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Calcium Phosphate Nanocomposite Particles: A Safer and More Effective Alternative to Conventional Chemotherapy?

2009; Future Medicine; Volume: 5; Issue: 3 Linguagem: Inglês

10.2217/fon.09.4

1744-8301

Erhan İ. Altınoğlu, James H. Adair,

Bone Tissue Engineering Materials

Future OncologyVol. 5, No. 3 EditorialFree AccessCalcium phosphate nanocomposite particles: a safer and more effective alternative to conventional chemotherapy?Erhan İ Altınoğlu & James H AdairErhan İ Altınoğlu221 Materials Research Laboratory, Department of Materials Science and Engineering, Pennsylvania State University, University Park, PA 16802, USA. & James H Adair† Author for correspondence249A Materials Research Laboratory, Department of Materials Science and Engineering, Pennsylvania State University, University Park, PA 16802, USA. Published Online:17 Apr 2009https://doi.org/10.2217/fon.09.4AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail The systemic nature of conventional chemotherapeutic dosing, and its indiscriminate circulation into both diseased and healthy cells, besets an abundance of side effects and treatment-associated conditions on current strategies for cancer therapy. Unfortunately, measures to counter balance the limited pharmacological efficiency and mitigate the pervasive physiological harm associated with systemic delivery are, at present, addressed by disproportionately high dosing and secondary management of associated side effects. However, these counter-measures are often insufficient and inadequate. We are at a crucial junction where alternate strategies can and must be used to eliminate, rather than simply cope with, these significant drawbacks. The key to evading a majority of the deleterious consequences of conventional chemotherapy is in circumventing the systemic dosing all together. Employing a methodology that does so would transform the present side-effect-laced protocols into safer and more efficient therapeutic strategies.Calcium phosphate nanoparticle (CPNP) [1] carrier systems open the door to an alternate dosing methodology that precludes the adverse side effects coupled with conventional administration. This developing approach grants targeted accumulation of therapeutics into sites of interest before releasing a localized, lower-dosed therapy. The active agent is encapsulated within the calcium phosphate matrix of the particle, preserving its pharmacological activity by preventing the abrupt degradation that is inherent in traditional deliveries, which in turn allows for lower dose administrations. Moreover, encapsulation not only shelters the internalized agents from biological degradations but, perhaps more appreciably, also the host from the toxic function of the cargo during early systemic circulation, allowing the CPNPs to localize at the targeted site before precisely delivering their load, thereby averting damaging incidences of systemic toxicity. The CPNPs afford such unique site-specificity through the facile modification of their outer surface with passivating coatings and unique recognition sequences for particular markers or cell types.This primary advantage of encapsulating the therapeutic agents within CPNP carriers, shielding the drug in an essentially dormant state until release, is a function of the physiological stability of the bioceramic matrix. All calcium phosphates, regardless of the Ca:P ratio or phase, are relatively insoluble at physiological pH, only to become increasingly soluble below pH 6.5 [2,3]. This long-term stability of the CPNP carriers has recently been illustrated for in vivo circulation of CPNPs passivated with polyethylene glycol (PEG) in a mouse model [1]. The PEGylation inhibits protein absorption, providing maximum retention in the circulatory system and allowing for long-term evaluation of systemic effects. These PEGylated CPNPs were found to remain in circulation for over 4 days with minimal dissolution and no adverse physiological effects to the mice [1]. Additionally, any initial concerns of retention toxicity from the delayed clearance of these CP carriers was addressed through a multicellular tumor spheroids (MTS) assay in which CPNPs in human smooth-muscle cells did not induce cytotoxicity, even at particle numbers approaching 1012 particles/ml [4]. Furthermore, eventual clearance was tracked through the biliary tree with negligible renal involvement [1]. The hepatobiliary clearance mechanism is favorable due to an implied lack of long-term accumulation within the liver and minor renal presence, signifying a minimal potential for hepatic or renal toxicology. These findings point to a key advantage of CPNP-encapsulated delivery, in that chemotherapeutic agents can be effectively delivered to tumor sites over long periods of circulation, while the delivery vehicle itself elicits no adverse responses.Once stable in circulation, the CPNP carriers are designed to