Molecularly Targeted Therapeutics - Lecture 4

Two approaches to achieve slow release of medications in the body.

A water-soluble polymer, often dense and entangled, used to control dissolution rates. This is "Option 1".

"Option 2", in which a polymer is designed to break down chemically (degrade) over time, releasing the medication.

High molecular weight polymers often dissolve too quickly, making slow release unreliable; renal excretion is problematic for large-sized polymers, as some can't be removed efficiently from the body.

Breaking of polymer chains (chemical-breakdown method) which releases smaller, soluble molecules. This is core to 'Option 2'.

A chemical group often used to target controlled polymer breakdown (hydrolysis).

These polymers need water insolubility, but water-soluble degradation products.

Crucial size limit of a polymer for efficient kidney removal.

Polylactic acid (PLA) exists in two forms: semi-crystalline (PLLA) and amorphous (PDLLA). PLLA forms a more organized crystal structure, leading to a higher density and less water penetration.

The rate at which PLA breaks down depends on its crystalline structure. PLLA degrades slower than PDLLA because its tightly packed structure hinders water penetration.

PLA undergoes bulk erosion, meaning both water penetration and chain scission occur simultaneously across the polymer.

PLGA is a copolymer made of both lactic acid (LA) and glycolic acid (GA) monomers. By varying the ratio of LA to GA, the degradation rate can be controlled.

Glycolic acid (GA) is more susceptible to hydrolysis than lactic acid (LA) due to its lack of a hydrophobic methyl group. Increasing GA content in PLGA speeds up degradation.

PLGA degradation follows a predictable pattern depending on its composition (ratio of LA to GA). As GA content increases, degradation time decreases.

Zoladex, a drug delivered via a depot system, uses a PLGA copolymer with a 50:50 ratio of LA and GA. This composition provides a controlled release for about 1 month.

To fine-tune the drug release profile, Zoladex uses a mixture of high and low molecular weight PLGA polymers. This strategy allows for a more precise control over the degradation rate.

A 3-month depot system that releases goserelin, a drug used in the treatment of certain cancers, using a controlled release mechanism. It's a cylindrical rod made of PLGA polymer.

A polymer blend of poly(lactic-co-glycolic acid), commonly used in controlled drug release systems due to its biodegradability and tunable rate of degradation.

A process where the breakdown products of a material accelerate its further degradation, leading to a faster release of the drug.

The process where water molecules enter and break down the polymer rod, increasing surface area and allowing drug diffusion before complete degradation.

Medicines designed to specifically target and inhibit a specific molecule or pathway involved in a disease, such as cancer.

Drugs that block the action of estrogen by preventing it from binding to its receptor, potentially inhibiting cancer cell growth.

Drugs that inhibit the enzyme aromatase, preventing the conversion of androgens into estrogens, thus lowering estrogen levels.

Drugs that activate the immune system to fight cancer cells by blocking checkpoints that normally prevent the immune system from attacking healthy cells.

Tamoxifen's anti-cancer effect relies on its metabolites, mainly 4-hydroxytamoxifen and endoxifen, which bind to estrogen receptors without activating them.

Tamoxifen exhibits different effects in different tissues. It's strongly anti-estrogenic in breast tissue but pro-estrogenic in uterine tissue.

Genotyping patients for CYP2D6 variants is crucial for optimizing tamoxifen therapy because it influences how quickly tamoxifen is converted into its active metabolites.

Variations in the CYP2D6 gene affect the metabolism of tamoxifen, potentially leading to delayed conversion of tamoxifen into its active forms.

Tamoxifen undergoes metabolic transformation by enzymes like CYP3A4, CYP2C9, and CYP2D6 to produce its active metabolites.

4-hydroxytamoxifen and endoxifen, the active metabolites of tamoxifen, are much stronger inhibitors of estrogen receptors than tamoxifen itself.

CYP3A4, CYP2C9, and CYP2D6 are major enzymes responsible for converting tamoxifen into its active metabolites.

Tamoxifen's effects vary depending on the tissue type due to differences in estrogen receptor expression and other factors.

Fulvestrant, a drug used to block estrogen receptors, rapidly degrades when combined with ERα, reducing the levels of ERα in cells and negating estrogen signaling.

Fulvestrant cannot be taken orally due to its poor water solubility and high protein binding. It's administered via injection, initially every two weeks, then monthly.

Fulvestrant remains in the body for a long time, with a terminal half-life of 40-50 days, allowing for infrequent injections.

Goserelin, a drug used to treat prostate cancer, initially increases testosterone or estrogen release. Long-term use blocks their release, causing chemical castration.

Desensitizing the body to hormones like testosterone or estrogen by using drugs like goserelin, effectively blocking their production.

Due to its short half-life of 2 hours, goserelin requires frequent injections. Finding a way to deliver it over a longer period is a challenge.

A single dose of goserelin that releases the drug over a longer period, typically 3 months, using a slowly dissolving polymer.

Polymers are used to control the release of drugs. They dissolve slowly, releasing the drug over time, instead of all at once.

Tamoxifen, an anti-estrogen drug, works by blocking estrogen receptors in breast tumors. However, its effectiveness can be reduced by drugs like paroxetine and fluoxetine, which compete for the same CYP2D6 enzyme.

Tamoxifen is a selective estrogen receptor modulator (SERM). It binds to estrogen receptors, but acts as an antagonist in breast tissue, blocking estrogen's effects. However, its effectiveness can vary depending on the individual.

Fulvestrant is another anti-estrogen drug, but it works differently from tamoxifen. Fulvestrant is a pure estrogen receptor antagonist, meaning it blocks estrogen's effects more potently.

Fulvestrant binds to estrogen receptors differently from tamoxifen. It prevents the receptor from binding to DNA and activating gene expression, effectively stopping estrogen's effects.

About 75% of breast tumors are positive for estrogen receptors (ERα-positive). However, only about two-thirds of these patients respond well to tamoxifen, highlighting the complex nature of breast cancer and its treatment.

Patients respond differently to anti-estrogen therapies like tamoxifen. Factors such as tumor characteristics and individual genetics can significantly influence treatment effectiveness.

Drugs like tamoxifen and fulvestrant target the estrogen receptors, disrupting the hormone's signaling pathway and hindering cancer cell growth. This is a key strategy in treating hormone-dependent cancers.

An increase in the number of copies of a specific gene, leading to higher expression of the gene's product.

The removal of a portion of DNA, resulting in the loss of the corresponding gene and its function.

Changes in the process of removing non-coding regions (introns) from a gene, altering the final protein product.

Changes in the structure of chromosomes, such as translocations or inversions, which can affect gene expression.

Changes in a single DNA base pair, potentially altering the amino acid sequence of a protein.

Mutations can alter the function of genes, leading to changes in the production of proteins. These altered proteins can disrupt normal cellular processes, contributing to disease development.

Genes like RB1, EGFR, INK4, ARF, MDM2, BCR-ABL, BCL2, and P53 are commonly targeted by mutations, contributing to various diseases, particularly cancer.

Understanding the different types of mutations and their impact on gene function is crucial for developing targeted therapies for diseases caused by these mutations. This knowledge allows for personalized medicine to address the unique genetic profile of each patient.