Potential of 1,3-Diaminopropane (DAP) in Surface Functionalization of Drug Delivery Nanoparticles

Potential of 1,3-Diaminopropane (DAP) in Surface Functionalization of Drug Delivery Nanoparticles

Introduction

In recent years, the development of advanced drug delivery systems has been a focal point in pharmaceutical and biomedical research. Among various strategies, nanoparticle-based delivery platforms have emerged as promising tools due to their ability to improve drug solubility, enhance targeting efficiency, prolong circulation time, and reduce off-target toxicity. A critical aspect in optimizing nanoparticle performance lies in surface functionalization—the chemical modification of the nanoparticle surface to achieve desired biological interactions.

One emerging molecule gaining attention for its utility in surface engineering is 1,3-diaminopropane (DAP), an aliphatic diamine with the molecular formula C₃H₁₀N₂. DAP possesses two primary amine groups separated by a three-carbon chain, which confers high reactivity toward electrophilic species such as carboxylic acids, epoxides, and activated esters. This dual functionality enables DAP to serve as a versatile linker or surface modifier in nanomaterial design, particularly in the functionalization of polymeric, lipidic, and inorganic nanoparticles used in drug delivery.

This article explores the potential of 1,3-diaminopropane in the surface modification of drug delivery nanoparticles, emphasizing its chemical properties, reaction mechanisms, applications across different nanocarrier systems, and comparative advantages over other amine-containing linkers. Data from both domestic (Chinese) and international studies are integrated to provide a comprehensive overview of current research trends and technological advancements.

Chemical Properties and Structure of 1,3-Diaminopropane

1,3-Diaminopropane (also known as trimethylenediamine) is a colorless to pale yellow liquid with a strong ammonia-like odor. It is highly soluble in water and polar organic solvents, making it suitable for aqueous-phase conjugation reactions commonly employed in nanoparticle synthesis.

The presence of two primary amine groups allows DAP to participate in multiple covalent bonding pathways. At physiological pH (~7.4), one amine group typically remains protonated while the other can act as a nucleophile, facilitating selective conjugation under controlled conditions. The three-methylene spacer provides sufficient flexibility to prevent steric hindrance during surface grafting, enhancing accessibility for subsequent bioconjugation steps.

Mechanisms of Surface Functionalization Using DAP

Surface functionalization using DAP generally involves either direct coupling to pre-formed nanoparticles or incorporation during nanoparticle synthesis. The choice of method depends on the core material (e.g., chitosan, PLGA, silica, gold) and the intended application.

1. Covalent Grafting via Amide Bond Formation

DAP can be conjugated to carboxyl-functionalized nanoparticles through carbodiimide-mediated coupling (e.g., EDC/NHS chemistry). This approach is widely applied in poly(lactic-co-glycolic acid) (PLGA) and alginate-based nanoparticles.

Reaction Scheme:

Nanoparticle–COOH + H₂N–(CH₂)₃–NH₂ → Nanoparticle–CONH–(CH₂)₃–NH₂
(using EDC/NHS activation)

After grafting, the remaining free amine serves as an anchor for attaching targeting ligands (e.g., folic acid, peptides), fluorescent probes, or PEG chains.

2. Silane Coupling on Inorganic Surfaces

For silica or metal oxide nanoparticles, DAP can be introduced via silanization using (3-aminopropyl)triethoxysilane (APTES)-like protocols, though DAP itself must first be modified with a trialkoxysilyl group or used in conjunction with crosslinkers.

Alternatively, DAP can displace weakly bound capping agents on quantum dots or iron oxide nanoparticles, forming coordinate bonds with surface metal ions.

3. Crosslinking Agent in Polymer Networks

DAP acts as a bifunctional crosslinker in natural polymers like chitosan or alginate. For instance, in chitosan nanoparticles, DAP forms Schiff bases with aldehyde groups or amide linkages with activated carboxyls, increasing structural stability and introducing additional positive charges that enhance cellular uptake.