target and localize at the site of disease. Numerous options are available to functionalize the calcium phosphate surface for targeting, and present work is investigating multiple peptides and antibodies as disease-specific markers for this high-precision targeting. The step beyond targeting the diseased site is the internalization and intercellular release of the therapeutic encapsulate. As mentioned, calcium phosphates have increasing solubility in acidic environments, such as those that can occur in endolysosomes [5] or around solid tumors [6]. This pH-dependent solubility is exploited as the functional mechanism for the safe and precise delivery of lower-dose antineoplastic agents to selected cells. Recent work has verified the dissolution of the CPNPs in the environment of endolysosomes during the late-stage endocytosis following intake into the cell of interest [4]. Fluorescent patterns of bovine aortic endothelial cells incubated with either a free solution of Cy3 fluorophore or Cy3-encapsulating CPNPs (Cy3-CPNP) were found to be indistinguishable, both highlighting internal membranous organelles, and indicating that the CPNPs had dissolved and released their fluorescent encapsulate. However, to verify that the process of dissolution was prompted by endocytosis, a similar fluorescent analysis was conducted in cells treated with cytochalasin-D (Cyto-D) and incubated with the Cy3-CPNPs. Cyto-D is known to disrupt the fusion of the endosomes with lysosomes in the late-stage endocytosis [7]. These Cyto-D-treated cells showed nonspecific staining of the entire cytoplasm, along with some bright points that could be attributed to groups of CPNPs [4]. No specific staining of internal membraneous organelles was seen, in contrast to the untreated cells, suggesting that the CPNPs were intact. Therefore, it was concluded that CPNPs dissolve, and thus release their encapsulate, only when the endosomes carrying them fuse with lysosomes, where they are exposed to low pH environments [4]. In this manner, the CPNP carriers provide a unique means of not only averting universal, uninhibited poisoning during systemic administration, but offer a manner to discretely deliver therapeutic agents precisely and locally to only targeted diseased cells, leaving neighboring healthy cells unharmed.Delivering lower dosages of drugs directly to target cells not only prevents damage to healthy cells and is safer for the host, but is pharmacologically more efficient than general administration. Recent work with CPNP delivery of ceramide highlights this improved efficiency. Ceramide (Cer) is an experimental amphiphilic neoplastic drug that has been shown to play an important role in the apoptosis of cancer cells [8]. In a proof-of-concept in vitro study, decanoylceramide (Cer10)-doped CPNPs were found to be more effective for inducing apoptosis in breast cancer cell lines than the unencapsulated Cer10 counterpart. Specifically, a fivefold lower dose of Cer10 in CPNPs prompted a sevenfold increase in caspase 3/7 activity (an apoptosis marker) than when Cer10 was administered in unencapsulated dimethylsulfoxide formulations [9]. Additionally, in an alternate cell viability study, Cer6-CPNPs were shown to induce up to 80% cell growth inhibition of human vascular smooth-muscle cells at an approximately 25-fold lower effective dose than if Cer6 were administered without encapsulated delivery [4]. These are just two of the many examples that serve to highlight the improved efficacy induced upon encapsulation. By nature of the CPNP architecture, shielding from environmental degradations, prevention of chemical interactions, and a concentrated local release, are all functions of the particulate carrier that combine to improve the efficiency of the expected function regardless of the agent encapsulated.While conventional chemotherapeutic dosing strategies are plagued with both undesirable and detrimental side effect, there is a new alternative that is simultaneously safer and more efficient in function. CPNPs as carrier systems for therapeutic agents impart a number of attractive characteristics that render them an excellent option in dosing methodologies. The underlying basis for the presented improvement is the avoidance of a general, systemic dosing of the toxic agents, which equally and indiscriminately impact both healthy and diseased cells. Furthermore, untargeted dosing necessitates disproportionately higher concentrations to ensure sufficient functionality at the required sites. However, CPNP encapsulation not only veils the host from the premature and deleterious effects of the internalized therapeutic, but the facility by which the CP surface can be functionalized provides an effective means to specifically target localization and eventual release to the desired site. Moreover, various trials have demonstrated that, by virtue of the localized intercellular delivery only to cells of interest, significantly lower doses