SlideShare a Scribd company logo
1 of 29
Polymer therapeutics:
smart drug delivery
system
ALOK KUMAR
DRDO – JRF
PHARMACOLOGY & TOXICOLOGY
Improving the therapeutic index of drugs is a major impetus for innovation in
many therapeutic areas such as cancer, inflammatory, and infective diseases.
The field of drug delivery system (DDS) utilizing polymeric carrier, which
covalently conjugates molecule of interest, plays an important role in modern
therapeutics.
Majority
of Drug
500 g/mol
Narrow
therapeutic
index
Short half life
in plasma
High
clearance
Distribute
evenly
Frequent side-Effects
nephrotoxicity, bone-marrow toxicity,
neurotoxicity, cardiotoxicity, mucositis,
and gastrointestinal toxicity, which are
dose-limiting and thus prevent effective
treatment.
Biologically active polymers: Friend or foe?
polymer therapeutics have confirmed that they can satisfy the requirements of
both industrial development, and the “Regulatory Authority Approval” process.
polymer therapeutics: “Conjugates of drugs and polymers as well as other polymeric
carrier systems”
The use of polymers in medicine is not new and undoubtedly natural polymers have
been used as components of herbal remedies for several millennia.
 Use of polymers in biomedical materials (e.g. as prostheses, medical devices,
contact lenses, dental materials and pharmaceutical excipients) became well
established in the last century
 In the early years, polymers studied clinically
were mainly plasma expanders
(e.g. and dextran and poly(vinylpyrolidone)
(PVP) materials for use as wound dressings and
antiseptics (called Povidone)
The choice of polymeric backbone for the conjugate has great implications on the
pharmacokinetics and pharmacodynamics of the drug.
The polymer characteristics, such as Mw, polydispersity, architecture, charge and
hydrophilicity, define the drug solubility and loading, its biodistribution, body
excretion and the interaction with the immune system.
The objectives for designing a polymer therapeutics:
(i) Enhancing water solubility, particularly relevant for some drugs
with low aqueous solubility.
(ii) Stability against degrading enzymes or reduced uptake by
reticuloendothelial system (RES).
(iii) Targeted delivery of drugs to specific sites of action in body
Three key technologies were the major factors that stimulated the immense activity and
clinical success of nanotherapeutics (1980s to present.)
First is the concept of “PEGylation”, drugs or drug carriers.
The second is the concept of “active targeting” of the drug conjugate by conjugating cell
membrane receptor antibodies, peptides or small molecule cell ligands to the polymer
carrier.
The third was the discovery of the “enhanced permeation and retention effect” (EPR)
by Hiroshi Maeda.
Macromolecules as Drug-Delivery Systems: Biological Rationale
Size, charge, conformation of macromolecule is crucial
Renal threshold-30–50 kDa to avoid leakage of body proteins into the bladder
Angew. Chem. Int. Ed. 2006
Passive Drug Targeting and Specific Tissue Targeting: The EPR Effect
“Differences in the biochemical and physiological characteristics of healthy and malignant
tissue are responsible for the passive accumulation of macromolecules in tumors”
In general, low-molecular-weight compounds diffuse into normal and tumor tissue
through the endothelia cell layer of blood capillaries. Macromolecules, however, cannot
pass through the capillary walls of normal tissue.
Smaller tumor nodules accumulate larger amounts of the polymer than larger nodules.
This observation points to the possibility that polymeric imaging agents could help to
detect small tumor nodules.
Controlled Release 2000
Cellular Uptake of Polymers, Site-Specific Drug Release, and Implications for Drug Design
drop in the pH value takes place from the
(7.2–7.4) in the extracellular space to pH
6.5–5.0 in the endosomes and to around
pH 4.0 in primary and secondary
lysosomes
Lysosomal enzymes activity
The design of drug–polymer conjugates initially focused on incorporating enzymatically
cleavable bonds that allow the prodrug to be cleaved intracellularly after cellular uptake.
Cancer Metastasis Rev. 1987
Polymer Conjugates for Protein Stabilization
More than 7000 naturally occurring peptides have been identified, and these often have
crucial roles in human physiology, including actions as hormones, neurotransmitters, growth
factors, ion channel ligands, or anti-infective
Peptide drugs market US$ 19 billions by 2016 end and expected to increase at over 10 %
peptide medicines : more than 60 (FDA)- approved on the market, 140 in clinical trial, more
than 500 in preclinical development
Nat. Rev. Drug discovery 2003, Trends and Forecast 2012–2018.
The most recent example of a novel peptide drug class is the group of glucagon-like peptide-1
(GLP-1) agonists for the treatment of type 2 diabetes mellitus (T2DM), which reached total sales
of over US$2.6 billion in 2013
Pegylation is now accepted tool and the
composition of biopharmaceutical is increasing
Linear and branched PEGs of Mw 5000-40000 g/mol
have been used to create conjugates sometime multiple
PEGs attached to per protein
Pharm. Res. 2010
Limitation: Short t1/2, low stability, costly production, poor bioavailability,
immunogenic and allergic potential
Attachment of PEG chains onto the surface of the protein. PEGylation is designed to
increase protein solubility, reduce immunogenicity and prolong plasma circulation,
IMTECH's Streptokinase contributions worthRs.20,000 crore
Other examples of PEGylated proteins on the market or in advanced clinical trials are
pegvisomant, a PEGylated form of the human growth hormone,
PEGylated receptor and antibody fragment directed against tumor necrosis factor-
(PEG-TNF-RI and PEG-anti-TNF Fab, respectively).
The increase in the MTD
No particular toxicity of polymer
Drug Discovery Today. 2015
Mol. Pharmacol. 2006
Bioscavengers of Organophosphate Compounds
Drug–Polymer Conjugates with Cleavable Linkers
Drug–Polymer Conjugates is promising strategy to improve the therapeutic index
Careful tailoring of polymer–drug linkers is essential to the creation of a polymeric
prodrug that is inert during transport but allows drug liberation at an appropriate rate
intratumorally.
Peptidyl polymer–drug linkers were popularized by the successful design of HPMA
copolymer–Gly-Phe-Leu-Gly-doxorubicin conjugates. (sensitive to cathepsin B)
pH sensitive cis-aconityl, hydrazone and acetal linkages have also been fashionable as
an alternative for drug conjugation
Adv. Drug Deliv. Rev. 2009
The field of polymer therapeutics is constantly growing, and when attempting to assemble a
new conjugate, the possibilities seem endless. The choice of drug should be the first step,
knowing it features whether it is suffering from low solubility, high toxicity and severe side
effects, short half-life in the circulation, is crucial for further decisions regarding the polymeric
backbone, the size and shape of the final conjugate and the required linker.
Mw 30 kDa, 8.5 % doxorubicine
Phase 1 CTC and MTD 320 mg m-2 (5 fold increase vs normal dose of free drug)
No acute cardiotoxicty, prolong plasma t ½, absence of rapid elimination
Phase 2 280 mg m-2 every three week
