💉 ABCT 102 — Drug Delivery & Nanomedicine Part 3 · self-study supplement
Delivery is the engineering half of pharmacology. The molecule is fixed, so you change where, when and how much of it arrives. This page covers the carriers (ADC, liposome, micelle, mesoporous silica, exosome, red-blood-cell membrane, cell-penetrating peptide), the release triggers, and why so few of them ever reach the clinic.
Source note — read this first
This page is built from supplementary explainer-video transcripts, not from an ABCT 102 lecture recording. Every claim was checked against standard sources before publication. Three claims in the source failed and are corrected below: “photodynamic therapy is research-only”, “RBCs circulate about 100 days”, and “recently approved cell-penetrating-peptide drugs for cystic fibrosis”.
D1 What delivery is actually for
The measure it moves — therapeutic index
Therapeutic index (TI) = toxic dose ÷ effective dose (TD50 / ED50). Higher TI = wider safety margin. A delivery system cannot change what the drug does; it changes how much of it reaches the wrong place, and that is what raises TI. Links back to L2 (dose–response) and L8 (dose-limiting toxicity).
Barriers a drug must survive
- Cell membranes — DNA, RNA and proteins are charged and/or large and cannot cross on their own.
- GI tract — acid and proteases destroy proteins; biologics are injection-only.
- Enzymatic degradation in blood and tissue.
- Clearance — renal filtration and uptake by the mononuclear phagocyte system (MPS: liver, spleen).
- Immune recognition — opsonisation, complement, anti-carrier antibodies.
Four jobs a carrier can do
| Job | What it means | Typical carrier |
|---|---|---|
| Target | Concentrate the drug at the diseased tissue | Antibody, ligand-coated nanoparticle |
| Protect | Shield cargo from enzymes, acid, clearance | Liposome, LNP, RBC membrane |
| Solubilise | Carry a hydrophobic drug in water | Micelle, liposome bilayer |
| Control release | Release at a rate or a trigger, not all at once | MSN, stimuli-responsive liposome |
Three strategies — and the one that wins
| Strategy | Definition | Example |
|---|---|---|
| Systemic | Into the blood, acts on the whole body; no localisation | Insulin injection |
| Targeted | A carrier with a targeting mechanism steers the drug to a tissue or cell | Antibody–drug conjugate |
| Controlled release | Drug is held until a location or a trigger, then released at a chosen rate | Mesoporous silica, pH-sensitive liposome |
Exam focus
Targeting and controlled release are different axes, and the strongest designs combine them. An ADC is the textbook answer because the antibody supplies targeting while the linker supplies controlled release. A plain nanoparticle supplies neither targeting nor a trigger unless you engineer one in.
D2 Antibody–drug conjugates (ADC)
An ADC is three parts bolted together: a targeting protein, a chemical switch, and a payload too toxic to give on its own.
| Component | Job | Detail |
|---|---|---|
| Antibody | Targeting ligand and carrier | Binds a tumour-associated antigen; usually a monoclonal IgG |
| Linker | Controls when the payload is freed | Cleavable or non-cleavable; the whole safety story sits here |
| Payload | Kills the cell | A cytotoxic drug (e.g. a tubulin or DNA-damaging agent) |
| Linker type | Cleaved by | Consequence |
|---|---|---|
| Acid-labile | Low pH (endosome / lysosome, tumour interstitium) | Releases inside the acidic compartment |
| Redox (disulfide) | High intracellular glutathione | Releases in the reducing cytosol |
| Protease-cleavable | Lysosomal proteases (e.g. cathepsins) | Requires internalisation — the most selective |
| Non-cleavable | Nothing — the antibody must be digested | Payload released only after lysosomal degradation; usually a wider therapeutic window in normal tissue |
The route, in order
- Antibody binds its antigen on the target cell.
- Complex is internalised by endocytosis.
- Endosome acidifies and matures; the linker is cleaved (or the antibody is digested).
- Free payload escapes into the cytoplasm and kills the cell.
