Recent advances in “smart” delivery systems for extended drug release in cancer therapy

Figures & data

Figure 1 Multifunctional targeting employed by “smart” nanoparticles.

Note: Smart nanoparticles employ passive- targeting, active- targeting, and stimuli-responsive targeting methods.

Abbreviations: EPR, enhanced permeability and retention; mAb, monoclonal antibody.

Table 1 Active targeting strategies and potential functionalization of “smart” nanoparticles

Nanoparticles	Functionalization	Target
Albumin-based targeting	Albumin	60 kDa endothelial cell-surface albumin-binding glycoprotein (Gp60)^Citation30
		Albumin-binding protein (BM40, SPARC, osteonectin)^Citation31,Citation32
Hyaluronic acid-based targeting	Hyaluronic acid	Glycoprotein CD44 receptor^Citation33
Biotin-based targeting	Biotin (vitamin H)	Biotin receptors^Citation34,Citation35
Folate-based targeting	Folic acid	Folate receptors^Citation6,Citation18,Citation36,Citation37
		Prostate-specific membrane antigen^Citation38,Citation39
Transferrin-based targeting	Transferrin	Transferrin receptors^Citation40^–^Citation44
Aptamer-based targeting	AS1411	Nucleolin^Citation45
Monoclonal antibody (mAB)-based targeting	EGF	EGFR^Citation46
	HER2 mABs	Anti-HER2 monoclonal antibodies^Citation47
Peptidic targeting	RGD peptide	αVβ3 integrin^Citation48^–^Citation50
	Angiopep 2	LRP^Citation51
	Cyclo(1,12)-Pen-lTDGEATDSGC or LFA1-derived cyclic peptide	ICAM1 receptors^Citation52,Citation53
Lectin-based targeting	Jacalin	Thomsen–Friedenreich carbohydrate antigen^Citation54
	Aleuria aurantia lectin	Lewis X^Citation55
	Galactose	Asialoglycoprotein receptors^Citation56
Other	IL2	IL2 receptor^Citation57

Note: Functionalization of nanoparticles and associated cellular targets for each active-targeting strategy.

Figure 2 Physiological benefits of “smart” and extended-release nanopolymers.

Note: Smart and extended-release nanopolymers each confer physiological benefits, with some being characteristic of both nanoparticle types.

Table 2 Current US FDA-approved nanoparticles and type of targeting employed, indications, advantages, and drawbacks

	Targeting	Indications	Advantages	Drawbacks
Protein-based formulations
Nab-paclitaxel (Abraxane)	Passive targeting	Breast cancer, non-small-cell lung cancer, metastatic pancreatic cancer	Greater solubility, increased delivery to tumors,^Citation102 corticosteroid and antihistaminic premeditations not needed, shorter time to infusion, eliminates toxicity associated with polyoxyethylated castor-oil solvent^Citation103	Limited efficacy against solid tumors^Citation104
Liposomal formulations
Liposomal vincristine (Marqibo)	Passive targeting	Acute lymphoid leukemia, Philadelphia chromosome-negative acute lymphoblastic leukemia	Increased delivery to tumor site, decreased systemic toxicity,^Citation102 ease of administration, higher dose of vincristine delivery can be achieved, once-per-week dosing,^Citation105 long-circulating slow-release properties,^Citation106 no PEG coating^Citation107	Response rate and duration of response are modest, optimal use remains to be defined^Citation108
Irinotecan liposomal (Onivyde)	Stimuli-responsive	Pancreatic cancer	Increased delivery to the tumor site, decreased systemic toxicity,^Citation102 photosensitive release, high drug loading, extended drug retention in vivo^Citation109	Potential for clinically relevant drug–drug interactions when coadministered with potent CYP3A4 inducers or inhibitors or strong UGT1A1 inhibitors, potential for severe or life-threatening neutropenia and severe diarrhea^Citation110
Doxorubicin liposomal (Doxil)	Passive targeting	Ovarian cancer, breast cancer, Kaposi’s sarcoma, multiple myeloma	Increased delivery to disease site, decreased systemic toxicity of free drug,^Citation102 contains “stealth” feature that allows it to evade premature clearance by the reticuloendothelial system,^Citation111 crystallization of drug in liposomes minimizes escape during circulation, lipid encapsulation for high drug:carrier ratio^Citation107	Preferentially concentrates in the skin due to PEG coating, drug leakage, resulting in hand–foot syndrome^Citation112
Liposomal daunorubicin (Daunoxome)	Passive targeting	Kaposi’s sarcoma	Extended drug circulation, steady liposomal carrier,^Citation113 improved pharmacokinetic profile compared to free daunorubcin,^Citation114 no PEG coating^Citation107	Insufficient drug entrapment^Citation115
Cytarabine/daunorubicin, liposomal (Vyxeos)	Passive targeting	Acute myeloid leukemia (AML)	Coencapsulates two drugs, significantly improves overall survival, event-free survival, and response observed in patients with acute high-risk AML,^Citation116 limited alopecia, shorter infusions^Citation117	Optimal patient populations to receive this compound remain unknown, mechanisms responsible for improved outcomes unclear, prolonged cytopenias^Citation117
Liposome-encapsulated doxorubicin citrate (Myocet)a	Passive targeting	Breast cancer	Minimizes cardiac toxicity associated with doxorubicin,^Citation114 no PEG coating^Citation112	Stability, drug release, arduous formulation, remote-loading method for preparation^Citation118
Polymeric formulations
Leuprolide acetate and PLGA (Eligard)	Passive targeting	Prostate cancer	Longer circulation, controlled payload delivery,^Citation102,Citation119 different formulations available depending on desired monthly dosage,^Citation120 can achieve a double dose of leuprolide release,^Citation121 PLGA can be processed into different device morphologies with relative ease^Citation122	PLGA-based NPs are generally subject to poor drug loading and burst release, many steps required for industrial reproduction^Citation123
Pegaspargase (Oncaspar)	Passive targeting	Acute lymphoid leukemia	Greater protein stability,^Citation102 reduces the number of injections of L-asparaginase required^Citation124	Possibility of anti-PEG antibody formation upon administration, occurrence of delayed hypersensitivity reactions to PEG-containing substances, nonbiodegradability of PEG^Citation125