Related to PK1 Mw 25 kDa
Additional targeting ligand,
Taken up by asialoglycoprotein receptor
Phase 1 MTD 160 mg m-2
Phase 2 120 mg m-2
Cancer Res. 1999,
Another approach to doxorubicin–polylactide conjugates was recently reported by Sengupta et
al. These conjugates have been embedded into a biodegradable polylactide nanoparticle to
achieve a better tumor selectivity through the EPR effect
Prothecan: Gastrooesophageal tumor
A. The EPR effect results in a drug-targeting effect,
B. Esterifying the 20-hydroxy group of CPT stabilizes the drug in its active
lactone form
C. Incorporation of a glycine spacer ensured a controlled release of the drug
D. Use of hydrophilic PEG leads to a highly water-soluble formulation of
camptothecin.
J. Pharm. Biomed. Anal. 2000, Clin. Oncol. 2003
Opaxio® (PGA-paclitaxel) has just finished enrolling patients in a Phase III trial in 2014
against ovarian cancer.
NC-6004 platinum-containing micelle being evaluated in Phase III as a treatment for
pancreatic cancer
DOXO-EMCH (6-maleimidocaproyl) hydrazone derivative of doxorubicin in Renal cell
carcinoma
Med. Chem. 2002
The PDPEPT concept:
Polymer- directed enzyme –prodrug therapy
Is novel two step antitumor aproach
(HPMA copolymer)–(cathepsin B) conjugate
HPMA-co-MA-GG-C-Dox
HPMA-co-MA-GG-β-L
Bioconjugate Chem. 2003,
Multivalent Drug Concepts: A number of multivalent inhibitors have been designed that
are based on low-molecular-weight drugs and target dimeric or multimeric proteins that
contain multiple identical receptor sites.
A pentavalent starlike carbohydrate ligand has been
reported that fitted precisely into the binding pocket
of the five subunits of the Shiga-like bacteria toxin,
(10 7 more affinity than monovalent interaction)
Tolevamer (GT160-246), a sodium salt of a styrene
sulfonate polymer designed to bind to Clostridium
difficile toxins A and B.
Angiogenesis is crucial for tumor growth. ngiogenesis
inhibitors, such as O-(chloracetyl-carbamoyl)
fumagillol (TNP-470), are thus emerging anticancer
drugs. HPMA copolymer–TNP-470 substantially
enhanced and prolonged the activity of TNP-470 in
vivo in tumor and hepatectomy models.
Telavancin: a highly bactericidal injectable antibiotic based on a vancomycin derivative
(bind to bacterial cell wall with high affinity)with multiple modes of action serious
infections arising from Staphylococcus aureus (including multidrug-resistant strains) and
other Gram-positive pathogens.
Oligo-G: (alginate oligoscharide) under clinical trial for cystic fibrosis
Inihibtion of virus attachment
The inhibition of virus attachment to cell surfaces is
a fundamental problem for the prevention of viral
infections, such as influenza and HIV.
Vivagel : a 3% (w/w) carbopol gel formulation of the
lysine based dendrimer SPL7013 that display broad
spectrum antiviral activity. e.g. against HIV-1, HIV-2 ,
Herpes simplex , human pappiloma
Polyanionic Polymers: Heparin Analogues
heparin analogues with a similar or even improved pharmacological profile, but
lacking the disadvantages of this animal product, are of interest.
simple and efficient approach to highly branched polysulfated heparin analogues
based on dendritic polyglycerols has been developed
Polycationic Polymers as DNA/RNA Transfection Agents
The search for nonviral alternatives remains a challenge because of problems
associated with viral gene transfection,
For the purpose of nucleic acid transfer, nanoparticles or polyplexes of polymers has
been created. Commonly used cationic polymer are: poly(ethylene imine) (PEI), poly(l-
lysine), polyamidoamine (PAMAM) , chitosans and Cyclodextrins
Incorporation of Delivery Functions: Targeting Domains
Shielding Domains
Transport Domains
Nuclear Import
Adv .Polym .Sci. 2006
Cancer Gene Therapy. 2002
TNF expression localized to the tumor
resulted in hemorrhagic tumor necrosis and
inhibition of tumor growth without systemic
TNF- related toxicity.
Nanocarriers Based on Dendritic Polymers
Dendritic polymers with their regular and well-defined unimolecular architecture, which
can be further chemically modified at either the core (to increase hydrophobicity) or the
shell (to increase hydrophilicity),
Pegaptanib – (PEG-aptamer)
approved US FDA 2004 (Macugen.
Pfizer). It bound to VEGF it
inhibits the interaction of VEGF
with VEGFR1 and VEGFR2, and
ameliorates the loss of visual
acuity in AMD
Biochem. 1995, Adv. Drug Delivery Rev. 2005
ADME of polymer Therapeutics
The choice of polymeric backbone for the conjugate:
pharmacokinetics and pharmacodynamics
The polymer characteristics, such as molecular weight,
polydispersity, architecture, charge and hydrophilicity, define
the drug solubility and loading, its biodistribution, body
excretion and the interaction with the immune system.
HPMA, PEI, PVP), PGA, PAM, PDMA, PVA, chitosan and dextran.
NKTR-118: PEG-Naloxone, orally administered
Use of LMWC: anticancer conjugate of taxel
Chitosan-insulin conjugate : oral deliver of insulin
Journal of Controlled Release 161. 2012
travelling to the site of action: EPR, active targetting , shape of polymer
Immune respone: antibody, RES clearance
Distribution of low Mw drugs: TNP-470
Distribution of biological drugs: PEG conjugates
Desease site environment: Ph, overexpressed enzymes like cathepsin B
ROS- can cleave boronic acid or ester linkers
Distribution:
Cell internization
Metabolism and degradation
Elimination of nonbiodegradable polymers
•No internalization above 400 kDa
•Rod shaped>spherical
•Branched> spherical
•Escape from ABC transporter no MDR
Biodegradable: hyaluronic acid, collagen, PG, PA
Semibiodegradable: HPMA , HPMA-polylactide
Mw, size and shape, of polymer have major
influence on its excreation and rate of
glomerular filtration.
Regulatory considerations
The urgent need for improved diagnostics and treatments for
Life threatening diseases Eg. Cancer, CVS, RA, blindness, neurodegeneratives
Next generation polymer therapeutics will continue to make a positive contribution to
healthcare improvement, but transition from laboratory-based research to first in
patient clinical trials must, however, always be carefully controlled in terms of
potential risk/benefit.
It is also important to stress that such complex, new medicines must be cost-effective,
practical to use and ideally should be available at a price that makes them accessible
to patients globally.
FDA
UK Medicines and Healthcare products
Regulatory Agency (MHRA)
European Medicines Agency (EMEA)
CDSCO
Adv. Drug Deliv. Rev. 61, 2009
Medco health service. 2015
Summary and conclusions
•The development of polymer therapeutics has emerged as
an exciting field of research for improving the therapeutic
potential of low-molecular-weight drugs and proteins.
•In the future more biodegradable polymers with high
molecular weights and high recision (Mn>30 000 gmol1,
polydispersity <1.5) as well as new modular approaches to
“intelligent” polymeric nanotransporters will be needed.
•To ensure eventual healthcare benefit, it is important that
basic researchers understand well the industrial
development and regulatory processes so that they can
ensure their new technologies have at least the potential
to meet regulatory requirements.

