Poly(anhydride) nanoparticles represent a significant advancement in controlled drug delivery due to their unique surface-eroding degradation mechanism. Unlike bulk-eroding polymers, which degrade uniformly throughout their structure, poly(anhydride) nanoparticles erode layer-by-layer from the surface inward. This property enables zero-order drug release kinetics, where the drug is released at a constant rate over time, making them particularly valuable for applications requiring precise and sustained therapeutic dosing, such as localized chemotherapy.

The synthesis of poly(anhydride) nanoparticles typically involves melt-condensation polymerization, a method that ensures high purity and controlled molecular weight. In this process, dicarboxylic acid monomers are heated under vacuum to remove water, forming anhydride linkages. The resulting polymer is then dissolved in an organic solvent and emulsified in an aqueous phase to form nanoparticles via solvent evaporation or nanoprecipitation. The size and polydispersity of the nanoparticles can be finely tuned by adjusting parameters such as polymer concentration, surfactant type, and emulsification energy. For instance, poly(sebacic anhydride) nanoparticles synthesized via this method often exhibit diameters ranging from 100 to 300 nm with narrow size distributions, making them suitable for intravenous administration or localized delivery.

The surface-eroding behavior of poly(anhydride) nanoparticles is governed by hydrolysis kinetics at the polymer-water interface. The anhydride bonds in the polymer backbone are highly susceptible to hydrolysis, but the hydrophobic nature of the polymer limits water penetration into the bulk. As a result, degradation occurs predominantly at the nanoparticle surface, leading to a gradual and predictable erosion process. Studies have demonstrated that the erosion rate follows zero-order kinetics, with the mass loss proportional to time rather than the remaining polymer mass. This contrasts sharply with bulk-eroding polymers like poly(lactic-co-glycolic acid) (PLGA), where water penetrates the entire matrix, causing random chain scission and a burst release of encapsulated drugs. The zero-order release profile of poly(anhydride) nanoparticles ensures minimal initial burst effects and sustained drug delivery over days to weeks, depending on the polymer composition and environmental conditions.

The hydrolysis rate of poly(anhydride) nanoparticles can be modulated by altering the monomer composition. For example, incorporating aromatic monomers such as 1,3-bis(p-carboxyphenoxy)propane (CPP) into the polymer backbone reduces the hydrolysis rate compared to aliphatic monomers like sebacic acid (SA). This tunability allows for the design of nanoparticles with degradation rates matched to specific therapeutic requirements. In vitro studies have shown that poly(SA-CPP) nanoparticles with a 20:80 molar ratio degrade over approximately three weeks, while those with an 80:20 ratio degrade within one week. Such precise control over degradation kinetics is critical for optimizing drug release profiles in clinical applications.

Localized chemotherapy is a major application of poly(anhydride) nanoparticles, particularly for treating solid tumors. Their surface-eroding property ensures that the drug is released in a controlled manner directly at the target site, minimizing systemic toxicity and enhancing therapeutic efficacy. For instance, poly(anhydride) nanoparticles loaded with chemotherapeutic agents like paclitaxel or doxorubicin have been investigated for intratumoral injection. Preclinical studies have demonstrated that these nanoparticles provide sustained drug levels within the tumor tissue while reducing off-target effects. In one study, poly(SA) nanoparticles delivering camptothecin achieved a 50% reduction in tumor volume over 14 days with no significant weight loss in treated animals, indicating low systemic toxicity.

Another advantage of poly(anhydride) nanoparticles is their compatibility with hydrophobic drugs, which can be encapsulated at high loading efficiencies due to the polymer’s hydrophobic nature. Drug loading is typically achieved by dissolving both the polymer and the drug in a common organic solvent before nanoparticle formation. Loadings of up to 20% w/w have been reported for drugs like temozolomide, with encapsulation efficiencies exceeding 90%. The high drug payload and sustained release profile make these nanoparticles particularly effective for treating malignancies with narrow therapeutic windows.

Beyond chemotherapy, poly(anhydride) nanoparticles have been explored for other biomedical applications, including localized antibiotic delivery and protein stabilization. Their surface-eroding mechanism ensures that sensitive biomolecules, such as proteins or peptides, are protected from rapid degradation and released in a controlled fashion. For example, poly(anhydride) nanoparticles encapsulating insulin have shown zero-order release over 10 days in simulated physiological conditions, suggesting potential for long-term diabetes management.

In contrast to bulk-eroding polymers, poly(anhydride) nanoparticles avoid the pitfalls of unpredictable drug release and premature polymer breakdown. Bulk-eroding systems often exhibit biphasic release profiles, with an initial burst followed by a slower phase, which can lead to suboptimal dosing and increased side effects. The linear release kinetics of poly(anhydride) nanoparticles provide a more reliable and reproducible delivery platform, particularly for drugs with dose-dependent toxicity.

The biodegradability of poly(anhydride) nanoparticles further enhances their clinical appeal. Degradation products are typically dicarboxylic acids, which are metabolized via normal physiological pathways, leaving no toxic residues. This contrasts with some synthetic polymers that generate acidic byproducts, potentially causing inflammation or tissue damage. The benign degradation profile of poly(anhydride) nanoparticles makes them suitable for repeated administration or long-term implants.

In summary, poly(anhydride) nanoparticles offer a robust platform for zero-order drug release through their unique surface-eroding degradation. Their synthesis via melt-condensation allows precise control over physicochemical properties, while hydrolysis kinetics can be tailored by monomer selection. Applications in localized chemotherapy highlight their ability to deliver drugs sustainably and with minimal systemic exposure. Compared to bulk-eroding polymers, poly(anhydride) nanoparticles provide superior control over release profiles, making them a promising candidate for advanced drug delivery systems.