Morphologies and functionalities of polymeric nanocarriers as chemical tools for drug delivery A review

Purpose: Polymeric nanocarriers such as dendrimers, micelles, nanoparticles, nanogels, nanocapsules, and vesicles are widely investigated for drug delivery, but their morphology, surface chemistry, and functionalization strongly influence drug loading, controlled release, and targeting. This review addresses the need for a systematic overview of how morphology and surface modifications of polymeric nanocarriers can improve controlled drug delivery and targeting.

Hypothesis: This is a review article and does not test a single formal hypothesis. Its central premise is that the surface chemistry and specific functionalization of polymeric nanocarriers — in addition to their morphology and size — are crucial for optimizing drug loading, enabling controlled and targeted release, and achieving precise cell-receptor targeting.

Aims: Provide a wide view of recent developments in drug delivery systems based on nanostructured polymers. - Describe the morphologies of dendrimers, micelles, polymeric nanoparticles, nanogels, nanocapsules, and vesicles. - Emphasize the role of surface chemistry and functionalization in drug loading, controlled release, and targeting. - Discuss critical physicochemical properties governing carrier–drug interactions and biological fate. - Summarize strategies for drug loading and release, including electrostatic interaction, covalent conjugation, and encapsulation. - Offer suggestions for systematizing data on the most relevant physicochemical parameters.

Delivery system: Carrier morphologies: Dendrimers (PAMAM, PPI, polyaryl ether), polymeric micelles, polymeric nanoparticles (spherical, branched, core–shell), nanogels, nanocapsules, vesicles (liposomes, niosomes), and polymeric multilayer capsules (PMLCs). - Polymers used: PEG, pMPC, pCBMA, PMMA, PLA, PLGA, PDMPA, heparin–Pluronic, alginate–PNIPAM–PDMA, PSS–PAH, chitosan, alginate, albumin, gelatin, polyacrylates, polycaprolactones, and cyclodextrin-based materials. - Payloads: Doxorubicin, curcumin, paclitaxel, dexamethasone, methotrexate, ibuprofen, ketoprofen, and other hydrophobic/hydrophilic drugs; also DNA for gene delivery. - Targeting ligands: Folate, glycyrrhizin, herceptin, transferrin, peptides, aptamers, antibodies, and small molecules. - Stimuli-responsive features: pH, temperature, light, redox potential, magnetic field, and ultrasound. - Functional groups: Amines, carboxyls, hydroxyls, sulfonates, and zwitterionic groups.

Approach: Review of recent literature (primarily 2000s–2010s) on polymeric nanocarriers for drug delivery. Covers in vitro and in vivo studies, including cancer models, brain targeting, topical administration, and oral bioavailability. No new primary experiments are reported.

Key methods: Size and morphology characterization (DLS, microscopy). - Zeta potential and surface charge measurements. - Drug loading and release profiles. - Cellular uptake and intracellular trafficking. - In vitro cytotoxicity and multidrug resistance reversal. - In vivo biodistribution, pharmacokinetics, and antitumor efficacy. - Protein corona formation and complement activation. - Stimuli-responsive release kinetics.

Key results: Dendrimers: Drug loading in interior core or on branched surface; size range 1–100 nm (mostly <10 nm); pH-responsive DOX release from FA-PEG-PAMAM-DOX@IONPs; GA-PPI dendrimers enhanced liver cell targeting and minimized cytotoxicity. - Micelles: Core–shell structures with hydrophobic core and hydrophilic corona; size <100 nm; pH-sensitive F-pHSM-L61/CUR/DOX micelles achieved synergistic MDR reversal; cross-linking improves stability but can slow release. - Polymeric nanoparticles: Size 10–1000 nm; sustained release over days to weeks; pH-responsive polysaccharide-based cisplatin cross-linked nanoparticles reduced A549 xenograft tumor size in vivo. - Nanocapsules and vesicles: Sizes 50–400 nm preferred; layer-by-layer assembly enables precise shell engineering; PMLCs can encapsulate various drugs and respond to stimuli with step-like release profiles. - Critical properties: Nanoparticles 1–20 nm have long circulation; 30–100 nm avoid capillary leakage and RES clearance; >100–150 nm accumulate in tumors via EPR; >200 nm activate complement and are cleared rapidly. - 2R2S requirements: Drug Retention in blood vs Release in tumor cells; Stealthy in blood vs Sticky in tumor. - Protein corona: Alters particle size, stability, and biological identity; can trigger hypersensitivity via complement activation.

Interpretation: Polymeric nanostructures hold great potential for efficiently targeting drugs to specific cell types, overcoming drug resistance, and facilitating movement across biological barriers. Smart polymeric nanodelivery systems combining passive and active targeting have shown remarkable ability to overcome anatomical and physiological barriers. The field is moving toward “smart drugs” that increase effectiveness and decrease toxicity, but precise characterization of molecular targets and ensuring selective action on targeted organs remain open challenges.

Limitations: This is a review, not a primary study; no new experimental data or meta-analysis. - Low drug concentrations at the active site and short drug residence time remain major problems. - Precise characterization of molecular targets and ensuring action only on targeted organs is still challenging. - Some degradable systems exhibit dose dumping, burst effect, and are non-retrievable after injection. - Scalability and clinical-grade purity of dendrimer-based systems remain difficult. - Protein corona formation can reduce targeting capability and trigger hypersensitivity. - No large-animal validation or detailed clinical trial data are presented.