Novel alginate-enclosed chitosan-calcium phosphate-loaded iron-saturated bovine lactoferrin nanocarriers for oral delivery in colon cancer therapy.
OBJECTIVE
To develop polymeric-ceramic nanocarriers (NCs) in order to achieve oral delivery of the anticancer neutraceutical iron-saturated bovine lactoferrin (Fe-bLf) protein.


METHODS
Fe-bLf or paclitaxel (Taxol®) were adsorbed onto calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate. The Fe-bLf or Taxol-loaded NCs indicated as AEC-CP-Fe-bLf or AEC-CP-Taxol NCs, respectively, were made by combination of ionic gelation and nanoprecipitation. Size distribution, morphology, internalization and release profiles of the NCs were studied along with evaluation of in vitro and in vivo anticancer activities and compared with paclitaxel.


RESULTS
AEC-CP-Fe-bLf NCs obtained spherical morphology and showed enhanced endocytosis, transcytosis and anticancer activity in Caco-2 cells in vitro. AEC-CP-Fe-bLf NCs were supplemented in an AIN 93G diet and fed to mice in both prevention and treatment human xenograft colon cancer models. AEC-CP-Fe-bLf NCs were found to be highly significantly effective when given orally, as a pretreatment, 1 week before Caco-2 cell injections. None of the mice from the AEC-CP-Fe-bLf NC-fed group developed tumors or showed any signs of toxicity, while the mice fed the control AIN 93G diet showed normal tumor growth. Fe-bLf or Taxol, when given orally in a diet as nanoformulations post-tumor development, showed a significant regression in the tumor size with complete inhibition of tumor growth later, while intratumoral injection of Taxol just delayed the growth of tumors. The pharmacokinetic and bioavailability studies indicated that nanoformulated Fe-bLf was predominantly present on tumor cells compared to non-nanoformulated Fe-bLf. Fe-bLf-loaded NCs were found to help in absorption of iron and thus may have utility in enhancing the iron uptake during iron deficiency without interfering with the absorption of calcium.


CONCLUSIONS
With the promising results of our study, the future potential of NC-loaded Fe-bLf in chemoprevention and in the treatment of human colon cancer, deserves further investigation for translational research and preclinical studies of other malignancies.
Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, Institute for Frontier Materials, Deakin University, Geelong Technology Precinct, Pigdons Road, Waurn Ponds, Geelong, Victoria 3216, Australia. jagat.kanwar@deakin.edu.au
Jagat R
JR
Kanwar
Ganesh
G
Mahidhara
Rupinder K
RK
Kanwar
D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D002130:Calcium Phosphates / Q000737:chemistry*; D002417:Cattle; D048271:Chitosan / Q000737:chemistry*; D003110:Colonic Neoplasms / Q000628:therapy*; D004705:Endocytosis; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry*; D007781:Lactoferrin / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000464:Alginates; D000970:Antineoplastic Agents; D002130:Calcium Phosphates; D006603:Hexuronic Acids; D020723:Glucuronic Acid; D048271:Chitosan; C020243:calcium phosphate; D007501:Iron; D007781:Lactoferrin; D017239:Paclitaxel