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4 - Lecture 3, Nanotechnology

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45 views24 pages

4 - Lecture 3, Nanotechnology

Uploaded by

abozizo063
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© © All Rights Reserved
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Pharmaceutical

Nanotechnology
Lec#3, Kareem Ebeid, Ph.D.
Assistant Professor of Pharmaceutics, Minia University
Minia, Egypt

1
What is nanoscale

In the International System of Units, the prefix "nano" means one-billionth,


or 10-9; therefore, one nanometer is one-billionth of a meter.

It’s difficult to imagine just how small that is, so here are some examples:
• A sheet of paper is about 100,000 nanometers thick
• A strand of human DNA is 2.5 nanometers in diameter
• A human hair is approximately 80,000- 100,000 nanometers wide
• On a comparative scale, if the diameter of a marble was one
nanometer, then diameter of the Earth would be about one meter

https://www.nano.gov/nanotech-101/what/nano-size (03/06/2022) 3
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What is Pharmaceutical Nanotechnology?

• Pharmaceutical nanotechnology is a term applied to the design,


characterization and production of pharmaceutical materials,
structures and products that have one or more dimensions between
approximately 1 nm and 100 nm. however, an upper limit of 1000 nm is
often considered (FDA).

https://www.nano.gov/nanotech-101/what/nano-size (03/06/2022) 7
Applications of pharmaceutical nanotechnology:

• The application of nanotechnology encompasses the formulation and


development of nanomedicines to increase drug potency and
efficacy, and the use of nanomaterials in tissue engineering and
implants to fabricate structures to support tissue regeneration within the
body.

https://www.nano.gov/nanotech-101/what/nano-size (03/06/2022) 8
Advantages of using nanotechnology in drug
formulation:
1. Enhanced solubility and dissolution. Because of the high surface
area to volume ratio offered by nanoparticles, the solubility and rate
of dissolution of drugs can be increased.
2. Enhanced drug delivery. The small particle size can prolong a drug’s
residence in the systemic circulation, it can modify drug distribution
and it may permit drug targeting and transport across biological
barriers.

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Polymer–drug conjugates

• To improve drug solubility and/or the delivery of drugs, drug molecules


may be conjugated to polymers, producing polymer–drug
conjugates.
• These polymer-drug conjugates are considered as new chemical
entities and, as their overall size is generally smaller than 100 nm, these
systems can be classified within the general area of nanotechnology.

11
Polymer–drug conjugates

• As these polymers are synthetic, they are generally less immunogenic


than naturally derived macromolecules.
• For the production of polymer–drug conjugates for parenteral
administration, water-soluble polymers are used.
• A polymer–drug conjugate can be described as being built of three
basic components
1. Water soluble polymer
2. Linker
3. Drug
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Polymer–drug conjugates
1- A water-soluble polymer backbone
• Synthetic polymers
• PEG,
• poly(ethyleneimine),
• polyvinylpyrrolidone,
• poly(vinyl alcohol),
• poly(glutamic acid) and
• Hydroxypropyl methacrylate copolymers.

• Natural polymers
• dextran,
• chitosans,
• hyaluronic acid

• Proteins 13
Polymer–drug conjugates
1- A water-soluble polymer backbone

• PEG is the most widely used;


• it is approved by the FDA for human use.
• Advantages:
• Low immunogenicity, antigenicity and toxicity.
• PEG chains also offer high hydration and flexibility, which is useful in
increasing solubility and improving drug delivery.
• Low polydispersity (in terms of molecular weight).
• It can be easily modified and conjugated to drugs and proteins.

