Macromolecular Anticancer Therapeutics, 2010
Cancer Drug Discovery and Development Series

In spite of the development of various anticancer drugs, the therapy of cancer has remained challenging for decades. The current therapy of cancer is overwhelmed because of the inability to deliver therapeutics to all regions of a tumor in effective therapeutic concentrations, intrinsic or acquired resistance to the treatment with currently available agents via genetic and epigenetic mechanisms, and toxicity. As a result, cancer therapy using conventional therapeutics and different types of treatment regimens using this therapeutics has not led to a convincing survival benefit of the patients. In this context, Macromolecular therapeutics offer several advantages over conventional low molecular therapeutics by various ways such as, enable the use of larger doses of these agents by limiting the toxicity, by enhanced permeability and retention into tumors, by tumor targeting using tumor-specific antibodies, by specific inhibition of oncogenes using anticancer oligonucleotides etc. Cancer treatment using this macromolecular therapeutics has considerably improved the survival benefit for patients. As a result, various macromolecular therapeutics are already commercialized or are under clinical development. Although we are far from a real magic bullet today, looking at the pace of research and current success in this field of macromolecular therapeutics, it appears that we are approaching a magic bullet for the efficient treatment of cancer. Thus, we believe that the subject of this book is very timely, and that the book will fill an unmet need in the market.

This book is unique and assembles various types and aspects of macromolecular anticancer therapeutics for cancer therapy in one shell and conveys the importance of this interdisciplinary field to the broad audience. Thus, in a nutshell, this book details the basics of cancer, and various therapeutic strategies such as those based on macromolecular therapeutics hence can become an important reference for practitioners, oncologists, medical pharmacologists, medicinal chemists, biomedical scientists, experimental pharmacologists, pharmaceutical technologists, and particularly it can essentially become a handbook of macromolecular therapeutics for cancer therapy for graduates, post-graduates and Ph.D. students in these fields.

Chapter 1. Classification of anticancer drugs based on therapeutic targets

Enrique Espinosa, César Gómez Raposo

Section

Contents

Abstract

1

Introduction

2

Drugs directed against tumour dna

2.1

Drugs directly affecting DNA helix: alkylators

2.2

Inhibitors of DNA-related proteins

2.2.1

Topoisomerases inhibitors

2.2.2

Antimetabolites

2.2.3

Histone related enzymes

2.2.4

Inhibitors of transcription factors

2.3

Specific genes

3

Drugs directed against tumour RNA

4

Drugs directed against proteins in the tumour cell

4.1

Receptors in the tumour membrane

4.2

Intracellular pathways in tumour cells

4.3

Tubulin

5

Drugs acting on the endothelium

5.1

Inhibition of pro-angiogenic factors

5.2

Inhibition of vascular receptors

5.3

Inside the endothelium

6

Drugs directed against extracellular matrix

6.1

Matrix metalloproteinases inhibitors

6.2

Anti-integrin therapy

6.3

Copper chelators

6.4

L1-CAM protein

6.5

Thrombospondin and others

7

Immunotherapy

7.1

Antibody-based immunotherapy of cancer

7.1.1

Unconjugated monoclonal antibodies

7.1.2

Conjugated monoclonal antibodies

7.1.3

Monoclonal antibodies as immunogens 

7.2

Cytokines in cancer immunotherapy

7.3

Cancer vaccines

7.3.1

Peptide vaccines

7.3.2

Dendritic cell-based cancer vaccines

7.3.3

Cellular vaccines

7.3.4

DNA vaccines 

7.3.5

Heat shock protein vaccines 

7.4

Adoptive TCell transfer for cancer immunotherapy

7.5

Natural killer cell-based immunotherapy

7.6

Regulatory cells and cancer immunotherapy

7.7

Toll-like receptors

8

Drugs acting on potentially metastatic sites and glands

9

Conclusion

References

Figure legends

Tables

Chapter 2. Signal transduction pathways as therapeutic targets in cancer therapy

Michele Milella, Ludovica Ciuffreda, Emilio Bria

Section

Contents

Abstract

1

Introduction

2

Protein tyrosine kinases (TK) as therapeutic targets

2.1

RTK as therapeutic targets: the paradigm of EGFR mutations in NSCLC

3

Cytoplasmic signaling intermediates

3.1

The Ras/Raf/MAPK pathway

3.2

The PI3K/AKT/mTOR pathway

3.3

Signaling crosstalk

4

Oncogenic addiction

4.1

Oncogenic shock

4.2

Oncogene amnesia

5

Open issues in the clinical development of signal transduction-targeted anticancer agents

5.1

The role of ‘early phases’: are phase II studies still necessary?