More Related Content

What's hot

High throughput screening
High throughput screening High throughput screening
High throughput screening RewariBhavya
 
Basics Of Molecular Docking
Basics Of Molecular DockingBasics Of Molecular Docking
Basics Of Molecular DockingSatarupa Deb
 
Characterization of Nanoparticles.
Characterization of Nanoparticles.Characterization of Nanoparticles.
Characterization of Nanoparticles.Manish Rajput
 
Drug development process
Drug development processDrug development process
Drug development processnasim arshadi
 
Nanotechnology in pharmaceutics
Nanotechnology in pharmaceuticsNanotechnology in pharmaceutics
Nanotechnology in pharmaceuticstabirsir
 
Polymeric nanoparticles A Novel Approach
Polymeric nanoparticles  A Novel ApproachPolymeric nanoparticles  A Novel Approach
Polymeric nanoparticles A Novel Approachshivamthakore
 
Role of nanoparticles in drug delivery
Role of nanoparticles in drug deliveryRole of nanoparticles in drug delivery
Role of nanoparticles in drug deliveryGautham Reddy
 
Solid lipid nanoparticles
Solid lipid nanoparticlesSolid lipid nanoparticles
Solid lipid nanoparticlesNIVETA SINGH
 
Nano drug delivery
Nano drug deliveryNano drug delivery
Nano drug deliverytabirsir
 
Liposomal drug delivery system
Liposomal drug delivery systemLiposomal drug delivery system
Liposomal drug delivery systemNazmul Islam
 
Future trends and perspectives in modern pharmaceutical biotechnology
Future trends and perspectives in modern pharmaceutical biotechnologyFuture trends and perspectives in modern pharmaceutical biotechnology
Future trends and perspectives in modern pharmaceutical biotechnologyinemet
 
Nanoparticle targeted drug delivery system
Nanoparticle targeted drug delivery systemNanoparticle targeted drug delivery system
Nanoparticle targeted drug delivery systemBINDIYA PATEL
 
NANOPARTICLE DRUG DELIVERY SYSTEM
NANOPARTICLE DRUG DELIVERY SYSTEMNANOPARTICLE DRUG DELIVERY SYSTEM
NANOPARTICLE DRUG DELIVERY SYSTEMvivek vyas
 
Drug discovery and development
Drug discovery and developmentDrug discovery and development
Drug discovery and developmentKarun Kumar
 

What's hot (20)

High throughput screening
High throughput screening High throughput screening
High throughput screening
 
Basics Of Molecular Docking
Basics Of Molecular DockingBasics Of Molecular Docking
Basics Of Molecular Docking
 
Characterization of Nanoparticles.
Characterization of Nanoparticles.Characterization of Nanoparticles.
Characterization of Nanoparticles.
 
Drug development process
Drug development processDrug development process
Drug development process
 
Nanotechnology in pharmaceutics
Nanotechnology in pharmaceuticsNanotechnology in pharmaceutics
Nanotechnology in pharmaceutics
 
Polymeric nanoparticles A Novel Approach
Polymeric nanoparticles  A Novel ApproachPolymeric nanoparticles  A Novel Approach
Polymeric nanoparticles A Novel Approach
 
Role of nanoparticles in drug delivery
Role of nanoparticles in drug deliveryRole of nanoparticles in drug delivery
Role of nanoparticles in drug delivery
 
Solid lipid nanoparticles
Solid lipid nanoparticlesSolid lipid nanoparticles
Solid lipid nanoparticles
 
Polymeric nano particles
Polymeric nano particles Polymeric nano particles
Polymeric nano particles
 
Nano drug delivery
Nano drug deliveryNano drug delivery
Nano drug delivery
 
Drug targeting
Drug targetingDrug targeting
Drug targeting
 
Liposomal drug delivery system
Liposomal drug delivery systemLiposomal drug delivery system
Liposomal drug delivery system
 
Future trends and perspectives in modern pharmaceutical biotechnology
Future trends and perspectives in modern pharmaceutical biotechnologyFuture trends and perspectives in modern pharmaceutical biotechnology
Future trends and perspectives in modern pharmaceutical biotechnology
 
MOLECULAR DOCKING
MOLECULAR DOCKINGMOLECULAR DOCKING
MOLECULAR DOCKING
 
Lead identification
Lead identification Lead identification
Lead identification
 
Nanoparticle targeted drug delivery system
Nanoparticle targeted drug delivery systemNanoparticle targeted drug delivery system
Nanoparticle targeted drug delivery system
 
Dendrimers
DendrimersDendrimers
Dendrimers
 
Nanoparticles
Nanoparticles Nanoparticles
Nanoparticles
 
NANOPARTICLE DRUG DELIVERY SYSTEM
NANOPARTICLE DRUG DELIVERY SYSTEMNANOPARTICLE DRUG DELIVERY SYSTEM
NANOPARTICLE DRUG DELIVERY SYSTEM
 
Drug discovery and development
Drug discovery and developmentDrug discovery and development
Drug discovery and development
 

Similar to Polymer therapeutics: smart drug delivery systems

Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdf
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdfPeptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdf
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdfDoriaFang
 
Peptide drug conjugates (pd cs) new generation of targeted cancer treatment
Peptide drug conjugates (pd cs) new generation of targeted cancer treatmentPeptide drug conjugates (pd cs) new generation of targeted cancer treatment
Peptide drug conjugates (pd cs) new generation of targeted cancer treatmentDoriaFang
 
Could PDC Be A New Direction For Targeted Therapy After ADC.pdf
Could PDC Be A New Direction For Targeted Therapy After ADC.pdfCould PDC Be A New Direction For Targeted Therapy After ADC.pdf
Could PDC Be A New Direction For Targeted Therapy After ADC.pdfDoriaFang
 
Phamacogenomics ppt.pptx 1
Phamacogenomics ppt.pptx 1Phamacogenomics ppt.pptx 1
Phamacogenomics ppt.pptx 1pooja joshi
 
Towards Personalized Medicine
Towards Personalized MedicineTowards Personalized Medicine
Towards Personalized MedicineMichel Dumontier
 
Anti cancer peptide drug conjugates (pd cs) an overview
Anti cancer peptide drug conjugates (pd cs) an overviewAnti cancer peptide drug conjugates (pd cs) an overview
Anti cancer peptide drug conjugates (pd cs) an overviewDoriaFang
 
Summary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdfSummary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdfDoriaFang
 
pharmacogenomicspptnsu-191212202112 (1).pptx
pharmacogenomicspptnsu-191212202112 (1).pptxpharmacogenomicspptnsu-191212202112 (1).pptx
pharmacogenomicspptnsu-191212202112 (1).pptxDr. majid farooq
 
Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy Drugs to Prost...
Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy  Drugs to Prost...Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy  Drugs to Prost...
Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy Drugs to Prost...Conference-Proceedings-CrimsonPublishers
 
Protein and peptide delivery system
Protein and peptide delivery systemProtein and peptide delivery system
Protein and peptide delivery systemYamini Shah
 
Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...
Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...
Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...CrimsonpublishersCancer
 
Pharmacogenomics- a step to personalized medicines
Pharmacogenomics- a step to personalized medicinesPharmacogenomics- a step to personalized medicines
Pharmacogenomics- a step to personalized medicinesApusi Chowdhury
 
Novel drugs approved by fda in 2021
Novel drugs approved by fda in 2021Novel drugs approved by fda in 2021
Novel drugs approved by fda in 2021DoriaFang
 

Similar to Polymer therapeutics: smart drug delivery systems (20)

Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdf
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdfPeptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdf
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdf
 