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Polymer–drug conjugates
2- A linker group

• Drug is attached via a linker or spacer group, to help avoid the


therapeutic action of the drug being blocked by the polymer.
• The linker can also be designed to be cleaved under certain conditions,
such as changes in pH, enzymatic degradation or hydrolysis.
• This property can be used to promote the triggered release of the drug
from the polymer conjugate under suitable conditions, thereby
enhancing drug targeting.
• Examples of linker groups that can be used include amine, carbamate
and ester groups, with an amide linker being the most common option.
15
Polymer–drug conjugates
3- Drug

1. Chemotherapeutic drugs, such as doxorubicin and paclitaxel.


• This is because polymer conjugates can improve delivery and reduce
unwanted side effects for these drugs, which have narrow
therapeutic windows.
2. Proteins, e.g. L-asparaginase or interferons.
• Generally, proteins have short half-lives and low stability after
administration into the body.
• By conjugating proteins to polymers, one can increase their half-life
by protecting the proteins from enzyme degradation and reducing
clearance rates. 16
Polymer–drug conjugates

• In addition to the three components of the system, targeting groups can


be added to the polymer conjugate with the aim of enhancing
specificity and cellular uptake.

17
Polymer–drug conjugates in the market

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Rationale for polymer conjugation

1. Increasing solubility
The conjugation of low-solubility drugs (e.g. paclitaxel) to water soluble
polymers can enhance the solubility of the overall system. The paclitaxel
conjugate has enhanced solubility compared with paclitaxel, and therefore the
conjugate can be administered without further solubilizing agents.

2. Enhancing bioavailability and plasma half-life


The increased hydrodynamic volume of the polymer–drug conjugate compared with
the free drug can reduce rates of excretion via the kidneys, leading to an increase in
their circulation half-life.
The renal clearance of compounds from the circulation is dictated by their molecular
weight, with clearance rates decreasing with increasing molecular weight
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Rationale for polymer conjugation

3. Protecting against degradation after administration


The polymeric chains in the polymer–drug conjugate can also prevent the approach of
antibodies and proteolytic enzymes to the drug. Water-soluble polymers become
strongly hydrated, and these hydrated polymer strands can promote steric hindrance,
and block enzymes and antibodies from reaching the drug. This protects the drug from
degradation and enhances its plasma half-life and bioavailability. This is of particular
advantage for protein-based therapeutic agents that are rapidly degraded by
enzymes.

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Rationale for polymer conjugation

4. Reducing aggregation, immunogenicity and antigenicity


The hydrophilic coating offered by the polymers to the conjugate compound is the key
to this property. The hydrated polymer chains can mask the hydrophobic regions in the
protein, increase solubility and provide a steric shield that can help prevent protein–
protein association, and reduce aggregation.
PEGylation of proteins can also help stabilize proteins during lyophilization, so helping to
produce products with acceptable storage conditions.

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Rationale for polymer conjugation

5. Promoting targeting to specific organs, tissue or cells


By conjugation of drugs or proteins to water-soluble polymers, not only can their half-
lives be increased, but the specific accumulation of the drug or protein can also be
promoted in certain tissues.
This can be achieved through the use of targeting groups (ACTIVE) or the
phenomenon known as the enhanced permeability and retention (EPR) effect
(PASSIVE)

22
Polymer–drug conjugates: case studies of small molecule conjugate
• In this polymer–drug conjugate, paclitaxel is conjugated to poly(L-
glutamic acid) (PGA) via an ester linker.
• Conjugating paclitaxel to the water-soluble PGA overcomes the poor
aqueous solubility of paclitaxel, and the conjugate can be infused into
the body without the addition of solvents.
• This conjugate is stable in the circulation, and whilst it remains bound
to the polymer, paclitaxel is inactive.
• Because of its construct, the conjugate can passively target tumour
sites via the EPR effect. The drug is then released intracellularly via
degradation of PGA by lysosomal proteases, and the ester linker is
degraded by esterases or acid hydrolysis.
23
Polymer–drug conjugates: case studies of protein conjugate
• Oncaspar®, In this conjugate, L-asparaginase is bound to PEG via an amide
linker.
• This conjugate is used in the treatment of acute lymphoblastic leukaemia,
and its mechanism of action is based on selective killing of leukaemic cells
due to the depletion of plasma asparagine. Asparaginase is an enzyme
which breaks downs the amino acid L-asparagine. This interferes with the
growth of malignant cells, which, unlike most healthy cells, are unable to
synthesize L-asparagine for their metabolism.
• PEGylation of the enzyme enhances the circulation time of the enzyme,
allowing less frequent dosing. It can also be given to patients with a history
of hypersensitivity to native L-asparaginase.
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Thank You

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