS Wild-Type Pancreatic Cancer , 2021, JCO precision oncology.

[34]  U. Capitanio,et al.  Neoadjuvant and adjuvant immunotherapy in renal cell carcinoma , 2021, World Journal of Urology.

[35]  A. Di Carlo,et al.  Surgical Management of Pancreatic Adenocarcinoma , 2021, Hepato-Pancreato-Biliary Malignancies.

[36]  Hepato-Pancreato-Biliary Malignancies , 2021 .

[37]  M. W. Saif,et al.  The Role of Olaparib in Metastatic Pancreatic Cancer. , 2021, Cancer medicine journal.

[38]  V. Dudeja,et al.  Role of the Microbiome in Pancreatic Cancer , 2021 .

[39]  Wei Liu,et al.  Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment , 2020, Technology in cancer research & treatment.

[40]  S. Ciernikova,et al.  The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma , 2020, Biomedicines.

[41]  A. Scarpa,et al.  KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities , 2020, Journal of Experimental & Clinical Cancer Research.

[42]  Reena Philip,et al.  FDA Approval Summary: Olaparib monotherapy or in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer. , 2020, The oncologist.

[43]  T. Gress,et al.  The Immune Microenvironment in Pancreatic Cancer , 2020, International journal of molecular sciences.

[44]  J. D'haese,et al.  Influence of Klebsiella pneumoniae and quinolone treatment on prognosis in patients with pancreatic cancer. , 2020, The British journal of surgery.

[45]  J. Desai,et al.  KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. , 2020, The New England journal of medicine.

[46]  M. O'Hara,et al.  Challenges and Opportunities for Pancreatic Cancer Immunotherapy. , 2020, Cancer cell.

[47]  A. Bertaut,et al.  Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment , 2020, BMC Cancer.

[48]  K. Toh,et al.  Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines , 2020, Science Advances.

[49]  F. Tacke,et al.  Enhancing the Efficacy of CAR T Cells in the Tumor Microenvironment of Pancreatic Cancer , 2020, Cancers.

[50]  E. Jaffee,et al.  The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities , 2020, Nature Reviews Clinical Oncology.

[51]  M. Karamouzis,et al.  Immunotherapy for pancreatic cancer: A 2020 update. , 2020, Cancer treatment reviews.

[52]  Lianfang Zheng,et al.  Novel therapeutic strategies and perspectives for metastatic pancreatic cancer: vaccine therapy is more than just a theory , 2020, Cancer Cell International.

[53]  Hengrui Zhu,et al.  PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications , 2020, Molecular Cancer.

[54]  E. Jaffee,et al.  Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future. , 2020, The Lancet. Oncology.

[55]  R. Ruiz-Cordero,et al.  Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer. , 2020, Surgical pathology clinics.

[56]  M. Mansournia,et al.  The potential role of chitosan‐based nanoparticles as drug delivery systems in pancreatic cancer , 2020, IUBMB life.

[57]  D. Slade PARP and PARG inhibitors in cancer treatment. , 2020, Genes & development.

[58]  Ying Zhang,et al.  Cancer vaccines: Targeting KRAS-driven cancers , 2020, Expert review of vaccines.

[59]  L. Buscail,et al.  Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer , 2020, Nature Reviews Gastroenterology & Hepatology.

[60]  Everolimus , 2020, Reactions Weekly.

[61]  Erlotinib , 2020, Reactions Weekly.

[62]  A. Tiwari,et al.  A Comprehensive Review of Diagnostic and Therapeutic Strategies for the Management of Pancreatic Cancer. , 2020, Critical reviews in oncogenesis.

[63]  M. Saif,et al.  Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer , 2019, Pancreas.

[64]  A. Maitra,et al.  Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma , 2019, British Journal of Cancer.

[65]  P. Hari,et al.  Gut microbiome and CAR-T therapy , 2019, Experimental Hematology & Oncology.

[66]  M. Hidalgo,et al.  From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer , 2019, Nature Reviews Clinical Oncology.

[67]  G. Miller,et al.  Harnessing the Microbiome for Pancreatic Cancer Immunotherapy. , 2019, Trends in cancer.