Peptide drug conjugates (pd cs) new generation of targeted cancer treatment
Peptide drug conjugates (pd cs) new generation of targeted cancer treatmentPeptide drug conjugates (pd cs) new generation of targeted cancer treatment
Peptide drug conjugates (pd cs) new generation of targeted cancer treatment
 
Pharmaogenomics
PharmaogenomicsPharmaogenomics
Pharmaogenomics
 
Could PDC Be A New Direction For Targeted Therapy After ADC.pdf
Could PDC Be A New Direction For Targeted Therapy After ADC.pdfCould PDC Be A New Direction For Targeted Therapy After ADC.pdf
Could PDC Be A New Direction For Targeted Therapy After ADC.pdf
 
Drug target & delivery system
Drug target & delivery systemDrug target & delivery system
Drug target & delivery system
 
Phamacogenomics ppt.pptx 1
Phamacogenomics ppt.pptx 1Phamacogenomics ppt.pptx 1
Phamacogenomics ppt.pptx 1
 
Towards Personalized Medicine
Towards Personalized MedicineTowards Personalized Medicine
Towards Personalized Medicine
 
Anti cancer peptide drug conjugates (pd cs) an overview
Anti cancer peptide drug conjugates (pd cs) an overviewAnti cancer peptide drug conjugates (pd cs) an overview
Anti cancer peptide drug conjugates (pd cs) an overview
 
Summary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdfSummary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdf
 
pharmacogenomicspptnsu-191212202112 (1).pptx
pharmacogenomicspptnsu-191212202112 (1).pptxpharmacogenomicspptnsu-191212202112 (1).pptx
pharmacogenomicspptnsu-191212202112 (1).pptx
 
Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy Drugs to Prost...
Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy  Drugs to Prost...Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy  Drugs to Prost...
Crimson Publishers-Nanoparticle (NP) Delivery of Chemotherapy Drugs to Prost...
 
Drug polymer conjugate in drug delivery
Drug polymer conjugate in drug deliveryDrug polymer conjugate in drug delivery
Drug polymer conjugate in drug delivery
 
ppt pharmacogenomic.pptx
ppt pharmacogenomic.pptxppt pharmacogenomic.pptx
ppt pharmacogenomic.pptx
 
Protein and peptide delivery system
Protein and peptide delivery systemProtein and peptide delivery system
Protein and peptide delivery system
 
Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...
Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...
Hitting the Bullseye: Are Cell Penetrating Peptides (CPP) the Future of Targe...
 
PhD
PhDPhD
PhD
 
Pharmacogenomics- a step to personalized medicines
Pharmacogenomics- a step to personalized medicinesPharmacogenomics- a step to personalized medicines
Pharmacogenomics- a step to personalized medicines
 
Novel drugs approved by fda in 2021
Novel drugs approved by fda in 2021Novel drugs approved by fda in 2021
Novel drugs approved by fda in 2021
 
Oct.13 tips ntn
Oct.13 tips ntn Oct.13 tips ntn
Oct.13 tips ntn
 
oct.13 tips NTN
oct.13 tips NTN oct.13 tips NTN
oct.13 tips NTN
 

Recently uploaded

Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...ggsonu500
 
Biology class 12 assignment neet level practise chapter wise
Biology class 12 assignment neet level practise chapter wiseBiology class 12 assignment neet level practise chapter wise
Biology class 12 assignment neet level practise chapter wiseNAGKINGRAPELLY
 
Single Assessment Framework - What We Know So Far
Single Assessment Framework - What We Know So FarSingle Assessment Framework - What We Know So Far
Single Assessment Framework - What We Know So FarCareLineLive
 
Russian Escorts Greater Kailash | 9711199171 | all area service available
Russian Escorts Greater Kailash | 9711199171 | all area service availableRussian Escorts Greater Kailash | 9711199171 | all area service available
Russian Escorts Greater Kailash | 9711199171 | all area service availableveenita788
 
Immediate care of newborn, midwifery and obstetrical nursing
Immediate care of newborn, midwifery and obstetrical nursingImmediate care of newborn, midwifery and obstetrical nursing
Immediate care of newborn, midwifery and obstetrical nursingNursing education
 
Artificial Intelligence Robotics & Computational Fluid Dynamics
Artificial Intelligence Robotics & Computational Fluid DynamicsArtificial Intelligence Robotics & Computational Fluid Dynamics
Artificial Intelligence Robotics & Computational Fluid DynamicsParag Kothawade
 
Models Call Girls Electronic City | 7001305949 At Low Cost Cash Payment Booking
Models Call Girls Electronic City | 7001305949 At Low Cost Cash Payment BookingModels Call Girls Electronic City | 7001305949 At Low Cost Cash Payment Booking
Models Call Girls Electronic City | 7001305949 At Low Cost Cash Payment Bookingnarwatsonia7
 
2025 Inpatient Prospective Payment System (IPPS) Proposed Rule
2025 Inpatient Prospective Payment System (IPPS) Proposed Rule2025 Inpatient Prospective Payment System (IPPS) Proposed Rule
2025 Inpatient Prospective Payment System (IPPS) Proposed RuleShelby Lewis
 
ILO (International Labour Organization )
ILO (International Labour Organization )ILO (International Labour Organization )
ILO (International Labour Organization )Puja Kumari
 
Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...
Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...
Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...ddev2574
 
『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书
『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书
『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书rnrncn29
 
lupus quiz.pptx for knowing lupus thoroughly
lupus quiz.pptx for knowing lupus thoroughlylupus quiz.pptx for knowing lupus thoroughly
lupus quiz.pptx for knowing lupus thoroughlyRitasman Baisya
 
Call Girls Rajendra Nagar 9999965857 Cheap and Best with original Photos
Call Girls Rajendra Nagar 9999965857 Cheap and Best with original PhotosCall Girls Rajendra Nagar 9999965857 Cheap and Best with original Photos
Call Girls Rajendra Nagar 9999965857 Cheap and Best with original Photosparshadkalavatidevi7
 
TEENAGE PREGNANCY PREVENTION AND AWARENESS
TEENAGE PREGNANCY PREVENTION AND AWARENESSTEENAGE PREGNANCY PREVENTION AND AWARENESS
TEENAGE PREGNANCY PREVENTION AND AWARENESSPeterJamesVitug
 
Clinical Education Presentation at Accelacare
Clinical Education Presentation at AccelacareClinical Education Presentation at Accelacare
Clinical Education Presentation at Accelacarepablor40
 
Monitoring patient during surgical procedure
Monitoring patient during surgical procedureMonitoring patient during surgical procedure
Monitoring patient during surgical procedureunperson346
 
Call Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 Hire
Call Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 HireCall Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 Hire
Call Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 HireCall Girls Delhi
 
Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...vrvipin164
 
ANTIGEN- SECTION IMMUNOLOGY DEPARTMENT OF MICROBIOLOGY
ANTIGEN- SECTION IMMUNOLOGY  DEPARTMENT OF MICROBIOLOGYANTIGEN- SECTION IMMUNOLOGY  DEPARTMENT OF MICROBIOLOGY
ANTIGEN- SECTION IMMUNOLOGY DEPARTMENT OF MICROBIOLOGYDrmayuribhise
 

Recently uploaded (20)

Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 86 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
 
Biology class 12 assignment neet level practise chapter wise
Biology class 12 assignment neet level practise chapter wiseBiology class 12 assignment neet level practise chapter wise
Biology class 12 assignment neet level practise chapter wise
 
