The tumour vasculature plays an important role in tumour growth and metastasis. Tumour angiogenesis provides more oxygen and nutrients to growing tumour cells, is not as tightly regulated as embryonic angiogenesis, and do not follow any hierarchically ordered pattern. The heterogeneity of the vasculature, high interstitial fluid pressure, poor extravasation due to sluggish blood flow, and larger distances between exchange vessels are potential barriers to the delivery of therapeutic agents to tumours. The prevention of angiogenesis, normalization of tumour vasculature, and enhancement of blood perfusion through the use of monoclonal antibodies against receptor proteins that are overexpressed on proangiogenic tumour cells, and improved, tumour-targeted delivery of therapeutic agents can all be achieved using nanocarriers of appropriate size. Nanomedicines such as polymeric nanoparticles, lipid nanoparticles, micelles, mesoporous silica particles, metal nanoparticles, noisomes, and liposomes have been developed for the delivery of anticancer drugs in combination with antiangiogenic agents. Amongst them, liposomal delivery systems are mostly approved by the FDA for clinical use. In this review, the molecular pathways of tumour angiogenesis, the physiology of tumour vasculature, barriers to tumour-targeted delivery of therapeutic agents, and the different strategies to overcome these barriers are discussed.
In general, there is an efficient vascular network that supplies blood to normal tissues. The hierarchal architecture and growth of blood vessels are maintained by the balance between pro-apoptotic and anti-apoptotic factors. This balance is controlled by the metabolic demands of the corresponding tissue. Lymphatic channels on the other hand, remove metabolic waste from the interstitium. Thus, the microstructure of the vascular network is capable of supplying adequate oxygen and nutrition to all associated cells[
The growth of tumour blood vessels does not follow any hierarchy. It is typically heterogeneous, tortuous, branches irregularly, and is enlarged circumferentially[
Tumour blood vessels also have a reduced surface area: volume ratio. The high interstitial pressure, coupled with a reduced surface area, impairs the delivery of oxygen, nutrients, and removal of metabolites. As such, the tumour microenvironment is typically characterized by hypoxia and acidosis which in turn, selects for apoptosis-resistant and metastasis competent tumour cells
Schematic representation of the physiological differences between normal blood vessels (A) and the tumour vasculature (B)
Cell signaling pathways in hypoxia-induced angiogenesis is shown in
Cell signalling pathways of hypoxia-induced tumour angiogenesis. MNK: mitogen-activated protein kinase interacting protein kinases; EGFR: endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor type 2; PDGFR: platelet derived growth factor receptor; VEGF: vascular endothelial growth factor; ECM: extracellular matrix; MMP: matrix metalloproteinase; mTOR: mammalian target of rapamycin; TCEB: transcription elongation factor B; FGFR: fibroblast growth factor receptor; IGFR: insulin-like growth factor receptor
List of angiogenic factors, corresponding receptors, and functions
Antigenic molecules | Receptors | Functions | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Initiation of angiogenesis | Neovessel formation | Adaptation to tissue needs | Maturation | ||||||||
Enhancement of vascular permeability | Detachment of pericytes | Degradation of basement membrane | Endothelial cell proliferation and migration | Pericyte proliferation and migration | Regression of neovessels due to lack of flow or presence of growth factors | Attachment of pericytes | Deposition of basement membrane | Endothelial assembly and lumen acquisition | Vessel maintenance | ||
VEGF | VEGFR1 (Flt1) VEGFR2 (Kdr) | √ | √ | √ | √ | √ | |||||
Ang-2 | Tie2 | √ | √ | √ | |||||||
FGF | FGFR | √ | √ | ||||||||
PDGFB | PDGFR | √ | √ | √ | √ | ||||||
PLGF | VEGFR1 (Flt1) | √ | |||||||||
THBS 1 | CD36, CD47, Integrins | √ | |||||||||
Integrins | Extracellular matrix | √ | √ | ||||||||
SDF1 | CXCR4 | √ | |||||||||
DLL1-4 | Notch | √ | |||||||||
SCF | cKit | √ | |||||||||
Interleukins | Interleukin receptors | √ | |||||||||
Ang-1 | Tie2 | √ | √ | √ | √ |
VEGF: vascular endothelial growth factor; FGF: fibroblast growth factor; PDGFB: platelet-derived growth factor subunit B; PLGF: placental growth factor; THBS 1: thrombospondin 1; SDF1: stromal cell-derived factor 1; DLL1-4: delta like1-4 (notch ligands); SCF: stem cell factor; Ang-1: angiopoietin-1; CXXR4: chemokine (C-X-C motif) receptor 4; VEGFR: vascular endothelial growth factor; PDGFR: platelet-derived growth factor receptor
The inducible enzyme cyclooxygenase-2 (COX-2) is also an important mediator of angiogenesis and tumor growth. It induces matrix metalloproteinases that have traditionally been associated with the degradation and turnover of most of the components of the extracellular matrix (ECM). Plasminogen activator inhibitor type 1 (PAI-1) though has the opposite effect of remodeling the ECM by regulating plasmin.