5.2

Phase II randomized studies: a new tale with targeted agents

5.3

Targeted agents: moving into phase III

Chapter 3. HPMA-anticancer drug conjugates

Rihova B, Hovorka O, Kovar L, Kovar M, Mrkvan T, Sirova M, Ulbrich K

Section

Contents

Abstract

1.

Introduction

2.

Synthesis and structure of N-(2-hydroxypropyl)methacrylamide copolymer-drug conjugates

2.1

Synthesis of linear polymer-drug conjugates

2.2

Polymer conjugates with biologically activeproteins

2.3

Polymer systems designed for targeted drug delivery

2.3.1

Passively targeted HPMA copolymer-drug conjugates

2.3.1.1

Branched and grafted high-molecular-weight HPMA copolymer conjugates

2.3.1.2

Self-assembled and micellar structures

2.3.2

Actively targeted HPMA copolymer-drug conjugates

2.3.2.1

Antibody-targeted HPMA copolymer conjugates

2.3.2.2

Lectin -targeted HPMA copolymer conjugates

2.3.2.3

Oligopeptide-targeted HPMA copolymer conjugates

2.3.2.4

HPMA copolymer conjugates targeted with other low-molecular weight moieties

3.

Immunogenicity of HPMA-based conjugates

3.1

The humoral response against HPMA

3.2

The cellular response to HPMA

3.3

Complement activation

3.4

The chronic treatment

3.5

The decreased immunogenicity of proteins bound to HPMA

3.6

Decrease of side toxicity of HPMA-copolymer carrier bound drugs

4.

HPMA copolymer–doxorubicin conjugates with pH-controlled activation

4.1

Linear Dox-HPMA^HYD conjugates

4.2

Branched and grafted Dox-HPMA^HYD conjugates

4.3

Micellar Dox-HPMA^HYD conjugates

4.4

Antibody-targeted Dox-HPMA^HYD conjugates

4.5

Immunomodulatory properties of Dox-HPMA^HYD conjugates

5.

HPMA copolymer doxorubicin conjugates with amide bond between the drug and carrier

5.1

Dox-HPMA^AM (PK1)

5.2

Dox-HPMA^AM conjugate containing human immunoglobulin (HuIg)

5.2.1

Preclinical evaluation of Dox-HPMA^AM-HuIg

5.2.2

Pilot clinical study with Dox-HPMA^AM-HuIg

5.3

HPMA-based polymer prodrugs in clinicaltrials

6.

Specific targeting of HPMA copolymer-bound drug conjugates to cancer cells

6.1

Targeting to asialoglycoprotein receptor

6.2

Targeting using lectins

6.3

Targeting using antibodies

6.4

Targeting to transferrin receptor

6.5

Targeting using synthetic peptides

7.

Intracellular destiny of polymeric conjugates based on HPMA

7.1

Lysosomotropic delivery of the polymeric drugs

7.2

Intracellular destiny of polymeric drugs

7.3

Effect of a doxorubicin derivative 7,8-dehydro-9,10-desacetyldoxorubicinone (D*) in the detection of fluorescence

7.4

The cleavability of conjugates

7.5

Apoptosis, necrosis and cell signalling

8.

Immunomodulatory properties of HPMA copolymer-bound doxorubicin

Chapter 4. Poly-L-Glutamic acid anti-cancer drug conjugates

Jack W. Singer, Marc McKennon, Gabriella Pezzoni, Stefano di Giovine, Mara Cassin, Paola de Feudis, Cecilia Allievi, Patrizia Angiuli, Marco Natangelo, Enrico Vezzali, and Stefano Fazioni

Section

Contents

Abstract

1.

Introduction

2.

CT-2103 (Paclitaxel Poliglumex)

2.1

Chemistry and Manufacturing

2.1.1.

Technical Issues in the synthesis of CT-2103

2.1.2.

Synthetic strategy

2.1.3.

Synthesis Optimization

2.1.4.

Formulation of CT-2103

2.1.5.

