Table 1.
An overview of the recent in vivo cancer therapeutic studies using calcium phosphate-based nanoparticles. Nanoparticles physiochemical properties (e.g., crystallographic phase, hydrodynamic size, shape, surface coating and targeting molecules), chemical procedures used for their surface functionalization, cancer models and therapeutic approaches are listed for each study. Observation of endocytosis in each study is shown with YES or NO. Endocytosis in tumor cells has been reported for CaP nanoparticles with different sizes, crystallographic phases, shapes and surface coatings. (abbreviations sorted alphabetically: 2DG: 2-deoxy-D-glucose; α-TOS: alphα-tocopheryl succinate; ABX-EGF scFv: EGFR- specific single chain fragment antibody; AHA: alendronate-hyaluronan graft polymer; BSA: bovine serum albumin; CaP: Calcium phosphate; DOX: Doxorubicin; Gd: Gadolinium MRI contrast agent; HAp: Hydroxyapatite; MIT: Mitoxantrone; mPEG-SH: methoxy-polyethylene glycol with thiol groups; NA: not applicable; NPs: Nanoparticles; NS: not characterized or specified in the reported study.; PAA: Poly acrylic acid; PDT: Photo dynamic therapy; PEG: Polyethylene glycol; PEGS: Pegylated poly(glycerol sebacate); PTT: Photothermal therapy; RGD: Arginyl glycyl aspartic acid; TPGS: Polyethylene glycol 1000 vitamin E succinate; TSG-6: (TNF)-stimulated gene 6; uPA: Urokinase plasminogen activator analogues peptide; VER: Verapamil.
| CaP phase | Shape | Size (nm) | Coating | Targeting molecule | Functionalization method | Application/Endocytosis reported? | Ref. |
|---|---|---|---|---|---|---|---|
| Amorphous CaP | Spherical | 40–50 | Lipid | Folic acid and/or ABX-EGF scFv | Two-step lipid coating and then covalent bonding of targeting molecules | siRNA delivery to breast tumor/ (NO) | [23] |
| CaP (NS) (degradable) | Spherical | 100–150 | Cupper sulfide/Pluronic® F-68 | NS | Electrostatic adsorption for F-68 capping | Mitochondrial Ca2+ homeostasis and PTT of breast tumor/ (YES) | [58] |
| CaP (NS) | Spherical | 150 | Hyaluronic acid | Hyaluronic acid | Electrostatic adsorption of cross-linked hyaluronic acid | siRNA delivery to mouse melanoma tumor/ (YES) | [59] |
| CaP (NS) | Spherical | 20 | PEG-RGD | RGD peptide | Formation of CaP’s inside drug-loaded PEG-RGD micelles | Delivery of Drug-resistance inhibitor (VER) and a chemotherapeutic agent (MIT) to hepatocellular carcinoma (liver cancer)/ (YES) | [60] |
| CaP (NS) | Spherical | 44–47 | Lipid/PEG | Bispecific antibody (BsAb) | Non-covalent adsorption of BsAb to lipid-coated CaP’s | Inhibit growth of the triple negative breast tumor by siRNA delivery and PTT in triple negative breast tumor/ (YES) | [61] |
| CaP (NS) | Spherical | 125 | Lipid | Galactose derivative | Two-step lipid coating and non-covalent bonding of galactose derivatives | siRNA delivery to hepatocellular carcinoma (liver cancer)/ (YES) | [62] |
| CaP (NS) | Spherical | 100 | PAA/ PEG/ gold nanorods | NA | Assembly of gold nanorods to the PAA-coated CaP’s and then coating with mPEG-SH | DOX delivery and PTT of liver cancer/ (YES) | [63] |
| CaP (NS) | Spherical | 170 | AHA | Hyaluronic acid | Electrostatic adsorption of hyaluronic acid to CaP | siRNA delivery to lung cancer/ (YES) | [64] |