Vascular morphology and blood flow rate govern the movement of blood-borne particles through tumour vasculature. Depending on the tumour type, location and growth rate, the architecture of the tumour vasculature may vary[
Microscopically, the tumour vasculature is highly heterogeneous. They are characterized by dilated, secular and tortuous blood vessels having tri-furcations, self-loops, and sprouts. The endothelial cell lining may even be absent. Blood flow is also chaotic and lacks a definite route between the arterial and venous systems. Therefore, in general, necrotic foci develop in a growing tumour. In turn, this decreases the average rate of perfusion.
Based on the rate of perfusion, there may be four regions in a tumour[
Regions I and II have a low blood flow rate whereas in regions III and IV, flow is more variable but still higher than that of surrounding normal host tissue. With tumour growth, the widths of regions I and II increase while that of III and IV remain unchanged, resulting in variation in vascular morphology at both the macroscopic and microscopic levels. The resulting spatial and temporal heterogeneities in blood supply is thus responsible for non-uniform distribution of the therapeutic agent. Generally, the average uptake of a therapeutic agent decreases with an increase in tumour mass.
Diffusion and convection are the main mechanisms behind the transport of drug molecules across the vascular wall. The concentration gradient of the therapeutic agent across the plasma (Cp) and interstitial fluid (Ci) is the driving force for the diffusion process. This mass transfer process is proportional to the surface area; the proportionality constant is known as vascular permeability P (cm/s). Transfer of therapeutic agents by convection is associated with the leakage of plasma/fluid across the vascular wall due to differences in hydrostatic pressure of fluid in the blood vessel and interstitial space. The associated experimental constant is known as hydraulic conductivity, Lp (cm/mmHg-s). Similarly, the convection process is also proportional to the osmotic pressure difference between the blood vessel and the interstitial space[
Diffusion and convection are the main mechanisms behind the movement of therapeutic agents that have extravasated into the interstitial space[
A tumour mass consists of proliferating cancer cells and stromal cells (i.e., fibroblasts, immune, and perivascular cells)[
Specific integrins can also contribute to tumour angiogenesis and tumour progression[
Therefore, the general strategy to overcome the barriers to vascular and tumour tissue permeability is functionalization of the surface of nanoparticles with tissue and cell-penetrating peptides, such as the iRGD[
A therapeutic agent is delivered to the target tissue via supplying arterioles to that particular tissue. As discussed in the previous sections, there are a number of barriers that hinder the distribution process of therapeutic agents in the tumour. First, the tumour vasculature is highly heterogeneous in distribution. Unlike the tight endothelium of normal blood vessels, the vascular endothelium in tumour microvessels is discontinuous and leaky. Elevated levels of growth factors such as VEGF and bFGF cause vasodilatation and enhancement of vascular permeability. Therefore, the gap sizes between endothelial cells can range from 100 to 780 nm, depending on the anatomic location of the tumour[
This problem can potentially be solved by delivering anticancer drugs encapsulated within nanoparticles[
The size of the tumour, degree of tumour vascularization, and angiogenesis are the main factors affecting EPR[
As discussed earlier, tumour blood vessels have sluggish blood flow. The hydrostatic fluid pressure in a blood vessel (Pv) is less than that of fluid in the interstitial space (Pi). This limits the distribution of therapeutic agents in the TME. Therefore, an increased rate of blood flow in tumour vessels will enhance the distribution of nanoparticles in the TME because of higher extravasation. Strategically there are two ways to increase the rate of blood flow in tumour vessels. First, vasoconstrictors such as angiotensin can be parenterally administered[