Development of analytic methods and characterization of CT-2103

2.1.6.

Setting molecular weight and loading limits, the four corners approach

2.2.

Preclinical Pharmacology

2.2.1.

Pharmacokinetics

2.2.2.

Tissue distribution in rats and dogs

2.2.3.

Tissue distribution in comparison with paclitaxel in tumor bearing mice:

2.2.4.

Mass balance in rat

2.2.5.

Toxicology studies

2.3.

Cellular pharmacology

2.3.1.

Cellular Metabolism

2.3.2.

The role of the macrophage

2.3.3.

Preclinical efficacy

2.3.4.

In vivo efficacy studies in combination with radiation

2.3.5.

The effect of estradiol on CT-2103

2.4.

Preclinical Summary

2.5.

Clinical studies

2.5.1.

Phase I Studies: Determination of a safe and effective dose

2.5.2.

Phase II Studies

2.6.

Use of CT-2103 as a radiosensitizer

2.7.

Phase III Programs

2.7.1

Non-small cell lung cancer (NSCLC)

2.7.2.

Ovarian Cancer

3.

CT-2106 (poly-L-glutamic acid gly-camptothecin)

3.1.

Design and Synthesis

3.2.

Overview of preclinical studies

3.3.

Phase I Clinical Studies

Chapter 5. Polysaccharide-based anticancer prodrugs

Paolo Caliceti, Stefano Salmaso and Sara Bersani

Section

Contents

Abstract

1.

Introduction

2.

Chitin and Chitosan

2.1

Mitomycin C

2.1.1

Insoluble Suc-Chitosan-MMC derivatives

2.1.2

Soluble MMC-Suc-Chitosan derivatives

2.1.3

Lactosyl-Suc-Chitosan-MMC derivatives

2.2

Epirubcin

2.3

Doxorubicin

2.4

1-ß -D-arabinofuranosylcytosine

2.5

5-fluorouracil

2.6

Tyr-Ile-Gly-Ser-Arg

2.7

DNA

3.

Hyaluronic Acid

3.1

Paclitaxel

3.2

Doxorubicin

3.3

Butyric acid

3.4

All-Trans RetinoicAcid

4.

Dextran

4.1

Doxorubicin

4.2

Daunomycin

4.3

Adriamycin

4.4

Mitomycin C

4.5

Paclitaxel

4.6

1-ß-D-arabinofuranosylcytosine

4.7

Cisplatin

4.8

Camptothecin

4.9

Methylprednisolone and Tacrolimus

4.10

Radionuclides

4.11

Proteins

5.

Arabinogalactan

6.

Pullulan

7.

Cyclodextrins

Chapter 6. PEG-anticancer drugs

Francesca Cateni, Marina Zacchigna

Section

Contents

Abstract

1

Introduction

1.1

Drug delivery using permanent PEGylation

1.2

Non permanently bonded PEG-drugs: PEG prodrugs

2

PEG-anticancer prodrugs

2.1

PEG-Paclitaxel

2.2

PEG-Camptothecin

2.3

PEG-Doxorubicin

2.4

PEG-Daunorubucin

2.5

PEG-Epirubicin

2.6

PEG-Ara-C

2.7

PEG-Gemcitabine

2.8

PEG-Platinum drugs

2.9

PEG-Methotrexate

Chapter 7. Poly(ethylene glycol)-protein, peptide and enzyme conjugates

F.M.Veronese, G. Pasut, S.Drioli and G.M.Bonora

Section

Contents

Abstract

1

Introduction

2

PEG-proteins and peptides

2.1

Antibodies and antibody fragments

2.2

Granulocyte colony-stimulating factor

2.3

Interferons

2.4

Thrombopoietin or megakaryocyte growth and development factor

2.5

Anti-cancer peptides

3

PEG-enzymes

3.1

Arginase

3.2

Argininedeiminase

3.3

Asparaginase

3.4

Methioninase

3.5

Glutaminase

3.6

Uricase

3.7

Other anti-cancer enzymes

Chapter 8. Lipid-based anticancer prodrugs

L. Harivardhan Reddy and Patrick Couvreur

S. No.

Contents

1

Introduction

2

Lipids applied in cancer treatment

2.1

Non-fatty acids

2.1.1

Cardiolipin

2.1.2

Ceramide

2.2

Fatty acids

2.2.1

Essential fatty acids (EFAs)