Notes:

a Available in Canada, but not the US. Other NPs approved for the treatment of cancer but not discussed herein include trastuzumab emtansine (Kadcyla), and NanoTherm (MagForce), which has been clinically discontinued.

Abbreviations: FDA, Food and Drug Administration; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); NPs, nanoparticles.

Figure 3 A pH-responsive, “smart” active polymer-delivery system.

Notes: Yellow spheres represent folic acid molecules, green represents hydrophobic drugs, blue shows the hydrophilic part of the polymer, and gray is the hydrophobic part of the polymer. Reprinted from Biophys Chem, 214–215, Li X, Mctaggart M, Malardier-Jugroot C, Synthesis and characterization of a pH responsive folic acid functionalized polymeric drug delivery system, 17–26, copyright 2016, with permission from Elsevier.¹⁸

Figure 4 Clinical benefits of “smart” and extended-release NPs.

Note: Smart and extended-release nanopolymers each confer clinical benefits, with some being characteristic of both nanoparticle types.

Table 3 Classical methods of extended-release delivery systems and their limitations

	Mechanism	Limitations
Diffusion system – reservoir^Citation159^–^Citation161	Drug-coated with polymers and released through slow diffusion out of the polymer	Drugs with higher molecular weight have difficulty diffusing through the membrane
Diffusion system – matrix^Citation162	Drug dispersed within the polymer and diffuses slowly	Matrix device cannot achieve zero-order release
Dissolution reservoir^Citation163	Drug coated with slowly dissolving surface	Different drug solubility and half-lives need to be considered
Dissolution matrix^Citation164,Citation165	Drug placed in a slowly dissolving matrix	Different drug solubility and half-lives need to be considered
Osmotic systems^Citation166^–^Citation169	Drug surrounded by semipermeable membrane held in a rigid tablet with laser drilled holes; as the tablet passes through the body, water is absorbed through the semipermeable membrane via osmosis, and the resulting osmotic pressure pushes the active drug through the opening in the tablet	A complicated system, difficult to manufacture, irritates the gastrointestinal tract
Ion-exchange resin^Citation170	Drug is attached to cross-linked polymers	Costly preparation, higher first-pass metabolism, less systemic availability compared to conventional formulations; reduced potential for dose adjustment
Floating systems^Citation171	Drug of lower density than gastric fluids floats on top and releases slowly	Requires enough gastric fluids present, as well as food
Matrix systems:^Citation172,Citation173 hydrophobic, lipid, hydrophilic, biodegradable, and mineral matrices	Drug held in a mixture of materials that forms channels (due to opposing chemical properties) through which drug is released slowly	Some preparations require extensive preparation and less cost-effective, eg, hydrophobic matrix

Figure 5 (A) RAGxCγ double-mutant mice bearing heterotopic xenografts of pancreatic PANC1 tumors. (B) Extended release of OP from PLGA-OP surgical implants, measurement of tumor volumes days post implantation, tumor weights at necropsy, and number of liver metastatic clusters.

Note: Copyright © 2015. Dove Medical Press. Reproduced from Hrynyk M, Ellis JP, Haxho F, et al. Therapeutic designed poly (lactic-co-glycolic acid) cylindrical oseltamivir phosphate-loaded implants impede tumor neovascularization, growth and metastasis in mouse model of human pancreatic carcinoma. Drug Des Devel Ther. 2015;9: 4573–4586.¹⁸²

Abbreviations: OP, oseltamivir phosphate; PLGA, poly(lactic-co-glycolic acid).

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