In experimental rats with subcutaneously transplanted AH109A solid tumours, Suzuki
Many research groups have developed nano-medicines that induce tumour-specific vasodilatation by releasing mediators such as NO[
Wei
Schematic representation of NO generating tumour vasculature targeted drug delivery systems. Copper ion-chelated porphyrin triggers tumour vasculature specific release of NO causing local vasodilation, whereas RGD peptide causes αvβ3 mediated tumour cell-specific nanoparticle uptake. The drug is released specifically within the cancer cells where the cytoplasmic levels of GSH is higher than normal cells. NO: nitric oxide; GSH: glutathione; RSNO: S-Nitroso alkane NP: nanoparticle; RGD: arginylglycylaspartic acid
Fang
The balance between pro-angiogenic (e.g., VEGF, PDGFB, IGF, PDGFRB, FGF-2, and TIE2) and anti-angiogenic factors (e.g., thrombospondin-1, angiostatin and endostatin) is responsible for the formation of normal tissue vasculature. This balance tips in favour of overexpression of pro-angiogenic factors in pathological conditions such as the progression of solid tumours[
Strategically, one may either block the pathways for synthesis of pro-angiogenic factors and their target receptor proteins, or neutralize the effects of these factors by inhibiting the corresponding target receptors with monoclonal antibodies. Such angiogenesis inhibitors can either target endothelial cells of the growing vasculature (known as direct inhibitors) or tumour cells and tumour-associated stromal cells (indirect inhibitors). Direct inhibitors like angiostatin[
Different types of nanomedicines such as polymeric nanoparticles, lipid nanoparticles, micelles, mesoporous silica particles, metal nanoparticles, noisomes, and liposomes have been developed for the delivery of anticancer drugs. Amongst them, liposomal delivery systems are mostly approved by the FDA for clinical use.
Therapeutic nucleic acids like small interfering RNA (siRNA) and short hairpin RNA (shRNA) are negatively charged and thus, frequently delivered with liposomes made up of cationic phospholipids. Cai
Chen
While positively charged liposomes are best suited for the delivery of negatively charged RNA molecules, they undergo nonspecific electrostatic adsorption with blood components and are quickly recognized by the immune system, leading to rapid clearance from the blood by the reticuloendothelial system (RES). This limitation can be overcome by coating the positively charged liposomes with negatively charged anionic polymers, which would then prolong circulation of the nanoparticles in blood and enhance the accumulation of nanoparticles within the tumour due to the EPR effect. In a recent study, VEGF siRNA and etoposide were loaded in a cationic liposome that was further coated with PEGylated histidine-grafted-chitosan-lipoic acid (PHCL), a pH triggered charge-controllable and redox responsive polymer
Schematic representation of using multifunctional nanoparticles for co-delivery of VEGF siRNA and etoposide (an anticancer drug) for enhanced anti-angiogenesis and anti-proliferation activity. RISC: siRNA induced silencing complex; VEGF: vascular endothelial growth factor; GSH: glutathione; EPR: enhanced permeation & retention
In the TME, at low pH (6.5), protonation of the imidazole group in the histidine segment of PHCL causes a reversal of nanoparticle charge from negative to positive, leading to deep tumour penetration and enhancement of internalization of nanoparticles. The positive charge is further enhanced in the lower pH of endo-lysosomes, where the disulphide bond of the lipoic acid segment in PHCL-liposomes undergo GSH induced redox-activated breakage, leading to the release of cargo within the liposome
The antiangiogenic agent bevacizumab is a humanized monoclonal antibody that inhibits tumour growth and metastasis. When combined with a cytotoxic anticancer agent such as paclitaxel, therapeutic efficacy was significantly improved because of the targeted accumulation of paclitaxel within tumours[
Gold nanoparticles have also been used for the targeted delivery of anti-angiogenic agents, either alone or in combination with an anticancer drug. Bartczak