2.2.2

Omega-3 fatty acids

2.2.3

Conjugated Linoleic acids

2.2.4

Olive oil constituent

2.2.4.1

Oleic acid

2.2.4.2

Elaidic acid

2.2.4.3

Squalene

2.2.5

Miscellaneous fatty acids

2.2.5.1

Valproic acid

2.2.5.2

Butyrates

3

Anticancer lipid prodrugs

3.1

Antibiotic anticancer drug-lipid conjugates

3.1.1

Mitomycin C-lipid conjugates

3.1.2

Doxorubicin-lipid conjugates

3.2

Antimetabolite anticancer drug-lipid conjugates

3.2.1

Methotrexate-lipid conjugates

3.2.2

Nucleoside analogue anticancer drug-lipid conjugates

3.2.2.1

Ara C-lipid conjugates

3.2.2.2

Gemcitabine-lipid conjugates

3.2.2.3

Troxacitabine-lipid conjugates

3.3

Taxane-lipid conjugates

3.4

Others: Camptothecin alkaloids-lipid conjugates

Chapter 9. Antibody-Cytotoxic Compound Conjugates for Oncology

Carol A. Vater and Victor S. Goldmacher

Section

Contents

Abstract

1

Introduction

2

Target selection

3

Antibody selection

4

Cytotoxic compounds used in Antibody-Cytotoxic compound Conjugates (ACCs¹)

5

Antibody-cytotoxic compound linker strategies

6

ACCs in clinical development

7

Conclusions and future prospects

Chapter 10. Immunoconjugate anticancer therapeutics

Serengulam V. Govindan and David M. Goldenberg

Section

Contents

Abstract

1.

Introduction

2.

mAb forms for conjugates

2.1

Radionuclide conjugates

2.1.1

Radionuclides for RAIT

2.1.2

Therapy of hematological cancers

2.1.3

Therapy of solid cancers

2.1.3.1

As an adjuvant

2.1.3.2

Combination therapy

2.1.3.3

Locoregional application

2.1.3.4

Pretargeting

2.1.4

Quo vadis?

2.2

Antibody-drug conjugates

2.2.1

Drugs

2.2.2

Cleavable linker in drug conjugate design

2.2.2.1

Hydrazone-containing conjugates

2.2.2.2

Disulfide-containing conjugates

2.2.2.3

Conjugates with a cleavable-peptide

2.2.2.4

Ester linker

2.2.3

MAb conjugates: Homogeneity and site-specificity

2.3

Toxin conjugates

2.3.1

Plant and bacterial toxin conjugates

2.3.2

Ribonuclease conjugates

Conclusions

Chapter 11. Antibody directed enzyme prodrug therapy (ADEPT) for cancer

Surinder K Sharma and Kenneth D Bagshawe

Section

Contents

Abstract

1.

Introduction and Principles

2.

Antibodies and targets

3.

Enzymes

3.1

Mammalian enzymes including human

3.2

Non-mammalian enzymes

3.3

Catalytic Antibodies

4.

Prodrugs

5.

Carboxypeptidase G2

5.1

Antibody-Enzyme conjugates

5.1.1

Pre-Clinical Studies

5.1.2

Clinical studies

5.2

Fusion Proteins

6.

Immunogenicity

Conclusion

Chapter 12. EGFR-directed monoclonal antibodies

Roberto Bianco, Teresa Gelardi, Sonia Garofalo, Roberta Rosa, Giampaolo Tortora

Section

Contents

Abstract

1.

EGFR and cancer

2.

EGFR inhibitors as anticancer therapy

3.

Anti-EGFR monoclonal antibodies (MAbs)

3.1.

Cetuximab (IMC-225)

3.2.

Panitumumab (ABX-EGF)

3.3.

Matuzumab (EMD72000)

3.4.

Nimotuzumab (hR3)

3.5.

Zalutumumab

3.6.

MDX-447

3.7.

ch806

Conclusion

Chapter 13. The Biology of the HER Family and Her2/neu Directed-Antibody

Jennifer K. Litton and Gabriel N. Hortobagyi

Section

Contents

Abstract

1.

Introduction

2.

The HER Family

3.