Single Assessment Framework - What We Know So Far
Single Assessment Framework - What We Know So FarSingle Assessment Framework - What We Know So Far
Single Assessment Framework - What We Know So Far
 
Russian Escorts Greater Kailash | 9711199171 | all area service available
Russian Escorts Greater Kailash | 9711199171 | all area service availableRussian Escorts Greater Kailash | 9711199171 | all area service available
Russian Escorts Greater Kailash | 9711199171 | all area service available
 
Immediate care of newborn, midwifery and obstetrical nursing
Immediate care of newborn, midwifery and obstetrical nursingImmediate care of newborn, midwifery and obstetrical nursing
Immediate care of newborn, midwifery and obstetrical nursing
 
Kidney Transplant At Hiranandani Hospital
Kidney Transplant At Hiranandani HospitalKidney Transplant At Hiranandani Hospital
Kidney Transplant At Hiranandani Hospital
 
Artificial Intelligence Robotics & Computational Fluid Dynamics
Artificial Intelligence Robotics & Computational Fluid DynamicsArtificial Intelligence Robotics & Computational Fluid Dynamics
Artificial Intelligence Robotics & Computational Fluid Dynamics
 
Models Call Girls Electronic City | 7001305949 At Low Cost Cash Payment Booking
Models Call Girls Electronic City | 7001305949 At Low Cost Cash Payment BookingModels Call Girls Electronic City | 7001305949 At Low Cost Cash Payment Booking
Models Call Girls Electronic City | 7001305949 At Low Cost Cash Payment Booking
 
2025 Inpatient Prospective Payment System (IPPS) Proposed Rule
2025 Inpatient Prospective Payment System (IPPS) Proposed Rule2025 Inpatient Prospective Payment System (IPPS) Proposed Rule
2025 Inpatient Prospective Payment System (IPPS) Proposed Rule
 
ILO (International Labour Organization )
ILO (International Labour Organization )ILO (International Labour Organization )
ILO (International Labour Organization )
 
Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...
Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...
Rohini Sector 6 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few Cl...
 
『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书
『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书
『澳洲文凭』买莫道克大学毕业证书成绩单办理澳洲Murdoch文凭学位证书
 
lupus quiz.pptx for knowing lupus thoroughly
lupus quiz.pptx for knowing lupus thoroughlylupus quiz.pptx for knowing lupus thoroughly
lupus quiz.pptx for knowing lupus thoroughly
 
Call Girls Rajendra Nagar 9999965857 Cheap and Best with original Photos
Call Girls Rajendra Nagar 9999965857 Cheap and Best with original PhotosCall Girls Rajendra Nagar 9999965857 Cheap and Best with original Photos
Call Girls Rajendra Nagar 9999965857 Cheap and Best with original Photos
 
TEENAGE PREGNANCY PREVENTION AND AWARENESS
TEENAGE PREGNANCY PREVENTION AND AWARENESSTEENAGE PREGNANCY PREVENTION AND AWARENESS
TEENAGE PREGNANCY PREVENTION AND AWARENESS
 
Clinical Education Presentation at Accelacare
Clinical Education Presentation at AccelacareClinical Education Presentation at Accelacare
Clinical Education Presentation at Accelacare
 
Monitoring patient during surgical procedure
Monitoring patient during surgical procedureMonitoring patient during surgical procedure
Monitoring patient during surgical procedure
 
Call Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 Hire
Call Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 HireCall Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 Hire
Call Girls Hari Nagar 9873940964 Elite Escort Service Available 24/7 Hire
 
Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
Gurgaon Sector 45 Call Girls ( 9873940964 ) Book Hot And Sexy Girls In A Few ...
 
ANTIGEN- SECTION IMMUNOLOGY DEPARTMENT OF MICROBIOLOGY
ANTIGEN- SECTION IMMUNOLOGY  DEPARTMENT OF MICROBIOLOGYANTIGEN- SECTION IMMUNOLOGY  DEPARTMENT OF MICROBIOLOGY
ANTIGEN- SECTION IMMUNOLOGY DEPARTMENT OF MICROBIOLOGY
 