| CaP (NS) | Spherical | 68 | folic acid/ PEG | Folic acid | Two-step lipid coating and then covalent bonding of folic acid | Prevention of breast tumor metastasis by vitamin E (α-TOS) delivery/ (YES) | [65] |
| Calcium phosphonate | Spherical | 42 | Lipid/PEG coated | miRNA-155 | Microemulsion to form miRNA loaded lipid-coated CaP’s and then coating with PEG-lipid in organic phase | miRNA delivery to tumor associated macrophages in murine sarcoma cancer/ (YES) | [66] |
| CaP (NS) | Spherical | 194 | Chitosan | NA | Co-precipitation of siRNA-loaded CaP’s in the presence of chitosan | siRNA delivery to Hela cervical cancer/ (YES) | [67] |
| HAp | Spherical nano-clusters | 30–40 | Polyglutamic acid | NA | Polyglutamic acid for self-assembly of ultrasmall HAp NPs | Synergistic DOX delivery and increased calcium influx for therapy of gastric adenocarcinoma/ (YES) | [54] |
| CaP (NS) | CaP shell to encapsulate siRNA | 113 | PEG | uPA | Formation of siRNA-loaded CaP’s inside PEG-uPA micells | siRNA delivery to triple negative breast cancer/ (YES) | [68] |
| HAp | Granular and nanorods | 17 and 61×29 | NA | NA | No surface functionalization was used | To evaluate effects of size and shape of HAp (no drug)in melanoma/ (YES) | [69] |
| HAp | Spherical | 38 | A54, TPGS and Gd | A54 peptide | CaP formation in the presence of A54-TPGS and Gd | MRI-guided DOX delivery to hepatic cancer/ (YES) | [70] |
| CaP (NS) | Spherical | 207 | PEI-cholesterol | VEGF siRNA | siRNA-loaded CaP’s were coated with a layer of PEI-cholestrol | siRNA delivery and inhibition of breast tumor angiogenesis/ (NO) | [71] |
| Amorphous CaP (degradable) | CaP coated upconversion NPs | 78 | PAA | NA | Silica-coated upconversion NPs were coated with CaP and PAA | DOX delivery and PDT of cervical cancer/ (YES) | [72] |
| HAp | nanorod | 10×50 | NA | NA | No surface functionalization was used | Mitochondria-targeting to inhibit lung cancer growth/ (YES) | [53] |
| HAp | almost spherical and porous | 217 | PEG/ Folic acid | Folic acid | Folic acid was covalently conjugated to polyethylene glycol-coated HAp NPs | Drug (epirubicin) delivery to murine colorectal cancer/ (YES) | [55] |
| HAp | mesoporous and spherical | NS | NA | NA | Electrostatic adsorption of 2DG, DOX and then radiolabeling for SPECT imaging | 2DG and DOX delivery to breast tumor and SPECT imaging using radiolabeling/ (NO) | [56] |
| CaP (NS) | Spherical | 140 | BSA | NA | CaP mineralization in the presence of BSA as template | TSG-6 delivery for treatment of liver fibrosis/ (NO) | [73] |
| HAp | core/shell PEGS/ HAp micelle | 20–30 | PEGS | NA | HAp NPs were formed in PEGS micelles | pH responsive DOX delivery to breast tumor/ (NO) | [74] |
| HAp | Nanorods loaded into a titanium implant | 46×13 | NA | NA | No surface functionalization was used | mitochondrial-dependent apoptosis and stimulating immune response in rabbit models/ (NO) | [75] |
| HAp and oligo-HAp (degradable) | silica/HAp hybrid | 99 | Hyaluronan (HA) and oligo-hyaluronan (oHA) | Hyaluronan (HA) and oligo-hyaluronan (oHA) | HA or oHA were covalently conjugated to the surface of silica/HAp | DOX delivery to breast cancer/ (YES) | [76] |
| CaP (NS) | spherical | 140 | MMP-2 cleavable peptide and PEG-lipid | NA | Peptide and PEG-lipid coating created by microemulsion | siRNA delivery to liver cancer/ (YES) | [77] |