[68]  D. Nielsen,et al.  Checkpoint inhibitors in pancreatic cancer. , 2019, Cancer treatment reviews.

[69]  Joon-Oh Park,et al.  Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. , 2019, The New England journal of medicine.

[70]  E. Jaffee,et al.  Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study) , 2019, Clinical Cancer Research.

[71]  Steven J. M. Jones,et al.  NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma , 2019, Clinical Cancer Research.

[72]  Eugene J Koay,et al.  Early Detection of Pancreatic Cancer: Opportunities and Challenges. , 2019, Gastroenterology.

[73]  V. Balachandran,et al.  Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities. , 2019, Gastroenterology.

[74]  D. Ribatti,et al.  Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies , 2019, Cancers.

[75]  P. Philip,et al.  Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  P. Keegan,et al.  FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors , 2019, Clinical Cancer Research.

[77]  A. Rademaker,et al.  Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. , 2016, The oncologist.

[78]  G. Mills,et al.  State-of-the-art strategies for targeting the DNA damage response in cancer , 2018, Nature Reviews Clinical Oncology.

[79]  G. Lesinski,et al.  The Potential of CAR T Cell Therapy in Pancreatic Cancer , 2018, Front. Immunol..

[80]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[81]  David Bonekamp,et al.  NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. , 2018, Cancer discovery.

[82]  W. Jin,et al.  Angiogenesis in pancreatic cancer: current research status and clinical implications , 2018, Angiogenesis.

[83]  Kazunori Kataoka,et al.  Block Copolymer Micelles in Nanomedicine Applications. , 2018, Chemical reviews.

[84]  A. Daud,et al.  Immunotherapy for melanoma , 2018, Seminars in cutaneous medicine and surgery.

[85]  Alexander H. E. Morrison,et al.  Immunotherapy and Prevention of Pancreatic Cancer. , 2018, Trends in cancer.

[86]  R. Weinberg,et al.  Understanding the tumor immune microenvironment (TIME) for effective therapy , 2018, Nature Medicine.

[87]  S. Pushalkar,et al.  The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. , 2018, Cancer discovery.

[88]  H. Friess,et al.  Meta‐analysis of the impact of neoadjuvant therapy on patterns of recurrence in pancreatic ductal adenocarcinoma , 2018, BJS open.

[89]  R. Straussman,et al.  Intratumoral bacteria may elicit chemoresistance by metabolizing anticancer agents , 2018, Molecular & cellular oncology.

[90]  Lei Zheng,et al.  HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  A. Avan,et al.  Targeting stroma in pancreatic cancer: Promises and failures of targeted therapies , 2017, Journal of cellular physiology.

[92]  Noam Shental,et al.  Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine , 2017, Science.

[93]  L. Rosen,et al.  Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars , 2017, Targeted Oncology.

[94]  A. Varghese,et al.  CAR T‐cell therapy for pancreatic cancer , 2017, Journal of surgical oncology.

[95]  J. Lacy,et al.  Identification of Targetable ALK Rearrangements in Pancreatic Ductal Adenocarcinoma. , 2017, Journal of the National Comprehensive Cancer Network : JNCCN.

[96]  Alan Ashworth,et al.  PARP inhibitors: Synthetic lethality in the clinic , 2017, Science.

[97]  G. Hortobagyi,et al.  PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression , 2017, Clinical Cancer Research.

[98]  D. Baker,et al.  Irinotecan Liposome Injection , 2017, Hospital pharmacy.

[99]  O. Sansom,et al.  PD‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy , 2016, EMBO molecular medicine.

[100]  P. Kantoff,et al.  Cancer nanomedicine: progress, challenges and opportunities , 2016, Nature Reviews Cancer.

[101]  Mithat Gönen,et al.  Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma , 2017, Annals of surgery.

[102]  I. Ilic,et al.  Epidemiology of pancreatic cancer , 2016, World journal of gastroenterology.

[103]  A. Dalgleish,et al.  Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer , 2016, British Journal of Cancer.

[104]  Ian D. McGilvray,et al.  Mechanism of hard nanomaterial clearance by the liver , 2016, Nature materials.

[105]  L. Wood,et al.  Pancreatic cancer , 2016, The Lancet.

