Nanotechnology: A magic bullet for HIV AIDS treatment

Figures & data

Figure 1. Structural arrangement of HIV.

Figure 2. Reservoirs of HIV in human body.

Table I. Marketed anti-retroviral drugs.

Generic names	Abbreviations	Brand name	Manufacturer	Adult dosage
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Etravirine	TMC125	Intelence^®	Tibotec	200 mg, b.i.d. (oral)
Nevirapine	NVP	Viramune^®	Boehringer Ingelheim	200 mg, b.i.d. (oral)
Efavirenz	EFV	Sustiva^®	Bristol-Myers Squibb	600 mg, daily (oral)
Nucleoside reverse transcriptase inhibitors (NRTIs)
Lamivudine	3TC	Epivir^®	GlaxoSmithKline	150 mg, daily (oral) OR 300 mg, daily (oral)
Abacavir	ABC	Ziagen^®	GlaxoSmithKline	300 mg, b.i.d. (oral) OR 600 mg, b.i.d. (oral)
Zidovudine	AZT	Retrovir^®	GlaxoSmithKline	200 mg, t.i.d. (oral) OR 300 mg, b.i.d. (oral)
Didanosine	ddI	Videx^®	Bristol-Myers Squibb	400 mg, daily (oral; delayed-release capsules)
Zalcitabine	ddC	HIVID^®	Roche	0.75 mg, t.i.d. (oral)
Stavudine	d4T	Zerit^®	Bristol-Myers Squibb	40 mg, b.i.d. (oral)
Integrase inhibitors
Raltegravir	MK-0518	Isentress^®	Merck	400 mg, b.i.d. (oral)
Entry inhibitors
Enfuvirtide	T20	Fuzeon^®	Roche & Trimeris	90 mg, b.i.d. (subcutaneous)
Maraviroc	UK-427,857	Selzentry^®	Pfizer	150 mg, b.i.d. (oral) OR 300 mg, b.i.d. (oral) OR 600 mg, b.i.d. (oral)
Protease inhibitors (PIs)
Indinavir	IDV	Crixivan^®	Merck	800 mg, b.i.d. (oral) OR 800 mg, t.i.d. (oral)
Nelfinavir	NFV	Viracept^®	Agouron Pharmaceuticals	1250 mg, b.i.d. (oral) OR 750 mg, t.i.d. (oral)
Saquinavir	SQV	Invirase^®	Roche	1000 mg, b.i.d. (oral
Atazanavir	ATV	Reyataz^®	Bristol-Myers Squibb	300 mg, daily (oral) OR 400 mg, daily (oral)
Darunavir	DRV	Prezista^®	Tibotec	600 mg, b.i.d. (oral) OR 800 mg, daily (oral)

b.i.d., twice daily; t.i.d., thrice daily

Table II. Bioavailability of some dosage form of antiretroviral drugs.

Drugs name	Dosage form	Bioavailibility (%)
Etravirine	Tablet	Unknown
Nevirapine	Tablet, syrup	> 90
Efavirenz	Tablet, capsule, solution	42–80
Lamivudine	Tablet, liquid	86
Abacavir	Tablet, liquid	83–100
Zidovudine	Capsule, liquid	60
Didanosine	Tablet, capsule, liquid	30–40
Zalcitabine	Tablet	85
Stavudine	Capsule, powder for reconstitution	80
Raltegravir	Tablet	No data
Enfuvirtide	Powder for subcutaneous injection	84.3
Maraviroc	Tablet	23–33
Indinavir	Capsule	65
Nelfinavir	Tablet, powder	20–80
Saquinavir	Tablet, capsule	Erratic, 4
Atazanavir	Capsule	No data
Darunavir	Tablet	37

Table III. Fixed dose combination for anti-HIV therapy.

Drug combination	Brand name	Manufacturer	Dosage form
Lopinavir + Ritonavir	Kaletra^®	Abbott Labs	Tablets (50 and 200 mg), oral solution (80 mg/mL and 20 mg/mL)
Abacavir + Lamivudine	Trizivir^®	Glaxosmithkline	Tablets (150 and300 mg)
Tenofovir + Emtricitabine	Truvada^®	Gilead Sciences	Tablets (200 and 300 mg)
Lamivudine + Zidovudine	Combivir^®	GlaxoSmithKline	Tablets (150 and 300 mg)

Table IV. Physicochemical and biopharmaceutical characteristics of anti-HIV drugs.

Drug	LOG P	t1/2 (hr)	Protein binding (%)	Solubility (mg/ml)
Efavirenz	4.6	40–55	99.5–99.75	< 0.001
Navirapine	1.75	45	60	0.007
Abacavir	1.1	1.54	50	77
Lamivudine	− 1.4	5–7	36	70
Stavudine	− 0.8	0.8–1.5	Negligible	83
Zalcitabine	− 1.3	2	< 4	76.4
Didanosine	− 0.2	0.5	< 5	27.3
Zidovudine	0.05	5–3	30–38	20.1
Lopinavir	4.69	5–6	98–99	1.92
Amprenavir	2.43	7.1–10.6	90	0.04
Ritonavir	3.9	3–5	98–99	1.26
Delavirdine	2.8	5.8	98	0.2942

Figure 3. Nanotechnology-based systems for HIV-AIDS treatment.

