nanoparticle based drug delivery in cancer therapy: passive and active targeting

hypervascularisation in heathy tissue

Vascular endothelial growth factor (VEGF) promotes

angiogenesis in embryos and wound healing in adults

tumour tissue hypervascualrisation

VEGF allows tumour to grow beyond 1–2 mm

with supply of nutrients and oxygen

extravasation healthy tissue

• Normal cells’ vasculature is only

  permeable to particles smaller than 2 nm

extravasation tumour tissue

Vasculature pore sizes of most solid tumours range from

10 to 1000 nm, depending on the stage and type of cancer

impaired lymphatic drainage healthy tissue

Interstitial fluid pressure ~ 0 mmHg

impaired lymphatic drainage tumour tissue

Interstitial fluid pressure reaches microvascular

pressure levels (a range of 10-40 mmHg)

enhanced permeability and retention

Nanoparticles (~ < 100 nm) will remain inside healthy vessels but

selectively leak into tumour tissue and accumulate there

passive targeting to active targeting

• ERP effect was discovered in 1986- principle for the design of nano medicines

active targeting

1. active targeting nanoparticles

2. over expressed receptor on cancer cells

3. internalisation

4. endosome

proteins

• HER2 in breast cancer, EGFR in many cancer

• nanoparticles conjugated with HER2 specific affibody or anti EGFR antibody

• Transferrin receptors (TfR) with

  high expression on BBB

  endothelium

polysaccharides

CD44 receptors overexpressed on various tumour cells

• Nanoparticles with hyaluronic acid (anionic polysaccharide) can bind

to CD44

peptides

Interleukin-4 receptors (IL-4R)

overexpressed in lung cancer

• Nanoparticles conjugated

with IL-4R-binding peptide-

1 (CRKRLDRNC)

aptamers

Short, single-stranded DNA or RNA (ssDNA or ssRNA) molecules,

selectively bind to a specific target

• Nucleolin protein upregulated in many cancer cells

• Nanoparticles conjugated with AS-1411 aptamer can specifically

recognise nucleolin

small molecules

Folate receptors overexpressed on the surfaces of most solid tumour cells

• Nanoparticles conjugated with folic acid as the active ligand

sigma receptor overexpressed on many human tumours including melanoma

• Nanoparticles conjugated with anisamide, an agonist of sigma receptors

focused ultrasound

• pore size of cell membrane increase due to

  • sonoporation \

  • cavitation

• drug release due to

  • hyperthermia

sonoporation

• Mechanical impact of ultrasound radiation

  on cell membrane molecules

cavitation

Microbubbles in blood undergo rapid changes in size & shape inducing high shear stresses on endothelium

hyperthermia

Elevating tissue temperature to a mild 42°C to increase blood flow and induce drug release

phototherapy

• cancer cell death due to hypethermia

• drug release

  • phototheramal polymers

  • thermosensitve linkers

photo thermal polymers

• Polymer contains light-

  responsive self-immolative groups which

  absorb wavelength-specific UV light leading to

  polymer degradation

thermosensitive linkers

Light-induced ROS

generation lead to the cleavage of chemical

bonds, e.g. thioketal (TK) linkers

magnetic drug delivery

Drug targeting

• Superparamagnetic iron

oxide nanoparticles (SPIONs)

pH

Tumour cells have a more acidic pHe (0.3–0.7 lower) and neutral/more

alkaline pHi than in normal cells

redox

Hypoxia arises due to a mismatch between oxygen delivery and consumption

• Anoxic metabolic cellular pathway in the hypoxic tumour core cells can generate

lactic acid making the tumour microenvironment highly acidic

• [O2] ↓, [ROS] ↑, increasing oxidative stress → tumour cells undergo apoptosis

• The azo group (–N=N–) present can be reductively cleaved under hypoxic

conditions to release drug

enzymes

• Smart enzyme-responsive nanoparticles can predictively and

  selectively react with specific enzymes expressed in tumour tissues