Polymer therapeutics: smart drug delivery systems

  • 1. Polymer therapeutics: smart drug delivery system ALOK KUMAR DRDO – JRF PHARMACOLOGY & TOXICOLOGY
  • 2. Improving the therapeutic index of drugs is a major impetus for innovation in many therapeutic areas such as cancer, inflammatory, and infective diseases. The field of drug delivery system (DDS) utilizing polymeric carrier, which covalently conjugates molecule of interest, plays an important role in modern therapeutics. Majority of Drug 500 g/mol Narrow therapeutic index Short half life in plasma High clearance Distribute evenly Frequent side-Effects nephrotoxicity, bone-marrow toxicity, neurotoxicity, cardiotoxicity, mucositis, and gastrointestinal toxicity, which are dose-limiting and thus prevent effective treatment.
  • 3. Biologically active polymers: Friend or foe? polymer therapeutics have confirmed that they can satisfy the requirements of both industrial development, and the “Regulatory Authority Approval” process. polymer therapeutics: “Conjugates of drugs and polymers as well as other polymeric carrier systems” The use of polymers in medicine is not new and undoubtedly natural polymers have been used as components of herbal remedies for several millennia.  Use of polymers in biomedical materials (e.g. as prostheses, medical devices, contact lenses, dental materials and pharmaceutical excipients) became well established in the last century  In the early years, polymers studied clinically were mainly plasma expanders (e.g. and dextran and poly(vinylpyrolidone) (PVP) materials for use as wound dressings and antiseptics (called Povidone)
  • 4. The choice of polymeric backbone for the conjugate has great implications on the pharmacokinetics and pharmacodynamics of the drug. The polymer characteristics, such as Mw, polydispersity, architecture, charge and hydrophilicity, define the drug solubility and loading, its biodistribution, body excretion and the interaction with the immune system.
  • 5. The objectives for designing a polymer therapeutics: (i) Enhancing water solubility, particularly relevant for some drugs with low aqueous solubility. (ii) Stability against degrading enzymes or reduced uptake by reticuloendothelial system (RES). (iii) Targeted delivery of drugs to specific sites of action in body Three key technologies were the major factors that stimulated the immense activity and clinical success of nanotherapeutics (1980s to present.) First is the concept of “PEGylation”, drugs or drug carriers. The second is the concept of “active targeting” of the drug conjugate by conjugating cell membrane receptor antibodies, peptides or small molecule cell ligands to the polymer carrier. The third was the discovery of the “enhanced permeation and retention effect” (EPR) by Hiroshi Maeda.
  • 6. Macromolecules as Drug-Delivery Systems: Biological Rationale Size, charge, conformation of macromolecule is crucial Renal threshold-30–50 kDa to avoid leakage of body proteins into the bladder Angew. Chem. Int. Ed. 2006
  • 7. Passive Drug Targeting and Specific Tissue Targeting: The EPR Effect “Differences in the biochemical and physiological characteristics of healthy and malignant tissue are responsible for the passive accumulation of macromolecules in tumors” In general, low-molecular-weight compounds diffuse into normal and tumor tissue through the endothelia cell layer of blood capillaries. Macromolecules, however, cannot pass through the capillary walls of normal tissue. Smaller tumor nodules accumulate larger amounts of the polymer than larger nodules. This observation points to the possibility that polymeric imaging agents could help to detect small tumor nodules. Controlled Release 2000
  • 8. Cellular Uptake of Polymers, Site-Specific Drug Release, and Implications for Drug Design drop in the pH value takes place from the (7.2–7.4) in the extracellular space to pH 6.5–5.0 in the endosomes and to around pH 4.0 in primary and secondary lysosomes Lysosomal enzymes activity The design of drug–polymer conjugates initially focused on incorporating enzymatically cleavable bonds that allow the prodrug to be cleaved intracellularly after cellular uptake. Cancer Metastasis Rev. 1987
  • 9. Polymer Conjugates for Protein Stabilization More than 7000 naturally occurring peptides have been identified, and these often have crucial roles in human physiology, including actions as hormones, neurotransmitters, growth factors, ion channel ligands, or anti-infective Peptide drugs market US$ 19 billions by 2016 end and expected to increase at over 10 % peptide medicines : more than 60 (FDA)- approved on the market, 140 in clinical trial, more than 500 in preclinical development Nat. Rev. Drug discovery 2003, Trends and Forecast 2012–2018. The most recent example of a novel peptide drug class is the group of glucagon-like peptide-1 (GLP-1) agonists for the treatment of type 2 diabetes mellitus (T2DM), which reached total sales of over US$2.6 billion in 2013
  • 10. Pegylation is now accepted tool and the composition of biopharmaceutical is increasing Linear and branched PEGs of Mw 5000-40000 g/mol have been used to create conjugates sometime multiple PEGs attached to per protein Pharm. Res. 2010 Limitation: Short t1/2, low stability, costly production, poor bioavailability, immunogenic and allergic potential Attachment of PEG chains onto the surface of the protein. PEGylation is designed to increase protein solubility, reduce immunogenicity and prolong plasma circulation, IMTECH's Streptokinase contributions worthRs.20,000 crore
  • 11. Other examples of PEGylated proteins on the market or in advanced clinical trials are pegvisomant, a PEGylated form of the human growth hormone, PEGylated receptor and antibody fragment directed against tumor necrosis factor- (PEG-TNF-RI and PEG-anti-TNF Fab, respectively). The increase in the MTD No particular toxicity of polymer Drug Discovery Today. 2015
  • 12. Mol. Pharmacol. 2006 Bioscavengers of Organophosphate Compounds
  • 13. Drug–Polymer Conjugates with Cleavable Linkers Drug–Polymer Conjugates is promising strategy to improve the therapeutic index Careful tailoring of polymer–drug linkers is essential to the creation of a polymeric prodrug that is inert during transport but allows drug liberation at an appropriate rate intratumorally. Peptidyl polymer–drug linkers were popularized by the successful design of HPMA copolymer–Gly-Phe-Leu-Gly-doxorubicin conjugates. (sensitive to cathepsin B) pH sensitive cis-aconityl, hydrazone and acetal linkages have also been fashionable as an alternative for drug conjugation Adv. Drug Deliv. Rev. 2009
  • 14. The field of polymer therapeutics is constantly growing, and when attempting to assemble a new conjugate, the possibilities seem endless. The choice of drug should be the first step, knowing it features whether it is suffering from low solubility, high toxicity and severe side effects, short half-life in the circulation, is crucial for further decisions regarding the polymeric backbone, the size and shape of the final conjugate and the required linker.
