pH-sensitive polymeric nanoparticles represent a promising approach for targeted drug delivery in cancer therapy by exploiting the acidic microenvironment of tumors. These nanoparticles are designed to remain stable at physiological pH but undergo structural changes or degradation in the acidic tumor extracellular environment or within endosomal compartments, enabling controlled drug release. The tumor microenvironment typically exhibits a pH of 6.5–6.9 due to the Warburg effect, where cancer cells rely on glycolysis even under aerobic conditions, leading to lactic acid accumulation. Endosomes and lysosomes further acidify to pH 4.5–6.0, providing additional triggers for pH-responsive drug release.

A key class of polymers used in these systems is poly(β-amino ester) (PBAE), which undergoes protonation of its tertiary amine groups in acidic conditions, leading to swelling or dissolution of the nanoparticle matrix. PBAEs are synthesized via Michael addition between diacrylates and amines, allowing tunable degradation rates based on monomer selection. For example, PBAEs with more hydrophobic backbones exhibit slower hydrolysis, while those with hydrophilic segments degrade more rapidly. The pKa of PBAEs can be adjusted between 5.5 and 7.0 to match the pH gradient of tumors, ensuring minimal drug leakage in circulation but rapid release in acidic niches.

Acid-labile linkers are another critical component, enabling covalent conjugation of drugs to polymeric carriers with pH-triggered cleavage. Common linkers include hydrazone, acetal, and β-thiopropionate bonds, which hydrolyze under acidic conditions. Hydrazone bonds, for instance, are stable at pH 7.4 but cleave rapidly below pH 6.5, making them suitable for tumor-specific release. The hydrolysis kinetics of these linkers follow first-order reactions, with half-lives varying from hours to days depending on pH. For example, a hydrazone linker may have a half-life of 50 hours at pH 7.4 but only 2 hours at pH 5.0.

Release kinetics are influenced by nanoparticle composition, drug hydrophobicity, and local pH. Studies show that doxorubicin-loaded PBAE nanoparticles exhibit less than 10% drug release at pH 7.4 over 24 hours but over 80% release at pH 6.5. The release profile often follows a biphasic pattern: an initial burst due to surface-associated drug and a sustained phase from matrix diffusion or degradation. Mathematical models like the Korsmeyer-Peppas equation describe this behavior, where the release exponent indicates diffusion or erosion mechanisms.

Despite their potential, pH-sensitive nanoparticles face challenges in tumor penetration and endosomal escape. Solid tumors exhibit high interstitial fluid pressure and dense extracellular matrix, limiting nanoparticle diffusion beyond perivascular regions. Penetration depths rarely exceed 50–100 µm from blood vessels, leaving distal tumor regions untreated. Strategies to improve penetration include smaller nanoparticles (sub-50 nm), matrix-degrading enzymes like hyaluronidase, or surface modifications with tumor-penetrating peptides.

Endosomal trapping is another barrier, as nanoparticles internalized via endocytosis risk degradation in lysosomes before drug release. To overcome this, polymers with proton sponge effects, such as polyethylenimine (PEI) or histidine-rich sequences, are incorporated. These polymers buffer endosomal pH, leading to osmotic swelling and endosomal rupture. For example, nanoparticles with 20% PEI show a 60% increase in endosomal escape efficiency compared to unmodified systems.

Combination strategies further enhance therapeutic efficacy. Co-delivery of pH-sensitive nanoparticles with proton pump inhibitors like omeprazole exacerbates tumor acidosis, accelerating drug release. Alternatively, dual-responsive systems incorporating redox or enzyme-sensitive elements provide additional triggers for precise release. For instance, a nanoparticle with both hydrazone linkers and glutathione-responsive disulfide bonds can exploit the acidic and reductive tumor microenvironment synergistically.

In summary, pH-sensitive polymeric nanoparticles leverage tumor acidosis for selective drug release, with PBAEs and acid-labile linkers offering tunable release kinetics. Challenges in tumor penetration and endosomal escape are being addressed through size optimization, surface engineering, and endosomolytic agents. Future directions include multi-stimuli responsiveness and combination therapies to maximize tumor-specific drug delivery while minimizing off-target effects. These advancements hold significant potential for improving the therapeutic index of anticancer drugs.