EGFR tyrosine kinase inhibitors like cetuximab, lapatinib, afatinib, gefitinib, erlotinib, fedratinib are well studied for anticancer therapy when used in combination with different chemotherapeutic agents including doxorubicin, gemcitabine, paclitaxel, and carboplatin. They help in the normalization of tumour vasculature and sensitize tumour cells to cytotoxic drugs. Additionally, monoclonal antibodies such as cetuximab have been used as a targeting agent. Lin
Strategies of tumour-targeted drug delivery exploiting tumour vasculature
Proangiogenic factor | Antiangiogenic agent | Anti-cancer drug | Formulation/delivery system | Mechanism of action | Year of study | Ref. | |
---|---|---|---|---|---|---|---|
VEGF | siRNA | Not applicable | Liposome with two peptides (Angiopep and tLyP-1) attached on the surface | Angiopep ligand helps in brain tumour targeting, tLyP-1 ensures tumour penetration. siRNAs inhibit VEGF production | 2014 | [ |
|
Not applicable | cis-di-ammine-di-nitro-platinum (II) | Anti-VEGF mAb and anti-VEGFR2 mAb were attached on the liposome surface | The mAb targets the liposome to tumour cells. Cis-di-ammine-di-nitro-platinum (II) kills cancer cells | 2016 | [ |
||
Sorafenib and Cy3-siRNA | Not applicable | pH-sensitive carboxymethyl chitosan-modified liposomes | Inhibition of angiogenesis due to downregulation of VEGF | 2019 | [ |
||
Not applicable | DOX | DOX-loaded Amino-triphenyl dicarboxylate-bridged Zr4+ metal-organic framework
|
VEGF overexpressed by cancer cells provides the mechanism to unlock the gate via the formation of the VEGF-aptamer complexes and the separation of the gating duplex. The released DOX kills the cancer cells | 2018 | [ |
||
siRNA | DOX HCl | Polycation liposome-encapsulated calcium phosphate nanoparticle | siRNA silences the expression of VEGF. DOX kills cancer cells | 2017 | [ |
||
Gambogic acid | Gambogic acid | PEGylated liposomes | Gambogic acid has both antiangiogenic and cytotoxic activity | Ex-vivo: MDA-MB-231 cells
|
2016 | [ |
|
siRNA | Docetaxel | Liposome with two peptides (Angiopep and tLyP-1) attached on the surface | Angiopep ligand helps in brain tumour targeting, tLyP-1 ensures tumour penetration. siRNA inhibits VEGF production. Docetaxel kills cancer cells | 2014 | [ |
||
siRNA | Etoposide | Cationic liposomes coated with PEGylated histidine-grafted chitosan-lipoic acid | siRNA silence |
Ex-vivo: A549-Luc |
2019 | [ |
|
Bevacizumab | Paclitaxel | Bevacizumab diluted with saline, paclitaxel dissolved in 1:1 mixture of cremophor el and ethanol solution | Inhibiting the binding of VEGF to its cell surface receptors with the anti-tubulin agent | 2010 | [ |
||
siRNA | Sorafenib | Lactobionic acid conjugated mesoporous silica nanoparticle | siRNA inhibits VEGF expression. Sorafenib has antiangiogenic and cytotoxic effects | 2018 | [ |
||
shRNA (Survivin) | Sorafenib | Pluronic P85- Poly-ethyleneimine/D-α-tocopheryl-PEG 1000 succinate nanocomplexes (nanomicelle) | shRNA inhibits VEGF expression. Sorafenib has antiangiogenic and cytotoxic effects | 2014 | [ |
||
Vatalanib | Not applicable | Oral tablet | Vatalanib is an angiogenesis inhibitor. It inhibits the tyrosine kinase domains VEGFR, PDGFR, and c-KIT | Clinical (Phase II): patients with metastatic pancreatic adenocarcinoma who failed first-line treatment with gemcitabine | 2014 | [ |
|
Sorafenib | Paclitaxel | Hyaluronic acid conjugated |
Sorafenib is an angiogenesis inhibitor. It also inhibits cancer cell proliferation (by inhibiting RAF/MEK/ERK signalling pathways). Paclitaxel arrests cancer cells at G2/M phase | 2019 | [ |
||
Sunitinib | Near-Infrared dye-IR780 | Liposome | Laser activated release of sunitinib inhibits tyrosine kinase associated with VEGF and PDGF receptors, whereas IR780 dye kills cancer cells by hyperthermia | Ex-vivo: 4T1 cell line
|
2018 | [ |
|
Sunitinib | Paclitaxel | Paclitaxel loaded pH-responsive micelle was coated with β-cyclodextrin via MMP-2 sensitive peptide that was cleavable in the tumour matrix. Sunitinib was loaded in this cyclodextrin layer | Drugs were released at the tumour microenvironment (low pH, presence of MMP). Sunitinib inhibits angiogenesis and paclitaxel arrests cancer cells at the G2/M phase | 2019 | [ |