Two numbers worth knowing
DAR (drug–antibody ratio) = how many payload molecules per antibody, typically about 2–4 (some up to ~8). Too low and the payload is too weak; too high and the antibody aggregates, clears faster, and off-target toxicity rises. Named clinical examples: trastuzumab emtansine (HER2, breast) and brentuximab vedotin (CD30, lymphoma).
Exam focus
The reason an ADC raises TI is not that the payload is less toxic — it is more toxic than conventional chemo. The reason is spatial restriction: the payload stays attached and inactive while it circulates, so normal tissue sees very little free drug.
D3 The carrier zoo — and the liposome/micelle trap
| Carrier | Structure | Good at | Limitation |
|---|---|---|---|
| Liposome | Lipid bilayer + aqueous core | Both hydrophilic and hydrophobic cargo; biocompatible | Leaks, cleared by MPS unless PEGylated |
| Micelle | Single layer, hydrophobic core | Solubilising hydrophobic drugs | Cannot hold charged/hydrophilic cargo; dissociates below its CMC |
| Polymeric NP | Solid polymer matrix | Tunable release, high loading | Batch variation, scale-up |
| Mesoporous silica NP | Porous mineral particle + cap | Very high loading; gated release | Non-degradable mineral → accumulation |
| Lipid nanoparticle (LNP) | Ionisable lipid + helper lipid + cholesterol + PEG-lipid | Nucleic acid delivery (mRNA vaccines) | Reactogenicity; anti-PEG antibodies |
| Exosome | Natural 30–150 nm vesicle | Biocompatible, carries protein/RNA | Heterogeneous, hard to load and to characterise |
| RBC membrane | Biological membrane shell | Long circulation, low immunogenicity | Donor supply, research-stage |
Liposome vs micelle — the question that catches people
| Liposome | Micelle | |
|---|---|---|
| Layers | Bilayer (two leaflets) | Monolayer |
| Interior | Aqueous core plus a lipid region | Hydrophobic core only |
| Hydrophilic drug | Goes in the aqueous core | No home for it |
| Hydrophobic drug | Dissolves in the bilayer | Goes in the core |
| Nucleic acid | Yes — with cationic or ionisable lipid | No |
Exam focus — the nucleic-acid rule
DNA and RNA are hydrophilic, anionic, and carry a phosphate backbone. They cannot sit in a hydrophobic micelle core — the micelle has nothing to hold them. Use a liposome, a lipid nanoparticle, or a cationic/ionisable-lipid carrier, where the nucleic acid is complexed by electrostatic attraction. This single rule explains why mRNA vaccines are LNPs and not micelles.
Carriers are not drugs
A nanoparticle is a vehicle. It has no therapeutic effect by itself; if anything, an unmodified one has no targeting at all and simply circulates until it is cleared or leaks into tissue. “Nanoparticle” describes a size range (~1–100 nm), not a mechanism.
D4 Controlled release — the triggers
| Trigger | Physiological basis | Where it is used |
|---|---|---|
| pH | Endosome/lysosome is acidic; tumour interstitium is mildly acidic | Acid-labile linkers, pH-sensitive liposomes |
| Enzyme | Lysosomal proteases, tumour-associated proteases | Peptide linkers (e.g. cathepsin-cleaved) |
| Redox | Cytosolic glutathione is far higher than plasma | Disulfide linkers |
| Light | Externally applied; needs a photosensitiser and oxygen | Superficial lesions only |
Mesoporous silica: drug in the pores, cap on top
A mesoporous silica nanoparticle (MSN) is a mineral particle riddled with nanoscale pores. Drug is loaded into the pores, then a gatekeeper / capping agent (a polymer, a protein, or a supramolecular cap) is placed over the openings. When the trigger fires, the cap is removed or degraded and the cargo diffuses out. This is a pure controlled-release design — it has no targeting unless a ligand is added, and being non-degradable mineral it tends to accumulate.