HER2 and Downstream Signaling Pathways

3.1

The PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway

3.2

HER2 and PTEN

3.3

The Ras/Raf/mitogen-activated protein kinase (MAPK) Pathway

3.4

HER2 and Endocrine Receptors (ER)

3.5

HER2 and p27

4.

HER2 Targeted Antibodies

4.1

Trastuzumab

4.1.1

Trastuzumab and Metastatic Breast Cancer: single agent trastuzumab

4.1.2

Dosing of Trastuzumab

4.1.3

Trastuzumab and Chemotherapy for Metastatic Breast Cancer

4.1.4

Trastuzumab and Aromatase Inhibitors for Metastatic Breast Cancer

4.1.5

Trastuzumab and Adjuvant Therapy

4.1.6

Trastuzumab and Neoadjuvant Chemotherapy

4.1.7

Treating with Trastuzumab Beyond Progression

4.1.8

Trastuzumab and Cardiotoxicity

4.1.9

Mechanisms of Resistance

4.2

HER and PTEN/PI3k/Akt/mammalian target of rapamycin (mTOR) Pathway

4.3

Insulin-like growth factor-1 receptor

4.4

MUC4 Over-expression

4.5

HER2 Receptor truncation or mutations

5.

Novel HER Family-directed antibodies

5.1

Pertuzumab

5.2

Trastuzumab-DM1

5.3

HER2 monoclonal antibodies and nanoparticles in development:

Conclusion

Chapter 14. Anti-Vascular Endothelial Growth Factor Monoclonal Antibodies

Ernest S. Han and Bradley J. Monk

S. No.

Contents

Abstract

1.1

Angiogenesis and Cancer

1.1.1

Biologic relevance of vascular endothelial growth factor in tumor angiogenesis

1.1.2

VEGF family and receptors

1.1.3

VEGF as a target for cancer therapy

1.2

VEGF Monoclonal antibodies and clinical experience

1.2.1

Bevacizumab

1.2.1.1

Pharmacology

1.2.1.2

Clinical experience

1.2.1.3

Side effects

1.2.2

VEGF Trap

1.2.2.1

Pharmacology

1.2.2.2

Clinical experience

1.2.3

HuMV833

1.2.3.1

Pharmacology

1.2.3.2

Clinical experience

1.3

VEGF receptor monoclonal antibodies

1.3.1

IMC-1121b

1.3.2

IMC-18F1

1.3.3

CDP791

1.4

Monoclonal antibodies to placental growth factor

Current issues emerging from anti-VEGF therapies

1.5.1

Biologic markers for dosing and efficacy

1.5.2

Resistance to Anti-VEGF therapy

1.6

Summary

Chapter 15. Monoclonal Antibody Therapy for Hematologic Malignancies

Kenneth A. Foon, Michael Boyiadzis, Samuel A. Jacobs

Section

Contents

Abstract

1.

Introduction

2.

Rituximab

2.1

Follicular Lymphoma

2.2

Marginal Zone B-Cell Lymphoma

2.3

Mantle Cell Lymphoma

2.4

Diffuse Large B-Cell Lymphoma

2.5

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

3.

90Y Ibritumomab Tiuxetan

4.

131I tositumomab

5.

Alemtuzumab

6.

Gemtuzumab Ozogamicin

7.

Ofatumumab

8.

AME-133v

9.

Epratuzumab

10.

CMC-544

11.

BL22

12.

Lumiliximab

13.

Galiximab

14.

SGN-40

15.

Bevacizumab

16.

CP-751,871

17.

Zanolimumab

18.

Limtuzumab

19.

IMC-EB10

20.

SGN-30

21.

Chimeric Anti-CD4 Monoclonal Antibody

22.

TRU-016

23.

Milatuzumab

24.

Ipilimumab

Conclusion

Chapter 16. Anticancer oligonucleotides

Anne Laure Ramon and Claude Malvy

Section

Contents

1.

Introduction

2.

Pre-clinical studies

2.1

Antisense oligonucleotides

2.1.1

Studies on bcl-2 proto oncogene

2.1.2

Studies on Raf kinases

2.1.3

Studies on Ras proteins

2.1.4

Studies on PKC-a

2.2

Small interfering RNA

2.2.1

Studies on bcl-2 proto oncogene

2.2.2

Studies on Raf kinases

2.2.3

Studies on Ras proteins and PKC-a

2.3

Decoys

2.4

Aptamers

2.5

Ribozymes

2.5.1

Studies on bcl-2

2.5.2

Studies on Ras proteins

2.5.3

Studies on PKC-a

2.6

Discussion

2.6.1

Immunostimulation

2.6.2

Minimal active doses

2.6.3

Selectivity and off-target effects

3.