||
KATWLPPR peptide | Gold nanoparticle | Gold NP capped with monocarboxy (1-mercaptoundec-11-yl) hexa (ethylene glycol) | Gold nanoparticle delivers the peptide within the cell, where it predominately binds to neuropilin-1 receptor and inhibits angiogenesis | 2013 | [ |
||
FGF | FGF1 (recombinant ligand for all FGFRs) | Gold nanoparticle (AuNP) | FGF1 conjugated gold nanoparticle | FGF1 helps in the targeted delivery of AuNP to FGFR positive cells to cause NIR induced photothermal destruction of cancer cells | 2012 | [ |
|
Epidermal growth factor | Cetuximab | Paclitaxel | Cetuximab conjugated paclitaxel loaded nanodiamond | Cetuximab helps in cancer cell-targeted delivery of paclitaxel that arrests cells at G2/M phase | Ex-vivo: human colorectal cell line (HCT116, SW620, and RKO)
|
2017 | [ |
Cetuximab | Gemcitabine | “2 in 1” nanoconjugates containing both cetuximab and gemcitabine on a single gold nanoparticle core | Cetuximab helps in the targeted delivery of gemcitabine to the EGFR positive cancer | 2008 | [ |
||
Lapatinib | Paclitaxel | Liposome | Lapatinib inhibits angiogenesis. Paclitaxel arrests cells at G2/M phase | 2015 | [ |
||
Lapatinib | Paclitaxel | Polylactide-co-poly-(ethylene glycol) filomicelles of 100 nm length and spherical micelles of 20 nm diameter | Lapatinib inhibits angiogenesis and p-GP protein. Paclitaxel arrests cells at G2/M phase | 2019 | [ |
||
Gefitinib | DOX | Gefitinib complexed with dioleoyl-phosphatidic acid via ion paring was loaded onto the nanoparticle made of DOX conjugated poly( |
At first, Gefitinib was released, followed by DOX. Gefitinib inhibits EGFR tyrosine kinase and DOX kills cancer cells | 2017 | [ |
||
Gefitinib | Gemcitabine | Gemcitabine was administered intravenously in saline solution. Gefitinib was dissolved in water and administered as oral gavage | Gefitinib inhibits EGFR tyrosine kinases and gemcitabine kills cancer cells | 2006 | [ |
||
Erlotinib and Fedratinib | Not applicable | Poly(ethylene glycol)-poly (lactic acid) nanoparticle | Inhibition of EGFR and suppression of the JAK2/STAT3 signalling pathway | 2018 | [ |
||
Lapatinib | Paclitaxel | Polylactide-co-Poly(ethylene glycol) micelles | Lapatinib inhibits EGFR and HER2 tyrosine kinase whereas paclitaxel arrests cancer cells at G2/M phase | 2019 | [ |
||
Lapatinib | Paclitaxel | Liposome | Lapatinib inhibits EGFR and HER2 tyrosine kinase whereas paclitaxel arrests cancer cells at G2/M phase | 2016 | [ |
||
Afatinib | Paclitaxel | Afatinib was loaded in stearic acid-based solid lipid nanoparticles. This nanoparticle and paclitaxel were loaded in polylactide-coglycolide-based porous microspheres | Afatinib inhibits EGFR and HER2 tyrosine kinase whereas paclitaxel arrests cancer cells at G2/M phase | 2019 | [ |
||
Erlotinib | Paclitaxel | Both erlotinib and paclitaxel were encapsulated in glyceryl monostearate nanoparticles, which was coated with a PEGylated polymeric layer | Erlotinib inhibits EGFR tyrosine kinase whereas paclitaxel arrests cancer cells at G2/M phase | 2018 | [ |
||
Erlotinib | Gemcitabine | Erlotinib (100 mg/d, orally), Gemcitabine (1000 mg/m2, i.v. infusion) | Erlotinib inhibits EGFR tyrosine kinase whereas gemcitabine kills cancer cells | Clinical (open level phase II clinical trial): patients with locally advanced, inoperable, or metastatic pancreatic cancer | 2013 | [ |
|
Erlotinib | DOX | pH-sensitive charge conversion nanocarrier. DOX was loaded in amino-functionalized mesoporous silica nanoparticles, which was coated with a synthetic zwitterionic oligopeptide lipid-containing erlotinib | Erlotinib and DOX were released sequentially and showed a synergistic effect. Erlotinib inhibits EGFR tyrosine kinase whereas DOX kills cancer cells | 2016 | [ |
||
Androgen receptor | Thalidomide | Not applicable | Methoxy poly(ethylene glycol)-poly(ε-caprolactone) nanoparticle | Thalidomide inhibits androgen receptor and TNF-α | 2018 | [ |
|
mTOR | Everolimus | Not applicable | Everolimus loaded 3’-(1-carboxy)ethyl sialyl LewisX mimic-decorated liposome | Sialyl LewisX (sLeX), the natural ligand of E-selectin directs the delivery of liposome to tumour endothelium. Everolimus inhibits angiogenesis | 2019 | [ |