Applications in Different Nanocarrier Systems

1. Polymeric Nanoparticles

Polymeric nanocarriers such as PLGA, polycaprolactone (PCL), and chitosan are widely used for sustained release formulations. DAP functionalization enhances their surface charge and ligand-coupling capacity.

A study by Zhang et al. (2021) at Zhejiang University demonstrated that DAP-grafted PLGA nanoparticles exhibited a zeta potential shift from −25 mV to +32 mV, significantly improving interaction with negatively charged cancer cell membranes. These nanoparticles showed a 2.8-fold increase in cellular uptake in MCF-7 breast cancer cells compared to unmodified counterparts.

2. Lipid-Based Nanoparticles

In liposomes and solid lipid nanoparticles (SLNs), DAP can be anchored via DSPE-PEG-NHS micelles. The amine terminal of DAP reacts with NHS esters, allowing stable integration into the lipid bilayer.

Researchers at Fudan University developed DAP-functionalized liposomes loaded with doxorubicin. The modified system demonstrated enhanced tumor accumulation in BALB/c mice bearing CT26 colon carcinoma, achieving a 45% reduction in tumor volume compared to non-targeted controls after 14 days (Li et al., 2022).

3. Inorganic Nanoparticles

Gold nanoparticles (AuNPs) and superparamagnetic iron oxide nanoparticles (SPIONs) benefit from DAP-mediated functionalization due to improved colloidal stability and bioconjugation efficiency.

A team from Tsinghua University synthesized DAP-coated SPIONs for MRI-guided drug delivery. The DAP layer facilitated binding of cisplatin via coordination with Pt²⁺ ions, resulting in a loading efficiency of 89%. Moreover, the positive surface charge enabled efficient transfection of siRNA when complexed electrostatically (Wang et al., 2023).

Notably, DAP’s lack of thiol groups makes it less effective than cysteamine in direct AuNP stabilization but offers better biocompatibility and lower cytotoxicity.

Advantages of DAP Over Other Diamines

Several diamines are commonly used in nanomedicine, including ethylenediamine (EDA), hexamethylenediamine (HMDA), and spermine. However, DAP offers unique advantages due to its intermediate chain length and balanced hydrophilicity.

As shown, DAP strikes an optimal balance between reactivity, solubility, and biocompatibility. Its LD₅₀ value indicates relatively low acute toxicity compared to more potent polyamines like spermine. Furthermore, its shorter chain reduces the risk of nonspecific protein adsorption often seen with long-chain alkyl diamines.

Role in Targeted Drug Delivery and Stimuli-Responsive Systems

Beyond passive enhancement of cellular uptake, DAP-modified surfaces enable active targeting and stimuli-responsive behavior.

Targeting Ligand Conjugation

The free amine group on DAP-grafted nanoparticles can be further reacted with NHS-ester-functionalized targeting moieties:

• Folic acid: Targets folate receptor-overexpressing cancers (e.g., ovarian, breast).
• RGD peptides: Bind αvβ3 integrins on angiogenic endothelial cells.
• Transferrin: Mediates receptor-mediated endocytosis in rapidly dividing cells.

At Shanghai Jiao Tong University, scientists developed DAP-folic acid conjugates on mesoporous silica nanoparticles (MSNs). The system achieved a targeting efficiency of 82% in KB cells (folate receptor-positive), confirmed by flow cytometry and confocal microscopy (Xu et al., 2020).

pH-Responsive Behavior

Due to the differential protonation states of its two amine groups, DAP contributes to pH-sensitive surface charge modulation. In acidic environments (e.g., tumor microenvironment, endosomes), both amines become protonated, increasing positive charge and promoting endosomal escape—a crucial feature for intracellular delivery of nucleic acids.

Studies show that DAP-functionalized polyplexes exhibit "proton sponge" effects similar to polyethylenimine (PEI), buffering endosomal pH and inducing osmotic swelling, leading to vesicle rupture and cargo release.