Clinical studies

3.1

Antisense oligonucleotides

3.1.1

Clinical trials on Bcl-2

3.1.2

Clinical trials on Raf kinase

3.1.3

Clinical trials on Ras

3.1.4

Clinical trials on PKC-a

3.2

Small interfering RNA

3.3

Ribozymes

3.4

Decoys

3.5

Discussion

4.

Conclusion

Chapter 17. New molecular therapeutic interventions: the case of breast cancers

Véronique Marsaud and Jack-Michel Renoir

Section

Contents

Abstract

1.

Introduction

2.

2. Estrogens, phytoestrogens and xenoestrogens

2.1

Biosynthesis of estrogens

2.2

Phytoestrogens and xenoestrogens

3.

Estrogen receptors

3.1

Structure

3.2

The classical genomic transactivation mechanisms

3.3.

Non-classical transactivation systems

3.4

Nuclear localization and nucleo-cytoplasmic shuttling

3.5

Estrogen receptors stability

4.

Estrogen Receptors in Breast cancers

4.1

Estrogen receptors in the normal mammary gland

4.1.1

Estrogen receptor isotypes in breastcancers

4.1.2.

Classical anti-hormonal treatments

4.1.2.1

SERDs and SERDs

4.1.2.2

Aromatase inhibitors

4.1.2.3

Resistance

5.

Emergence of innovative strategies for specific targets

5.1

Apoptosis induction and Cell cycle inhibition

5.1.1

Apoptosis

5.1.2

Cdk inhibitors

5.1.3

Survivin

5.1.4

Nuclear factor-k B

5.1.5

Ubiquitine-proteasome system

5.1.6

Histone deacetylase inhibitors

5.1.7

Hsp90 inhibitors

5.1.8

p53

5.1.9

Pi3K/Akt pathway

5.1.10

Farnesyl transferase inhibitors (FTI)

5.2

Vascular and angiogenesis inhibitors

5.3

Monoclonal antibodies and tyrosine kinase inhibitors for EGFR and Erb-B2

6.

Breast cancer and stem cells

6. 1.

Implication of stem cells in metastasis

6.2.

Targeting CD44 for breast cancer therapy

7.

Conclusion and future perspectives

L. Harivardhan Reddy is Head of Nanovectors group at Sanofi-aventis, France. He completed Ph.D. in Pharmaceutics and Drug delivery in 2005 from The M.S. University of Baroda, India. He has worked for 4 years in two popular pharmaceutical companies (Sun Pharmaceutical Industries Ltd., and Aristo Pharmaceuticals Ltd.) in India, on drug delivery applications. He worked for 3 years (2005-2008) with anticancer drug delivery specialist Prof. Patrick Couvreur in CNRS lab at Université Paris-Sud, Chatenay-Malabry, France. He is an inventor of 3 patents belonging to macromolecular therapeutics and drug delivery. He has published, as an author and co-author, more than 60 publications in various reputed journals. He is also a reviewer for more than 15 journals of the fields of biomacromolecules, drug delivery, cancer therapy, and pharmacology. He is a member of The European Association for Cancer Research. His principal research interests are supramolecular lipidic prodrug nanomedicines and nanotherapeutics for cancer.

Patrick Couvreur is a Full Professor of Pharmacy at the University Paris-Sud, France, and holder of the chair of "Innovation Technologique" (2009-2010) at the prestigious ‘Collège de France’. He is a member of the Academy of Technologies (France), of the Academy of Pharmacy (France) and corresponding member of the Royal Academy of Medicine (Belgium). Prof. Patrick COUVREUR’s contributions in the field of drug delivery and targeting are highly recognized and respected around the world. Patrick COUVREUR performed a pioneer work together with Peter SPEISER, and demonstrated for the first time in 1977 that nanoparticles may be used as intracellular carriers for compounds which don’t diffuse spontaneously into cells. Patrick COUVREUR’s research is primarily on polymer-based and metallic-based nanomedicines, surface engineered nanosystems, and also focuses on lipid-based nanocarriers. He has publishedas an author an