|
Everolimus | Paclitaxel | Poly(ethylene glycol)-b-poly(lactide-coglycolide) copolymer nanoparticle. Everolimus:Paclitaxel molar ratio = 0.5:1 | Everolimus suppresses tumour growth by antiangiogenic effect. Paclitaxel kills the cancer cells | 2018 | [ |
||
Rapamycin | Cisplatin | Nanoprecipitate of cisplatin was coated with di-oleoyl-phosphatidic acid. It was further encapsulated in PLGA nanoparticles. Rapamycin was dispersed in PLGA shell | Rapamycin inhibits tumour growth by the antiangiogenic effect. It promotes vascular normalization to improve tumour perfusion. Thus the tumour cells are sensitized to cytotoxic cisplatin molecule | 2014 | [ |
VEGF: vascular endothelial growth factor; DOX: Doxorubicin; siRNA: small interfering RNA; shRNA: short hairpin RNA; BMVEC: brain microvascular endothelial cells; PDGF: platelet derived growth factor; MMP: matrix metalloproteinase; EGFR: endothelial growth factor receptor; VEGFR: vascular endothelial growth factor receptor; PDGFR: platelet derived growth factor receptor; c-KIT: a type of receptor tyrosine kinase and tumor marker, also called CD117 and stem cell factor receptor; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen activated protein kinase; ERK: extracellular signal-regulated kinases; FGF: fibroblast growth factor; NSCLC: non-small cell lung cancer; mTOR: mammalian target of rapamycin; NP: nanoparticle; NIR: near infrared; FGFR: fibroblast growth factors receptor; BJ: Normal human fibroblasts cell line; SD: sprague dawley; PLGA: poly(lactic-co-glycolic acid)
List of FDA-approved anti-angiogenic agents for the treatment of cancer
Serial No. | Agents | Marketed name | Mechanism | FDA approved therapy | Ref. |
---|---|---|---|---|---|
1. | Afatinib | Gilotrif® | Inhibits EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) receptors | 1st-line treatment of patients with metastatic NSCLC (Jan 12, 2018) | [ |
2. | Axitinib and pembrolizumab | Inlyta® and Keytruda® | Axitinib inhibits tyrosine kinase 1, 2 and 3 of VEGFR. Pembrolizumab binds to the Programmed cell death protein 1 (PD-1) receptor, blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to help restore T-cell response and immune response against cancer cells | Advanced renal cell carcinoma (Jan 27, 2017) | [ |
3. | Bevacizumab | Avastin® | It acts by selectively binding circulating VEGF, thereby inhibiting the binding of VEGF to its cell surface receptors. This inhibition leads to a reduction in microvascular growth of tumour blood vessels and thus limits the blood supply to tumour tissues | Avastin was approved for the most aggressive form of brain cancer (Dec 5, 2017), metastatic cervical cancer (Aug 14, 2014), and breast cancer (Nov 18, 2011).
|
[ |
4. | Bosutinib | Busulif® | It is an ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an additional inhibitory effect on SRC family kinases (including Src, Lyn and Hck). It is also active against the receptors for PDGF and VEGF | Philadelphia chromosome-positive (Ph+) CML with resistance, or intolerance to prior therapy (Sep 5, 2012) | [ |
5. | Cabozantinib | Cabometyx® and Cometriq® | It is a multiple tyrosine kinase inhibitor
|
Advanced renal cell carcinoma (Feb 15, 2018), renal cell carcinoma and hepatocellular carcinoma (Apr 25, 2016) | [ |
6. | Cetuximab | Erbitux® | Epidermal growth factor receptor inhibitor | Squamous cell carcinoma of the head and neck (Mar 2016) | [ |
7. | Crizotinib | Xalkori® | Inhibitor of receptor tyrosine kinases including ALK, hepatocyte growth factor receptor (HGFR, c-Met), and RON | NSCLC (Aug 26, 2011) | [ |
8 | Dasatinib | Sprycel® | It is a dual Bcr-Abl and Src family tyrosine kinase inhibitor. It also targets tyrosine kinases of EPHA2, PDGFR, GFR, and c-KIT | Paediatric patients with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (Nov 9, 2017) | [ |
9. | Erlotinib | Tercava® | It inhibits the intracellular phosphorylation of tyrosine kinase associated with the EGFR | Lung and pancreatic cancer (Nov 18, 2004) | [ |
10. | Everolimus | Afinitor® | Inhibitor of mTOR | Renal cell carcinoma, breast cancer, neuroendocrine carcinoma (Mar 30, 2009) | [ |