  • 15. Mw 30 kDa, 8.5 % doxorubicine Phase 1 CTC and MTD 320 mg m-2 (5 fold increase vs normal dose of free drug) No acute cardiotoxicty, prolong plasma t ½, absence of rapid elimination Phase 2 280 mg m-2 every three week Related to PK1 Mw 25 kDa Additional targeting ligand, Taken up by asialoglycoprotein receptor Phase 1 MTD 160 mg m-2 Phase 2 120 mg m-2 Cancer Res. 1999,
  • 16. Another approach to doxorubicin–polylactide conjugates was recently reported by Sengupta et al. These conjugates have been embedded into a biodegradable polylactide nanoparticle to achieve a better tumor selectivity through the EPR effect Prothecan: Gastrooesophageal tumor A. The EPR effect results in a drug-targeting effect, B. Esterifying the 20-hydroxy group of CPT stabilizes the drug in its active lactone form C. Incorporation of a glycine spacer ensured a controlled release of the drug D. Use of hydrophilic PEG leads to a highly water-soluble formulation of camptothecin. J. Pharm. Biomed. Anal. 2000, Clin. Oncol. 2003
  • 17. Opaxio® (PGA-paclitaxel) has just finished enrolling patients in a Phase III trial in 2014 against ovarian cancer. NC-6004 platinum-containing micelle being evaluated in Phase III as a treatment for pancreatic cancer DOXO-EMCH (6-maleimidocaproyl) hydrazone derivative of doxorubicin in Renal cell carcinoma Med. Chem. 2002
  • 18. The PDPEPT concept: Polymer- directed enzyme –prodrug therapy Is novel two step antitumor aproach (HPMA copolymer)–(cathepsin B) conjugate HPMA-co-MA-GG-C-Dox HPMA-co-MA-GG-β-L Bioconjugate Chem. 2003,
  • 19. Multivalent Drug Concepts: A number of multivalent inhibitors have been designed that are based on low-molecular-weight drugs and target dimeric or multimeric proteins that contain multiple identical receptor sites. A pentavalent starlike carbohydrate ligand has been reported that fitted precisely into the binding pocket of the five subunits of the Shiga-like bacteria toxin, (10 7 more affinity than monovalent interaction) Tolevamer (GT160-246), a sodium salt of a styrene sulfonate polymer designed to bind to Clostridium difficile toxins A and B. Angiogenesis is crucial for tumor growth. ngiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging anticancer drugs. HPMA copolymer–TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models.
  • 20. Telavancin: a highly bactericidal injectable antibiotic based on a vancomycin derivative (bind to bacterial cell wall with high affinity)with multiple modes of action serious infections arising from Staphylococcus aureus (including multidrug-resistant strains) and other Gram-positive pathogens. Oligo-G: (alginate oligoscharide) under clinical trial for cystic fibrosis Inihibtion of virus attachment The inhibition of virus attachment to cell surfaces is a fundamental problem for the prevention of viral infections, such as influenza and HIV. Vivagel : a 3% (w/w) carbopol gel formulation of the lysine based dendrimer SPL7013 that display broad spectrum antiviral activity. e.g. against HIV-1, HIV-2 , Herpes simplex , human pappiloma
  • 21. Polyanionic Polymers: Heparin Analogues heparin analogues with a similar or even improved pharmacological profile, but lacking the disadvantages of this animal product, are of interest. simple and efficient approach to highly branched polysulfated heparin analogues based on dendritic polyglycerols has been developed
  • 22. Polycationic Polymers as DNA/RNA Transfection Agents The search for nonviral alternatives remains a challenge because of problems associated with viral gene transfection, For the purpose of nucleic acid transfer, nanoparticles or polyplexes of polymers has been created. Commonly used cationic polymer are: poly(ethylene imine) (PEI), poly(l- lysine), polyamidoamine (PAMAM) , chitosans and Cyclodextrins Incorporation of Delivery Functions: Targeting Domains Shielding Domains Transport Domains Nuclear Import Adv .Polym .Sci. 2006
  • 23. Cancer Gene Therapy. 2002 TNF expression localized to the tumor resulted in hemorrhagic tumor necrosis and inhibition of tumor growth without systemic TNF- related toxicity.
  • 24. Nanocarriers Based on Dendritic Polymers Dendritic polymers with their regular and well-defined unimolecular architecture, which can be further chemically modified at either the core (to increase hydrophobicity) or the shell (to increase hydrophilicity), Pegaptanib – (PEG-aptamer) approved US FDA 2004 (Macugen. Pfizer). It bound to VEGF it inhibits the interaction of VEGF with VEGFR1 and VEGFR2, and ameliorates the loss of visual acuity in AMD Biochem. 1995, Adv. Drug Delivery Rev. 2005
  • 25. ADME of polymer Therapeutics The choice of polymeric backbone for the conjugate: pharmacokinetics and pharmacodynamics The polymer characteristics, such as molecular weight, polydispersity, architecture, charge and hydrophilicity, define the drug solubility and loading, its biodistribution, body excretion and the interaction with the immune system. HPMA, PEI, PVP), PGA, PAM, PDMA, PVA, chitosan and dextran. NKTR-118: PEG-Naloxone, orally administered Use of LMWC: anticancer conjugate of taxel Chitosan-insulin conjugate : oral deliver of insulin Journal of Controlled Release 161. 2012
  • 26. travelling to the site of action: EPR, active targetting , shape of polymer Immune respone: antibody, RES clearance Distribution of low Mw drugs: TNP-470 Distribution of biological drugs: PEG conjugates Desease site environment: Ph, overexpressed enzymes like cathepsin B ROS- can cleave boronic acid or ester linkers Distribution: Cell internization Metabolism and degradation Elimination of nonbiodegradable polymers •No internalization above 400 kDa •Rod shaped>spherical •Branched> spherical •Escape from ABC transporter no MDR Biodegradable: hyaluronic acid, collagen, PG, PA Semibiodegradable: HPMA , HPMA-polylactide Mw, size and shape, of polymer have major influence on its excreation and rate of glomerular filtration.
  • 27. Regulatory considerations The urgent need for improved diagnostics and treatments for Life threatening diseases Eg. Cancer, CVS, RA, blindness, neurodegeneratives Next generation polymer therapeutics will continue to make a positive contribution to healthcare improvement, but transition from laboratory-based research to first in patient clinical trials must, however, always be carefully controlled in terms of potential risk/benefit. It is also important to stress that such complex, new medicines must be cost-effective, practical to use and ideally should be available at a price that makes them accessible to patients globally. FDA UK Medicines and Healthcare products Regulatory Agency (MHRA) European Medicines Agency (EMEA) CDSCO Adv. Drug Deliv. Rev. 61, 2009
  • 29. Summary and conclusions •The development of polymer therapeutics has emerged as an exciting field of research for improving the therapeutic potential of low-molecular-weight drugs and proteins. •In the future more biodegradable polymers with high molecular weights and high recision (Mn>30 000 gmol1, polydispersity <1.5) as well as new modular approaches to “intelligent” polymeric nanotransporters will be needed. •To ensure eventual healthcare benefit, it is important that basic researchers understand well the industrial development and regulatory processes so that they can ensure their new technologies have at least the potential to meet regulatory requirements.

