Poly(hydroxyethylaspartamide) derivatives as colloidal drug carrier systems

Area of Science:

• Polymer Chemistry
• Drug Delivery Systems
• Biomaterials Science

Background:

• Poly(hydroxyethylaspartamide) (PHEA) is a biodegradable polymer with potential for drug delivery.
• Developing effective polymeric colloidal drug carriers is crucial for improving the solubility and bioavailability of hydrophobic drugs.
• Existing drug delivery systems often face challenges with drug stability and in vivo pharmacokinetics.

Purpose of the Study:

• To investigate novel poly(hydroxyethylaspartamide) (PHEA) derivatives as polymeric colloidal drug carriers.
• To evaluate the drug solubilization capabilities of PHEA derivatives with varying pendant moieties, including polyethylene glycol (PEG) and hexadecylalkylamine.
• To assess the stability, in vitro pharmacological activity, and in vivo pharmacokinetics of drug-loaded PHEA-based carriers.

Main Methods:

• Synthesis and characterization of PHEA derivatives with grafted PEG (2000 or 5000 Da) and/or hexadecylalkylamine.
• Solubilization studies using hydrophobic drugs: paclitaxel, amphotericin B, and methotrexate.
• Physicochemical stability assessment of drug/carrier systems at different pH conditions.
• In vitro cytotoxicity evaluation using murine myeloid leukaemia NFS-60 cell line.
• In vivo pharmacokinetic studies in Balb/c mice following intravenous administration.

Main Results:

• PHEA derivatives co-grafted with PEG and hexadecylalkylamine significantly enhanced the solubilization of hydrophobic drugs.
• PEGylation alone did not confer significant drug carrier properties to PHEA.
• The paclitaxel/PHEA-PEG(5000)-hexadecylalkylamine system exhibited pH-dependent physicochemical instability but offered partial protection against drug degradation.
• Paclitaxel-loaded PHEA-PEG(5000)-hexadecylalkylamine demonstrated high in vitro pharmacological activity (IC50 = 22.3 ng/ml).
• In vivo studies showed that the carrier prolonged paclitaxel's distribution and elimination phases by 6 and 17 times, respectively, and increased systemic availability (AUC) approximately 30-fold.

Conclusions:

• Co-grafting PHEA with PEG and hexadecylalkylamine creates effective polymeric colloidal drug carriers with enhanced solubilization capacity.
• The developed carrier system demonstrates promising in vitro and in vivo therapeutic potential for hydrophobic drugs like paclitaxel.
• Further investigation into optimizing carrier stability and formulation is warranted for clinical translation.