11. | Gefitinib | Iressa® | Selective inhibitor of the EGFR | NSCLC (May 2003) | [ |
12. | Imatinib | Gleevec® | Protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML | Acute lymphoblastic leukaemia, chronic myelogenous leukaemia, myelodysplastic diseases, gastrointestinal stromal tumour (May 10, 2001) | [ |
13. | Lapatinib with Capecitabine | Tykerb® | Dual tyrosine kinase inhibitor which interrupts the HER2/neu and EGFR pathways | Breast cancer (Mar 13, 2007) | [ |
14. | Lenalidomide | Revlimid® | Directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects | Follicular lymphoma (May 28, 2019) | [ |
15. | Nilotinib | Tasigna® | Acts as TKI and blocks a tyrosine kinase protein called Bcr-Abl | CML (Mar 22, 2018) | [ |
16. | Nintedanib | Ofev® and Vargatef® | It binds to the intracellular ATP binding pockets of FGFR 1-3, PDGFRα/β, and VEGFR 1-3. This results in blockage of the autophosphorylation of these receptors and the downstream signalling cascades | Idiopathic pulmonary fibrosis (2014) | [ |
17. | Osimertinib | Tagrisso® | It targets the mutated EGFR T790M within the cancer cells | NSCLC (Apr 2018) | [ |
18. | Pazopanib | Votrient® | It inhibits VEGFR, PDGFR, c-KIT and FGFR | Advanced soft tissue sarcoma (Apr 27, 2012) | [ |
19. | Ponatinib | Iclusig® | It inhibits Bcr-Abl, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL | Adult patients with chronic phase, accelerated phase, or blast phase CML or Ph+ ALL for whom no other TKI therapy is indicated (Dec 14, 2012) | [ |
20. | Ramucirumab | Cyramza® | It is a direct VEGFR2 antagonist, that binds with high affinity to the extracellular domain of VEGFR2 and block the binding of natural VEGFR ligands (VEGF-A, VEGF-C and VEGF-D) | Gastric cancer, NSCLC, colorectal cancer, hepatocellular carcinoma (Apr 21, 2014) | [ |
21. | Regorafenib | Stivarga® | Dual targeted VEGFR2 and Tie2 tyrosine kinase inhibition | Hepatocellular carcinoma (Apr 27, 2017)
|
[ |
22. | Sorafenib | Nexavar® | Protein kinase inhibitor with activity against many protein kinases, including VEGFR, PDGFR and RAF kinases | Advanced renal cell carcinoma (Dec 20, 2005) | [ |
23. | Sunitinib | Sutent® | Multi-targeted RTK inhibitor | Renal cell carcinoma (Nov 16, 2017) | [ |
24. | Temsirolimus | Torisel® | Inhibitor of mTOR | Renal cell carcinoma (May 30, 2007) | [ |
25. | Thalidomide | Thalomid® | Inhibitor of Akt phosphorylation | Multiple myeloma (May 26, 2006) | [ |
26. | Vandetanib | Caprelsa® | It inhibits EGFR | Advanced thyroid cancer (Apr, 2011) | [ |
27. | Ziv- aflibercept | Zaltrap® | It is a recombinant protein that strongly binds with VEGFR and blocks all known ligands for this receptor | Colorectal cancer (Aug 15, 2012) | [ |
NSCLC: non-small cell lung cancer; EGFR: endothelial growth factor receptor; VEGFR: vascular endothelial growth factor receptor; VEGF: vascular endothelial growth factor; PDGF: platelet derived growth factor; CML: chronic myelogenous leukaemia; RON: recepteur d’Origine nantais; EPHA2: erythropoietin producing hepatocellular-carcinoma type A receptor 2; PDGFR: platelet derived growth factor receptor; c-KIT: a type of receptor tyrosine kinase and tumor marker, also called CD117 and stem cell factor receptor; GFR: growth factor receptor; mTOR: mammalian target of rapamycin; TKI: tyrosine kinase inhibitor; RAF: rapidly accelerated fibrosarcoma; RTK: receptor tyrosine kinase; FGFR: fibroblast growth factor receptor; ALL: acute lymphoblastic leukemia
EPR is a highly heterogeneous phenomenon. It is variable, even amongst different regions of the same tumour. In fact, within a single tumour, not all blood vessels are permeable to the same extent. Moreover, in many clinical settings, it has been found that tumours do not have a sufficient level of EPR to ensure the accumulation of nanomedicines. This is mainly because of the insufficient permeability of the vascular endothelium of tumour blood vessels. This problem can be addressed by local application of physical treatments such as sonoporation, hyperthermia, and radiotherapy that enhance tumour vasculature permeability, and aid in extravasation of nanomedicines uniformly throughout the TME.