Editor's Notes

  1. One of the major problems in drug development is the poor solubility of many existing and new drugs. Very often the therapeutic effectiveness of these drugs is diminished by their inability to gain access to the site of action at an appropriate dose. Therefore, these drugs are either not clinically used, delivered in large volumes of aqueous or ethanolic solutions,delivered in conjunction with surfactants, or chemically derivatized to soluble prodrugs. Unfortunately, all of these modifications can result in reduced efficacy or adverse effects.
  2. Figure 6: (a) Active and passive targeting by nanocarriers [35]; (b) (1) polymer-conjugated drug is internalized by tumor cells through receptor-mediated endocytosis following ligand-receptor docking, (2) transport of DDS in membrane limited organelles; (3) fusion with lysosomes; (4) the drug will usually be released intracellularly on exposure to lysosomal enzymes or lower pH (pH 6.5–<4.0) [31]. If the drug is bound to the polymer by an acid-sensitive linker then the extracellular release of drug takes place, especially if the drug is trapped by the tumor for longer period of time.
  3. As a general rule, a polymer with a molecular weight above the renal threshold (ca. 30 kDa) as well as a neutral charge ensures a long half-life in plasma. This prolonged plasma residence time is an important prerequisite for a significant accumulation of the circulating polymer in the tumor.
  4. Actively-targeted drugs mostly undergo internalization through receptor-mediated endocytosis, in which macromolecules bind to complementary receptors on the cell surface and enter the cell as receptor-macromolecule complex in clathrin-coated vesicles. This process increases the efficiency of internalization of particular macro molecules more than 1000-fold compared with ordinary pinocytosis The size of clathrin-coated vesicles depends on the size of its cargo, with an observed upper limit of about 200 nm external di ameter, which should be taken into account when designing any polymer therapeutic Following internalization by pinocytosis or by receptor-mediated endocytosis the conjugates are carried to the early endosome (EE). In the early endosome a slightly acidic pH (6.0–6.8) is maintained.
  5. There are three requrment for optimized synthesisi of a polymer protein conjugate : a semitelichelic polymer that is one with a single reactive grop at one terminal end to avoid protein crosslinking ; ability to introduce a linker that will not generate toxic or immunogenic by product and tha will provide appropiate stability charecteristics; and a aprach that will provide site specific protein modification.
  6. Efficacy of IFN-α in the treatment of melanoma and renal cell carcinoma is well established, but there are problems, including toxic side effects and a short plasma half-life (t ½ = 2.3 h) that necessitate administration three times per week. In a Phase I/II study, PEGylated IFN-α–2b was given by subcutaneous injection once per week for twelve weeks to patients with advanced solid tumours (primarily, renal cell carcinoma). PEGylated IFN-α–2b had a maxi mum tolerated dose of 6.0 µg kg–1 week–1 , and produced an objective response rate of 14% in 44 previously untreated renal-cell carcinoma patients7
  7. The use of cholinesterases in prophylactic treatments against OP agents requires that these reside in the circulation for sufficiently long periods. Chemical modification of various recombinant proteins by covalent conjugation of PEG chains was shown to increase their circulatory residence (Harris and Chess, 2003); however, in many instances, the conjugation of PEG moieties to various proteins was accompanied by a concomitant loss of biological activity (Harris and Chess, 2003). We have demonstrated in the past that under a certain set of conditions, rHuAChE can be efficiently PE. The superior protection of PEGylated rHuAChE was also manifested when this enzyme was administered intramuscularly to mice 20 h before VX challenge, resulting in nearly 90% survival of the animals.
  8. A number of polymer–anticancer-drug conjugates are being tested clinically (TABLE 2). Routinely used cytotoxic chemotherapy distributes randomly in the body, and this feature, which is frequently combined with poor tumour selectivity in the mechanism of action, results in a relatively low therapeutic index. Those common solid tumours (breast, prostate, lung and colon cancer) that are the major cause of cancer mortality are particularly difficult to treat, hence the global quest for improved tumour targeting.Many researchers are trying to design improved low-molecular-weight prodrugs81
  9. Pk 2 Gamma camera imaging confirmed galactose-mediated liver targeting to 15–20% dose at 24 h .Although most of the conjugate was localized to normal liver hepatocytes, it was estimated that the doxorubicin concentration in hepatoma tissue would still be 12–50-fold higher than could be achieved by administration of free drug.
  10. Conjugating the 20-OH position of camptothecin with PEG through a glycine spacer
  11. In the polymer-bound form, the (HPMA copolymer)–(cathepsin B) conjugate retained approximately 20–25% of the cathepsin B activity in vitro. After intravenous administration of the conjugate to tumorbearing B16F10 mice there was a 4.2-fold increase in its accumulation in tumors relative to the free enzyme. When PK1 and the PDEPT combination were used to treat established B16F10 melanoma tumors, the antitumor activity (%T/C, the survival time of treated versus control animals) for the PDEPT combination was 168% compared to 152% for PK1 alone, and 144% for free doxorubicin.[84] Intraveneous administration of HPMA-co-MA-GG-C-Dox to mice bearing subcutaneously implanted B16F10 melanoma, followed after five hours by HPMA-co-MA-GG-b-L induced the release of free doxorubicin in the tumor. Whereas the PDEPT combination caused a significant decrease in the size of the tumor (T/C=132%), neither free doxorubicin nor HPMA-co-MAGG- C-Dox alone displayed activity. Furthermore the PDEPT combination showed no toxicity at the doses used.
  12. Another therapeutic approach, instead of direct tumor targeting with polymer-bound cytostatic drugs, is the targeting of angiogenesis with an HPMA–polymer conjugate of the angiogenesis inhibitor TNP-470.[86, 87] This approach showed very promising results in a mouse model, and no drug-related toxicities were observed . Tolevamer (GT160-246), a sodium salt of a styrene sulfonate polymer designed to bind to Clostridium difficile toxins A and B was evaluated as an orally adminis- tered solution to treat C. difficile-induced diarrhoea.
  13. The inhibition of virus attachment to cell surfaces is a fundamental problem for the prevention of viral infections, such as influenza and HIV. As depicted in Figure 11, traditional monovalent drugs cannot prevent the multiple adhesion of the virus to the cell surface. Therefore, the development of multivalent ligands (Figure 5) that bind to membrane proteins of viruses is an important goal. Interest in the development of natural aswell as synthetic polymers 307 as polymeric drugs continues. One noteworthy example is the alginate 308 oligosaccharide (Oligo-G) being developed as a novel antibacterial 309 agent [56,57]. Oligo-G reduces the viscosity of cystic fibrosis patient 310 sputum allowing improved efficacy of antibiotics, and it is currently in 311 early clinical trials as an inhaled formulation for the treatment of cystic 312 fibrosis. In a first Phase 1 study involving healthy volunteers Oligo-G 313 waswell tolerated and all adverse events seen weremild and transient. 314 Pharmacokinetic studies suggested no systemic absorption [58]. This is 315 an interesting example of a polymeric drug being developed for pulmo- 316 nary administration.
  14. Heparin, a glycosaminoglycan (Scheme 5), has been the drug of choice in the prevention and treatment of thromboembolic disorders for nearly 70 years. There is great interest in finding alternatives to both unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) because heparin has several disadvantages: First, it has to be isolated from mammalian organs, which implies a potential risk of contamination with pathogens such as viruses or prions, second, the increased use of heparin, especially of LMWH, means there is a growing shortage of the raw material, and third, heparin is a polydisperse mixture of molecules with different chain lengths and chemical structures.[102] Numerous parameters, such as the animal species used for providing heparin, the method of isolation, and the purification step of the product, influence its respective composition and results in wide chemical and subsequent pharmacological variations between different heparin preparations. polyglycerol sulfates prolong the time of activated partial thromboplastin as well as thrombin and inhibit both the classical and alternative complement activation more effectively than heparin itself. In contrast to sulfated polysaccharides, their activities are not directly dependent on the molecular weight, which might be a result of the globular 3D structure of the dendritic polyglycerol sulfates.
  15. The search for non viral alternatives remains a challenge because of problems associated with viral gene transfection, such as immune response and limited selectivity,. The colloidal surface and chemical properties of DNA and RNA complexes with polycations are responsible for controlling the extent and rate of delivery of genes to cells. H The polymer has to compact DNA into particles of virus-like dimensions that can migrate through the blood circulation into the target tissue, it has to protect the DNA from degradation and against undesired interactions with the biological environment, to facilitate target cell binding and internalization [12–16], ideally in a target cell specific manner [17, 18], endosomal escape [19], trafficking the cytoplasmic environment [20] and localizing into the nucleus [21, 22] as well as vector un packing [23]. In addition, the polymer should be non-toxic, non-immunogenic and biodegradable. In reality, no polymer is able to carry out all the extra cellular and intracellular delivery functions; therefore additional functional elements have to be included into the polyplex formulation (see Fig. 1b).
  16. Although physical aggregates such as liposomes and micelles are frequently used as drug-delivery systems,[5] they can be unstable under shear force and other environmental effects, such as high dilution,[143] temperature, and pressure required, for example, for sterilization. An alternative approach is the covalent modification of dendritic macromolecules with an appropriate shell that results in stable micelle-type structures suitable for noncovalent ncapsulation A simple and general concept for the generation of core– shell-type architectures from readily accessible hyperbranched polymers was recently reported.[160] Several pHsensitive nanocarriers have been prepared by attaching pHsensitive shells through acetal or imine bonds to commercially available dendritic core structures (polyglycerol and polyethylene imine; Figure 16). In some cases the pH-responsive nanocarriers showed a very high transport capacity which is an important criterion for efficient drug delivery. Various guest molecules, such as polar dyes, oligonucleotides, and anticancer drugs have been encapsulated inside these dendritic core–shell architectures. of guest molecules (Figure 15)
  17. The choice of polymeric backbone for the conjugate has great implications on the pharmacokinetics and pharmacodynamics of the drug. The polymer characteristics, such as molecular weight, polydispersity, architecture, charge and hydrophilicity, define the drug solubility and loading, its biodistribution, body excretion and the interaction with the immune system. The polymeric backbone of the conjugate can be biodegradable, non-biodegradable, or semibiodegradable.
  18. Properties of the carrier. Once in the bloodstream, the size, shape, surface charge and decorations, and mechanical properties of the conjugate play key roles in its biodistribution, vascular dynamics, targeting, clearance, uptake, drug release kinetics and degradation. Naturally, interactions with the immune system and with serum proteins, if occur, have also great influence on these processes. The impact of size on biodistribution has largely been elucidated using spherically shaped particles. However, particle shape was indicated just as important, showing that shape has a significant impact on biodistribution . [27,28].EPR effect help
  19. No medical product, or indeed medical procedure is without any risk. The role of such Agencies is therefore to ensure that all new medicines and medical devices do actually work, and that they are acceptably safe in terms of the risk–benefit balance. Nanotechnology, in all its forms, offers considerable societal benefit, and there are large number of potential beneficiaries and stackholder. Accompanying the hype of ‘nano’, on one side many have been over-promoting the enormous future potential of nanopharmaceuticals, and on the other scaremongering as to the potential hazards associated with all nanomaterials per se.