[106]  M. Falasca,et al.  Pancreatic cancer: Current research and future directions. , 2016, Biochimica et biophysica acta.

[107]  E. Giovannetti,et al.  Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective , 2016, Cancer Chemotherapy and Pharmacology.

[108]  Huan Meng,et al.  Irinotecan Delivery by Lipid-Coated Mesoporous Silica Nanoparticles Shows Improved Efficacy and Safety over Liposomes for Pancreatic Cancer. , 2016, ACS nano.

[109]  L. Buscail,et al.  Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. , 2016, European journal of cancer.

[110]  G. Stamp,et al.  Extended Survival after Complete Pathological Response in Metastatic Pancreatic Ductal Adenocarcinoma Following Induction Chemotherapy, Chemoradiotherapy, and a Novel Immunotherapy Agent, IMM-101 , 2015, Cureus.

[111]  R. Salgia,et al.  Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  T. Conroy,et al.  Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[113]  K. Toh,et al.  Ternary polyplex micelles with PEG shells and intermediate barrier to complexed DNA cores for efficient systemic gene delivery. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[114]  R. Brekken,et al.  Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. , 2015, Cancer letters.

[115]  Caroline H. Diep,et al.  Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer , 2015, Clinical Cancer Research.

[116]  E. Jaffee,et al.  PD-1/PD-L1 Blockade Together With Vaccine Therapy Facilitates Effector T-Cell Infiltration Into Pancreatic Tumors , 2015, Journal of immunotherapy.

[117]  A. Dalgleish,et al.  IMM-101, an immunotherapeutic agent in clinical development as an adjunctive treatment for pancreatic cancer , 2014, Journal of Immunotherapy for Cancer.

[118]  M. Sawyer,et al.  A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[119]  K. Kataoka,et al.  Optimized rod length of polyplex micelles for maximizing transfection efficiency and their performance in systemic gene therapy against stroma-rich pancreatic tumors. , 2014, Biomaterials.

[120]  Zhong-sheng Xia,et al.  Gene therapy in pancreatic cancer. , 2014, World journal of gastroenterology.

[121]  David Goldstein,et al.  Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. , 2013, The New England journal of medicine.

[122]  Rakesh K. Jain,et al.  Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels , 2013, Nature Communications.

[123]  R. Andersson,et al.  Experimental studies on treatment of pancreatic cancer with double-regulated duplicative adenovirus AdTPHre-hEndo carrying human endostatin gene. , 2013, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[124]  D. Gerber,et al.  BIBF 1120 (Nintedanib), a Triple Angiokinase Inhibitor, Induces Hypoxia but not EMT and Blocks Progression of Preclinical Models of Lung and Pancreatic Cancer , 2013, Molecular Cancer Therapeutics.

[125]  C. Logsdon,et al.  Roles for KRAS in pancreatic tumor development and progression. , 2013, Gastroenterology.

[126]  Jianjun Cheng,et al.  Protein corona significantly reduces active targeting yield. , 2013, Chemical communications.

[127]  S. Demaria,et al.  Combining radiotherapy and cancer immunotherapy: a paradigm shift. , 2013, Journal of the National Cancer Institute.

[128]  Derek S. Chan,et al.  Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer , 2012, Gut.

[129]  M. Uesaka,et al.  Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. , 2011, Nature nanotechnology.

[130]  Rakesh K. Jain,et al.  Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases , 2011, Nature Reviews Drug Discovery.

[131]  Pierre Michel,et al.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. , 2011, The New England journal of medicine.

[132]  M. Lauth,et al.  Hedgehog signaling and pancreatic tumor development. , 2011, Advances in cancer research.

[133]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[134]  C. Guillén-Ponce,et al.  Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib , 2010, Anti-cancer drugs.

[135]  Y. Ouchi,et al.  Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor‐β receptor inhibitor on extravasation of nanoparticles from neovasculature , 2009, Cancer science.

[136]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[137]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[138]  C. Walko,et al.  Capecitabine: a review. , 2005, Clinical therapeutics.

[139]  P. Johnston,et al.  5-Fluorouracil: mechanisms of action and clinical strategies , 2003, Nature Reviews Cancer.

[140]  Gert Storm,et al.  Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system , 1995 .

[141]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.