Sonoporation involves the application of ultrasonic sound to increase the gap between vascular endothelial cells. The mechanical effects can be further augmented with microbubbles and nanobubbles. The acoustic waves generate acoustic radiation force that causes bulk streaming and microstreaming. Bulk streaming is the movement of localized fluid current in the direction of propagation of ultrasonic sound while microstreaming involves localized eddies that are generated next to cavitating bodies. All these mechanical outputs may result in the release of drugs from carriers and the associated movement of drug molecules into targeted tissues. The efficiency of drug release is controlled by acoustic parameters like ultrasound frequency, power density, and pulse duration. Gas-filled micro-bubbles and nano-bubbles undergo violent collapse under large acoustic pressures. This phenomenon is known as inertial cavitation and is responsible for the generation of micro-streaming[
Theek
In another study, Yan
As an alternative approach, Meng
Schematic representation of cancer treatment with anticancer drug-loaded liposome-micro-bubble complexes (PLMC) assisted by ultrasound (US). A: when flowing through the target region, drugs remain attached to the lipid shells of MBs but are unable to cross the tumour vasculature by simple diffusion; B: application of high-intensity focused US bursts the micro-bubbles to release drugs. The cavitating and imploding MBs also enhance permeability of the plasma membrane, leading to higher uptake of released drugs. MBs: micro-bubbles
In response to temperatures of 41-45 °C, there is increased tissue perfusion to dissipate heat. For healthy tissues like muscle and skin, this increase in perfusion can be as high as 10- and 15-fold respectively.
In tumour tissue, perfusion rates are increased by 1.5-2 folds only[
Controlled, local heating of tumour tissue with radiofrequency[
There are different well-studied thermoresponsive nanomedicines such as liposomes[
Again, to control drug release at mild hyperthermia, leucine zipper peptide was incorporated into the liposome[
The thermo-responsive bubble generating liposomes[
Schematic diagram showing the structure and function of thermoresponsive, bubble-generating liposomes and the mechanism of localized extracellular drug release triggered by heat. A: drug release mechanism upon application of hyperthermia; B: internalization of the released drug by the target cell
Gold nanoparticles coated with thermo-responsive hydrogel was developed for cancer therapy[
Sato
Hyperthermia by NIR laser irradiation causes shrinkage of blood vessels and tumour ablation. Combining hyperthermia and chemotherapy could be an efficient treatment approach. This is known as photothermal chemotherapy[
Whole-body hyperthermia at the mild fever range (39.5 °C, for 4-6 h) was found to help in the therapeutic efficacy of doxorubicin-loaded liposome in syngeneic CT26 colorectal mice carcinoma[
Hypoxia-induced formation of new blood vessels is the key factor in the progression of tumours. Tumour vasculature is heterogeneous, tortuous, irregularly branched, and hyperpermeable. Due to poor lymphatic drainage, the TME has high IFP. This heterogeneity of the vasculature, high IFP, poor extravasation due to sluggish blood flow, and larger distance between exchange vessels are all potential barriers to the delivery of therapeutic agents to tumours. A rationally designed delivery system should overcome all these barriers to reach deep tumour tissue. As the endothelial cells of tumour vasculature have longer gaps, and the IFP is high, nanoparticles of proper size can inherently be accumulated in the tumour due to the EPR effect. This is known as passive targeting. The surface of nanocarriers can also be coated with monoclonal antibodies against receptor proteins overexpressed in proangiogenic tumour cells for active targeted drug delivery. The vascular barrier can be further reduced by enhancing blood perfusion in the tumour and normalization of tumour vasculature. Local delivery of mediators such as NO and CO enhance blood perfusion whereas inhibition of proangiogenic pathways and the use of antiangiogenic agents help in the accumulation of anticancer drugs loaded nanocarriers deep within tumour tissues. Furthermore, the use of sonoporation and hyperthermia boosts nanocarrier mediated tumour-targeted drug delivery.
The authors are grateful to the Guru Nanak Institute of Pharmaceutical Science & Technology and Department of Biotechnology, University of Calcutta for providing literature resources and other software facilities required for writing the manuscript.
Contributed in writing the manuscript: Dastidar DG
Contributed in editing the manuscript: Chakrabarti G
Did the literature survey and prepared the diagrams: Ghosh D
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All authors declared that there are no conflicts of interest.
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© The Author(s) 2020.