Poly(amidoamine), or PAMAM, is a class of dendrimer which is made of repetitively branched subunits of amide and amine functionality. PAMAM dendrimers, sometimes referred to by the trade name Starburst, have been extensively studied since their synthesis in 1985, and represent the most well-characterized dendrimer family as well as the first to be commercialized. Like other dendrimers, PAMAMs have a sphere-like shape overall, and are typified by an internal molecular architecture consisting of tree-like branching, with each outward 'layer', or generation, containing exponentially more branching points. This branched architecture distinguishes PAMAMs and other dendrimers from traditional polymers, as it allows for low polydispersity and a high level of structural control during synthesis, and gives rise to a large number of surface sites relative to the total molecular volume. Moreover, PAMAM dendrimers exhibit greater biocompatibility than other dendrimer families, perhaps due to the combination of surface amines and interior amide bonds; these bonding motifs are highly reminiscent of innate biological chemistry and endow PAMAM dendrimers with properties similar to that of globular proteins. The relative ease/low cost of synthesis of PAMAM dendrimers (especially relative to similarly-sized biological molecules such as proteins and antibodies), along with their biocompatibility, structural control, and functionalizability, have made PAMAMs viable candidates for application in drug development, biochemistry, and nanotechnology.

Divergent synthesis refers to the sequential "growth" of a dendrimer layer by layer, starting with a core "initiator" molecule which contains functional groups capable of acting as active sites in the initial reaction. Each subsequent reaction in the series increases the number of available surface groups exponentially. Core molecules which give rise to PAMAM dendrimers can vary, but the most basic initiators are ammonia and ethylene diamine. Outward growth of PAMAM dendrimers is accomplished by alternating between two reactions:

Each round of reactions forms a new "generation", and PAMAM dendrimers are often classified by generation number; the common shorthand for this classification is "GX" or "GX PAMAM", where X is a number referring to the generation number. The first full cycle of Michael addition followed by coupling with ethylene diamine forms Generation 0 PAMAM, with subsequent Michael additions giving rise to "half" generations, and subsequent amide coupling giving rise to "full" (integer) generations.

With divergent synthesis of dendrimers, it is extremely important to allow each reaction to proceed to completion; any defects caused by incomplete reaction or intramolecular coupling of new surface amines with unreacted methyl ester surface groups could cause "trailing" generations, stunting further growth for certain branches. These impurities are difficult to remove when using the divergent synthetic approach because the molecular weight, physical size, and chemical properties of the defective dendrimers are very similar in nature to the desired product. As generation number increases, it becomes more difficult to produce pure products in a timely fashion due to steric constraints. As a result, synthesis of higher-generation PAMAM dendrimers can take months.

Convergent synthesis of a dendrimer begins with what will eventually become the surface of the dendrimer and proceeds inward. The convergent synthetic approach makes use of orthogonal protecting groups (two protecting groups whose deprotection conditions will not remove one another); this is an additional consideration not present when using a divergent approach. The figure below depicts a general scheme for a convergent synthetic approach.

Convergent synthesis as shown above begins with the dendritic subunit composed of reactive "focal group" A and branched group B (B can be multiply branched in the most generalized scenario, but PAMAMs only split once at each branching point). First, A is orthogonally protected and set aside for further reactions. B is also orthogonally protected, leaving the unprotected A on this molecule to couple with each of the unprotected B groups from the initial compound. This results in a new higher-generation species that is protected on both A and B. Selective deprotection of A yields a new molecule which can again be coupled onto the original monomer, thus forming another new generation. This process can then be repeated to form more and more layers.

It has been established that cationic macromolecules in general destabilize the cell membrane, which can lead to lysis and cell death. The common conclusion present in current work echoes this observation: increasing dendrimer molecular weight and surface charge (both being generation-dependent) increases their cytotoxic behavior.

Initial studies on PAMAM toxicity showed that PAMAM was less toxic (in some cases, much less so) than related dendrimers, exhibiting minimal cytotoxicity across multiple toxicity screens, including tests of metabolic activity (MTT assay), cell breakdown (LDH assay), and nucleus morphology (DAPI staining). However, in other cell lines, the MTT assay and several other assays revealed some cytotoxicity. These disparate observations could be due to differences in sensitivity of the various cell lines used in each study to PAMAM; although cytotoxicity for PAMAM varies among cell lines, they remain less toxic than other dendrimer families overall.