of the agents can be utilized, sparing the host from excessive concentrations and minimizing both treatment costs and systemic exposures. These favorable characteristics underscore the notion that these CPNP carriers offer a truly safer and more effective alternative to conventional chemotherapy.Financial & competing interests disclosureThis work was made possible through the generous support of the Materials Research Institute and the Milton S Hershey Medical Center of the Pennsylvania State University. Partial support was also provided by Keystone Nano, Inc. and in part by grants to Peter J Butler from the National Heart Lung and Blood Institute (R01 HL 07754201-A1) and the National Science Foundation (CAREER Award BES 0238910). Dr Adair also serves as CSO for Keystone Nano in Boalsburg, PA, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Altınoğlu Eİ, Russin JT, Kaiser JM et al.: Near-infrared emitting fluorophore-doped calcium phosphate nanoparticles for in vivo imaging of human breast cancer. ACS Nano2(10),2075–2084 (2008).Crossref, Medline, CAS, Google Scholar2 Lai C, Tang S, Wang Y, Kun W: Formation of calcium phosphate nanoparticles in reverse microemulsions. Mater. Lett.59,210–214 (2005).Crossref, CAS, Google Scholar3 Maitra A: Calcium phosphate nanoparticles: second-generation nonviral vectors in gene therapy. Expert. Rev. Mol. Diagn.5,893–905 (2005).Crossref, Medline, CAS, Google Scholar4 Morgan TT, Muddana HS, Altınoğlu Eİ et al.: Encapsulation of organic molecules in calcium phosphate nanocomposite particles for intracellular imaging and drug delivery. Nano Lett.8,4108–4115 (2008).Crossref, Medline, CAS, Google Scholar5 Panyam J, Labhasetwar V: Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Delivery Rev.55,329–347 (2003).Crossref, Medline, CAS, Google Scholar6 Andreev OA, Dupuy AD, Segala M et al.: Mechanism and uses of a membrane peptide that targets tumors and other acidic tissues in vivo. Proc. Natl Acad. Sci. USA104,7893–7898 (2007).Crossref, Medline, CAS, Google Scholar7 Qualmann B, Kessels MM, Kelly RB: Molecular links between endocytosis and the actin cytoskeleton. J. Cell Biol.150(5),F111–F116 (2000).Crossref, Medline, CAS, Google Scholar8 Stover TC, Sharma A, Robertson GP, Kester M: Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin. Can. Res.11,3465–3474 (2005).Crossref, Medline, CAS, Google Scholar9 Kester M, Heakal Y, Fox T et al.: Calcium phosphate nanocomposite particles for in vitro imaging and encapsulated chemotherapetutic drug delivery to cancer cells. Nano Lett.8,4116–4121 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByPD-L1-Targeted Co-Delivery of Two Chemotherapeutics for Efficient Suppression of Skin Cancer Growth18 July 2022 | Pharmaceutics, Vol. 14, No. 7A Comprehensive Review on Intracellular Delivery16 February 2021 | Advanced Materials, Vol. 33, No. 13Nanodimensional and Nanocrystalline Calcium Orthophosphates24 October 2017Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancerNanomedicine: Nanotechnology, Biology and Medicine, Vol. 13, No. 7Biomimetic deposition of carbonate apatite and role of carbonate substitution on mechanical properties at nanoscaleMaterials Letters, Vol. 185Role of magnesium on the biomimetic deposition of calcium phosphate26 October 2016 | Journal of Physics: Conference Series, Vol. 765Biomimetic growth and substrate dependent mechanical properties of bone like apatite nucleated on Ti and magnetron sputtered TiO 2 nanostructure10 March 2016 | Journal of Physics D: Applied Physics, Vol. 49, No. 14Synthesis of Calcium Phosphate Nanoparticle‐Based Docetaxel Delivery System and its In Vitro Anticancer Activity13 August 2013 | International Journal of Applied Ceramic Technology, Vol. 12, No. 2PhotoImmunoNanoTherapy Reveals an Anticancer Role for Sphingosine Kinase 2 and Dihydrosphingosine-1-Phosphate14 February 2013 | ACS Nano, Vol. 7, No. 3Biological and Medical Significance of Nanodimensional and Nanocrystalline Calcium Orthophosphates16 October 2012Calcium Phosphate and Calcium Phosphosilicate Mediated Drug Delivery and Imaging27 April 2011Nanodimensional and Nanocrystalline Apatites and Other Calcium Orthophosphates in Biomedical Engineering, Biology and Medicine27 November 2009 | Materials, Vol. 2, No. 4 Vol. 5, No. 3 STAY CONNECTED Metrics History Published online 17 April 2009 Published in print April 2009 Information© Future Medicine LtdFinancial & competing interests disclosureThis work was made possible through the generous support of the Materials Research Institute and the Milton S Hershey Medical Center of the Pennsylvania State University. Partial support was also provided by Keystone Nano, Inc. and in part by grants to Peter J Butler from the National Heart Lung and Blood Institute (R01 HL 07754201-A1) and the National Science Foundation (CAREER Award BES 0238910). Dr Adair also serves as CSO for Keystone Nano in Boalsburg, PA, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download