Light-triggered release — and a correction
The mechanism is photodynamic: a photosensitiser absorbs light of a specific wavelength, transfers energy to oxygen, and generates reactive oxygen species (ROS). ROS damage membranes — including the membrane of the liposome carrying the drug — so the cargo spills out.
Correction — the source is wrong here
The transcript says light-triggered therapy is “just for fun, research use, not approved”. Photodynamic therapy itself is fully approved and routine for superficial skin lesions — actinic keratosis, Bowen’s disease and superficial basal cell carcinoma — and for palliation of some oesophageal and lung tumours. Two further corrections: clinical ALA/MAL-PDT requires a 1–3 hour incubation, not the “30 minutes” in the transcript; and what remains genuinely experimental is using ROS to rupture a carrier so that a separate drug is released (photochemical internalisation). Keep those two ideas apart.
Why skin, specifically
Light penetrates tissue only millimetres to a few centimetres. So light-triggered approaches are restricted to surface-accessible disease, or require a fibre-optic probe. That physical limit — not a lack of interest — is the main reason light is a niche trigger in vivo.
D5 Case study — PEGylated liposomal doxorubicin
The one nanomedicine that every pharmacology course uses, because it is approved, it works, and its mechanism is a neat illustration of passive targeting.
| Feature | Detail |
|---|---|
| Structure | Lipid bilayer vesicle, roughly 80–100 nm, with a PEG coating on the surface |
| Loading | Remote loading against an ammonium-sulfate gradient: doxorubicin is drawn in and precipitates as a doxorubicin–sulfate crystal inside the aqueous core |
| Why PEG | Reduces opsonisation and MPS uptake → longer circulation time → more chances to reach the tumour |
| Accumulation | EPR effect — enhanced permeability and retention: tumour vessels are leaky, and tumour lymphatics are poor, so carriers leak in and stay |
| Entry | Endocytosis into the tumour cell |
| Release | The acidic endosome dissolves the crystal and frees the drug |
Two honest caveats — do not overclaim EPR
(1) EPR is not a law. It reproduces well in rodent tumour models but is heterogeneous and much weaker in human tumours; the gap between mouse and patient is one of the field’s central criticisms. Say “passive accumulation is favoured”, not “tumours selectively capture nanoparticles”.
(2) PEG has a cost. Repeat dosing can induce anti-PEG antibodies, which trigger accelerated blood clearance (ABC) — the second dose is cleared faster than the first. This is why PEGylated carriers are not simply “stealth” forever.
(2) PEG has a cost. Repeat dosing can induce anti-PEG antibodies, which trigger accelerated blood clearance (ABC) — the second dose is cleared faster than the first. This is why PEGylated carriers are not simply “stealth” forever.
Exam focus
PEGylated liposomal doxorubicin is the standard answer for passive targeting, and it is the counter-example to the claim that nanomedicine is all promise: it is approved and it reduces cardiotoxicity and infusion reactions compared with free doxorubicin. Note that liposomal formulations of other cytotoxics are also in clinical use — liposomal doxorubicin, irinotecan and vincristine all appear in the L7 formulary.
D6 Exosomes — the natural carrier
An exosome is a small vesicle that a cell secretes. It is not synthetic, which is both its appeal and its problem.
| Property | Detail |
|---|---|
| Size | About 30–150 nm — the smallest class of extracellular vesicle |
| Origin | Formed inside the cell in multivesicular bodies, then released by fusion with the plasma membrane |
| Structure | Lipid bilayer with surface proteins inherited from the parent cell |
| Cargo | Protein, lipid and nucleic acid — the reason they are studied both as disease markers and as carriers |
| Markers | Tetraspanins CD9, CD63, CD81 |
| Distribution | Secreted by essentially all cell types, including plant cells |
How you load one
| Method | How it works | Used mainly for |
|---|---|---|
| Incubation / diffusion | Mix carrier with a high concentration of drug; it partitions in | Small hydrophobic drugs |
| Electroporation | An electric field transiently permeabilises the membrane | Nucleic acids |
| Sonication | Ultrasound loosens the membrane so cargo diffuses in | General lab loading |
| Extrusion / freeze–thaw | Mechanical or thermal cycling disrupts and reseals the membrane | Proteins |
| Transfection of the parent cell | Engineer the donor cell to express the protein of interest; the cell then packages it into its own exosomes | Proteins, RNA — the exosome-specific trick |
| Chemical / surface engineering | Conjugate ligands or drugs to the surface after isolation | Targeting, imaging |
Exam focus — there is no universal loading method
Which method you use depends on the cargo (small molecule vs nucleic acid vs protein) and on the carrier. Transfection is the one that is specific to exosomes, because it exploits the cell’s own packaging machinery rather than forcing cargo through a membrane.
