ABSTRACT
The use of hybrid materials, where a matrix sustains nanoparticles controlling the release of the chemotherapeutic drug, could be beneficial for the treatment of primary tumors prior or after surgery. This localized chemotherapy would guarantee high drug concentrations at the tumor site while precluding systemic drug exposure minimizing undesirable side effects. We combined bacterial cellulose hydrogel (BC) and nanostructured lipid carriers (NLCs) including doxorubicin (Dox) as a drug model. NLCs loaded with cationic Dox (NLCs-H) or neutral Dox (NLCs-N) were fully characterized and their cell internalization and cytotoxic efficacy were evaluated in vitro against MDA-MB-231 cells. Thereafter, a fixed combination of NLCs-H and NLCs-N loaded into BC (BC-NLCs-NH) was assayed in vivo into an orthotopic breast cancer mouse model. NLCs-H showed low encapsulation efficiency (48%) and fast release of the drug while NLCs-N showed higher encapsulation (97%) and sustained drug release. Both NLCs internalized via endocytic pathway, while allowing a sustained release of the Dox, which in turn rendered IC50 values below of those of free Dox. Taking advantage of the differential drug release, a mixture of NLCs-N and NLCs-H was encapsulated into BC matrix (BC-NLCs-NH) and assayed in vivo, showing a significant reduction of tumor growth, metastasis incidence and local drug toxicities.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Breast Neoplasms/drug therapy , Cellulose/chemistry , Doxorubicin/pharmacology , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Lipids/chemistry , Nanoparticles/chemistry , Acetobacteraceae/chemistry , Animals , Antibiotics, Antineoplastic/administration & dosage , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Drug Delivery Systems , Drug Screening Assays, Antitumor , Female , Humans , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Particle Size , Surface Properties , Tumor Cells, CulturedABSTRACT
HYPOTHESIS: Biopolymer-CaCO3 hybrid microparticles exposed to hydrolytic enzymes can provide new surface tailorable architectures. Soluble Alginate Lyase hydrolyzed alginate chains exposed on microparticle surface are generating considerable matrix changes. The change of porosity and surface to volume ratio is expected to influence absorption of drugs, thereby affecting controlled release profiles. The developed hybrid system potentially shows interesting properties for lung drug administration. EXPERIMENTAL: Hybrid microparticles were developed by colloidal co-precipitation of CaCO3 in presence of biopolymers: alginate (Alg) or Alg-High Methoxylated Pectin (HMP), followed by treatment with Alginate Lyase (AL). Surface architectures were observed by SEM. The increase in area to volume ratio was confirmed by BET isotherms. Also, enzymatic changes were elucidated by biophysical methods (EDAX, DSC, FTIR, XRD) and determination of the total carbohydrates content. Levofloxacin (a fluoroquinolone antibiotic) as model drug was incorporated by absorption. The drug release profile and the antimicrobial activity of the microparticles were tested against Pseudomonas aeruginosa. FINDINGS: After enzyme treatment, microspheres showed 4µm diameter and increased porosity. While CaCO3-Alg microspheres resulted in a rougher surface, CaCO3-Alg-HMP ones exhibited "nano-balloon" patterns on surface. Both AL-treated microparticles showed up to 3 and 7 times higher Levofloxacin encapsulation than no treated ones. Microparticles showed controlled drug release profiles and enhanced antimicrobial effect. The present work demonstrates a significant progress in the development of new carriers with potential application for lung infections treatment.