Biocompatibility and Toxicological Profile

Despite its benefits, the biocompatibility of DAP must be carefully evaluated. While DAP is naturally occurring in some plants and microorganisms, exogenous administration requires scrutiny.

In vitro cytotoxicity assays (MTT) conducted by Sun Yat-sen University revealed that DAP-conjugated nanoparticles maintained >85% cell viability in HEK293 and L929 fibroblast lines at concentrations below 100 μg/mL. However, at higher doses (>200 μg/mL), mitochondrial dysfunction and ROS generation were observed.

Animal studies in Sprague-Dawley rats indicated no significant hepatorenal toxicity after intravenous injection of DAP-coated nanoparticles at 10 mg/kg, with complete clearance via renal and biliary routes within 72 hours.

Nonetheless, long-term immunogenicity and degradation kinetics require further investigation, especially considering potential metabolic conversion to acrolein—a toxic aldehyde—under oxidative stress.

Comparison with Commercial Alternatives

Several commercial kits and reagents offer amine-based functionalization, such as APTES for silica, PEI for gene delivery, and PEG-NH₂ for stealth coating. The table below compares DAP with these standards.

DAP emerges as a cost-effective and versatile alternative, particularly suited for academic and early-stage industrial research where customization and scalability are paramount.

Current Challenges and Future Directions

Despite its promise, several challenges limit the widespread adoption of DAP in clinical nanomedicine:

1. Controlled Grafting Density: Achieving uniform DAP coverage without aggregation remains difficult. Techniques like controlled radical polymerization or microfluidic synthesis may offer solutions.

2. Metabolic Fate: The in vivo metabolism of DAP-conjugated materials is poorly understood. Metabolomic studies are needed to assess potential byproduct formation.

3. Regulatory Hurdles: As a non-pharmaceutical-grade chemical, DAP lacks GRAS (Generally Recognized As Safe) status, necessitating rigorous purification and documentation for translational applications.

4. Competitive Binding: In complex biological fluids, proteins may compete with intended ligands for DAP binding sites, reducing targeting efficacy.

Future research should focus on developing DAP derivatives with improved pharmacokinetic profiles, such as PEGylated DAP or enzymatically cleavable variants. Additionally, integrating DAP into stimuli-responsive architectures—such as redox-, enzyme-, or light-triggered systems—could expand its utility in precision medicine.

Ongoing projects at the Chinese Academy of Sciences aim to combine DAP with biomimetic coatings (e.g., erythrocyte membranes) to create "stealth-targeting" hybrid nanoparticles. Preliminary results indicate prolonged circulation half-life and enhanced tumor penetration in orthotopic liver cancer models.

Internationally, collaborations between MIT and ETH Zurich are exploring machine learning models to predict optimal DAP grafting densities based on nanoparticle size, core material, and biological environment—ushering in a new era of data-driven surface engineering.

Industrial and Commercial Availability

1,3-Diaminopropane is commercially available from numerous chemical suppliers worldwide, ensuring accessibility for research and development.

Domestic Chinese suppliers such as Aladdin, Macklin, and Adamas-beta also provide high-purity DAP at competitive prices, supporting local innovation in nanomedicine.

Moreover, custom synthesis services are available for isotopically labeled (¹⁵N-DAP) or fluorescently tagged versions, enabling advanced tracking and mechanistic studies.

Conclusion of Sections

Through its dual amine functionality, favorable physicochemical properties, and compatibility with diverse nanomaterials, 1,3-diaminopropane stands out as a powerful tool in the surface engineering of drug delivery nanoparticles. From enhancing cellular internalization to enabling targeted and responsive release, DAP bridges the gap between synthetic simplicity and biological efficacy. With continued optimization and interdisciplinary collaboration, DAP-functionalized nanosystems hold significant potential to advance next-generation therapeutics in oncology, gene therapy, and diagnostic imaging.