Caution — plant exosomes in cosmetics
Plant-derived exosome-like nanovesicles are a real research field (for example cucumber-derived vesicles studied for skin depigmentation). But cosmetic “exosome” products are marketed far ahead of the evidence, and there is no accepted potency, purity or dosing standard. Treat the brightening claim as unproven, and note that exosome therapeutics are not approved medicines.
D7 Biomimetic carriers — the red blood cell
| RBC fact | Why it matters for delivery |
|---|---|
| Biconcave disc, ~7–8 µm | Flexible; squeezes through capillaries |
| No nucleus, no mitochondria, no ribosomes | Nothing to disrupt — a mature human RBC is essentially a haemoglobin-filled membrane bag |
| Packed with haemoglobin; carries oxygen | The haemoglobin can be removed, leaving an empty membrane shell |
| Lifespan about 120 days | The membrane is inherently long-circulating in the patient’s own blood |
| No MHC display; patient-matched transfusion is routine | Biocompatible and poorly immunogenic |
Correction
The transcript says RBCs circulate “about 100 days”. The accepted figure is about 120 days. Use 120.
Three ways to exploit it
- Load the inside — drug or enzyme goes into the internal volume, protected from the immune system and released slowly.
- Modify the surface — attach targeting ligands or antigens to the outside.
- Use the membrane as a coat — wrap a rigid nanoparticle in RBC membrane so it inherits the RBC’s long circulation and its “self” identity.
Proposed uses follow directly from those properties: enzyme replacement therapy, sustained release of a drug over days or weeks, and detoxification — carrying an enzyme that destroys a circulating toxin. All three are research-stage: RBC-membrane-camouflaged carriers are an active review topic, not an approved product class. Practical obstacles are donor supply, sterility, and keeping the membrane intact through processing.
Exam focus
The logic chain to remember is property → use: because the RBC has no nucleus and no organelles it can be emptied; because it lasts 120 days in circulation it gives long release; because it is the patient’s own cell type it avoids immune recognition. Every RBC-carrier application is one of those three properties being spent.
D8 Cell-penetrating peptides (CPP)
A cell-penetrating peptide is a short peptide that crosses the plasma membrane carrying cargo — the solution to the barrier that blocks proteins and nucleic acids from entering cells.
- Chemistry — usually strongly cationic, rich in arginine and lysine; the classic examples are the Tat peptide (from HIV-1 Tat) and penetratin.
- Mechanism — two routes, and the field still argues about the balance: direct translocation through the membrane, and endocytosis followed by endosomal escape. Some helical peptides assemble into a pore and disrupt the membrane outright.
- Use — conjugate the peptide to a drug, protein or oligonucleotide and the cargo rides in. The peptide itself has no targeting specificity, so a CPP delivers everywhere it reaches.
Correction — do not repeat the source’s clinical claim
The transcript claims there are “recently approved drugs for cystic fibrosis… by cell-penetrating peptides”. I could not verify any approved CPP–drug conjugate, and none for cystic fibrosis. CPPs are best described as largely preclinical, with the field’s recurring problems being endosomal trapping and a lack of selectivity. If an exam asks for an approved peptide therapeutic, reach for insulin, the GLP-1 agonists, or the HIV fusion inhibitor enfuvirtide — not a CPP.
Exam focus
CPPs solve entry, not targeting. That is the exact opposite of an antibody, which solves targeting but cannot carry a payload inside a cell on its own. An ADC is the field’s answer to “what if you need both”.
D9 Why so few carriers reach the clinic
| Hurdle | What goes wrong |
|---|---|
| Organ accumulation & toxicity | Inorganic and metal particles are taken up by the MPS and accumulate in liver and spleen; they do not clear like a small molecule |
| Immune activation | Particles can trigger complement and inflammation; reactogenicity is a real clinical problem, not a theoretical one |
| Batch-to-batch reproducibility | A particle is a mixture, not a single molecule: size, loading and surface vary between batches, and each batch must be characterised separately |
| Scale-up / GMP | Processes that work in a research lab often do not survive transfer to a licensed manufacturing facility at dose scale |
| Regulation | Regulators must approve a heterogeneous product whose “active ingredient” is not a single defined structure |
The lecturer’s argument, stated fairly
The transcript’s core claim is sound: because nanoparticle products are mixtures whose every batch differs slightly, regulators cannot simply accept them the way they accept a small molecule, and this — not a lack of clever ideas — is why very few reach market. That is why the approved successes are the ones with simple, characterisable chemistry: PEGylated liposomal doxorubicin, and the lipid nanoparticles of the mRNA vaccines.
Correction — the LNP “no toxicity” claim
The transcript says lipid nanoparticles “have no toxicity because lipid is just like cell membrane” and therefore escaped the problem. That is too strong. LNPs are not inert: they cause injection-site reactions and fever, can activate complement, and induce anti-PEG antibodies. The defensible version is narrower and more interesting: an LNP vaccine carries a transient nucleic acid rather than a cytotoxic small molecule, so the safety calculus is different from a drug-loaded particle — not that the carrier is harmless.
D10 Exam focus & self-check
The five traps on this page
- Micelle for DNA/RNA — wrong; nucleic acids are anionic and hydrophilic and need a cationic/ionisable lipid carrier.
- Therapeutic index direction — TI = toxic ÷ effective; higher is safer. Delivery raises TI by keeping drug away from normal tissue.
- “Photodynamic therapy is experimental” — wrong; PDT is approved for superficial skin lesions. Only carrier-rupture by ROS is experimental.
- EPR as a guarantee — overstated; it is variable in human tumours.
- RBC lifespan — about 120 days, not 100.
✅ Self-check — try before you look
1. A liposome and a micelle are both made of lipid. Which can carry a negatively charged oligonucleotide, and why?
2. An ADC carries a payload far more toxic than conventional chemotherapy. Why is it safer?
3. Name the two properties of a tumour that produce the EPR effect, and one reason to be cautious about it.
4. Which exosome loading method could not be applied to a synthetic liposome, and why?
5. Give the two structural reasons a mature red blood cell makes a good carrier shell.
Answers. 1. The liposome — it has an aqueous core and can be built with cationic or ionisable lipids that complex the anionic backbone; a micelle offers only a hydrophobic core. 2. Spatial restriction: the payload stays attached and inactive in circulation, so normal tissue sees little free drug. 3. Leaky tumour vasculature (permeability) and poor tumour lymphatic drainage (retention); caution because EPR is heterogeneous and much weaker in human tumours than in rodent models. 4. Transfection of the parent cell — it uses a living cell’s own packaging machinery, which a synthetic liposome does not have. 5. No nucleus or organelles, so it can be emptied into a membrane shell; and a ~120-day circulating lifespan with no MHC display, giving long circulation and low immunogenicity.
One-line Summary
A delivery system raises the therapeutic index by doing one or more of four jobs — target, protect, solubilise, control release — the strongest designs combine targeting with a release trigger (the ADC), the workhorse is the PEGylated liposome exploiting EPR, the natural alternatives are exosomes and RBC membranes, and the reason the clinic stays empty is not imagination but heterogeneity, immune activation and manufacturing reproducibility.