Table V. Advantages and limitations of nanosystems used in HIV-AIDS treatment.

Nanosystem	Advantage	Disadvantage
Liposomes	Liposomes are biocompatible, amphiphilic in nature and their surface can be modified easily	They may have drug leakage problem and their loading capacity is weak. Their physical and chemical stability during storage is very poor
Polymeric nanoparticles	They are biocompatible, biodegradable and numerous classes of drugs can be entrapped in them	They may show polymer toxicity and difficulty in the large-scale production
Solid lipid nanoparticles	They are biocompatible, biodegradable and highly efficient. They may show flexibility of size and surface manipulation	They are having poor stability, and poor batch to batch
		Reproducibility. They may show sterilization difficulties and poor drug loading
Nanostructured lipid carriers	They are biodegradable and having high drug payload. Drug leakage is minimum from them during storage	Their sterilization is very difficult
Niosomes	They improve the bioavailability of inadequately absorbed drugs (oral) and increase the penetration power of drugs through skin. They are less toxic as that of liposomes	They are not suitable for targeting deeper layer of skin
Polymeric micelles	They are self-assembling carriers with very high thermodynamic stability and targeting capability	They are not suitable for delivery of hydrophilic drugs
Dendrimers	They are easy to prepare and their surface can be modified easily for effective targeting	They show polymer dependent biocompatibility

Figure 4. Selective uptake of drug-loaded liposomes by mononuclear phagocytes.

Table VI. Brief summary of different nanotechnology-based systems of potential antiretroviral drugs.

Drug	Nanosystem	Route of administration	Key findings	References
Efavirenz	Polymeric micelles	Oral	Polymeric micelles significantly improved the oral bioavailability of the drug compared to suspension prepared with the content of Efavirenz capsules	Chiappetta et al. (2010)
	Mixed polymeric micelles	Oral	Drug-loaded mixed micelles displayed increased drug Solubility and physical stability over time in comparison with pure poloxamine ones	Chiappetta et al. (2011a)
	Polymeric micelles	Intranasal for targeting brain	Bioavailability of the drug in the CNS was increased four folds and the relative exposure index (ratio between the area under the curve in the CNS and plasma) was increased five folds with respect to the same system administered intravenously	Chiappetta et al. (2013)
	Dendrimer	–	Cellular uptake of drug by Mo/Mac cells observed in case of mannose conjugated dendrimer was 12 times higher than that of free drug and 5.5 times higher than that of t-Boc-glycine conjugated dendrimer	Dutta et al. (2007)
Navirapine	Liposomes	–	Drug showed better encapsulation and quick release from liposomes in PBS and Dulbecco's Modified Eagle’s Medium (DMEM) under the effect of external stimulus such as low frequency ultrasound	Ramana et al. (2010)
	Polymeric nanoparticles grafted with transferrin (Tf)	–	An increase in the concentration of transferrin (Tf) enhanced the permeability of nanoparticles in human brain microvascular endothelial cells (HBMECs)	Kuo et al. (2011)
	Solid lipid nanoparticles and nanostructured lipid carrier	–	SLN and NLC coated with human serum albumin (HSA) increased the viability of human brain microvascular endothelial cells (HBMECs) about 10% when the concentration of NLCs and SLNs was higher than 0.8 mg/mL	Kuo and Chung (2011)
Lamivudine	Polymeric micelles	–	Prepared polymeric micelles showed a low cytotoxicity and high cellular uptake percentage of drug against HBV transfected tumor cells (HepG2.2.15)	Li et al. (2010)
	Polymeric nanoparticles	–	In-vitro BBB (blood–brain barrier) permeability of drug increased up to 10–18 folds with Polymeric nanoparticles compared to conventional formulation	Kuo and Chen (2006)
	Solid lipid nanoparticles	Intraperitoneal	Solid lipid nanoparticles showed higher concentration of drug in RES organs compared to polymeric nanoparticles of drug	Sankar et al. (2012)
Stavudine	Liposomes	Bolus intravenous	Mannosylated liposomes maintained a significant level of stavudine in the liver, spleen and lungs up to 12 h and had greater systemic clearance as compared with free drug or the uncoated liposomal formulation	Garg et al. (2006)
	Solid lipid nanoparticles	–	ex-vivo cellular uptake studies in macrophages depicted several times enhanced drug uptake in case of SLN as compared to pure drug solution	Shegokar and Singh (2011)
Zalcitabine	Liposomes	–	Intracellular uptake of drug loaded liposome was very high and was due to anionic charge on liposomes	Gagne et al. (2002)
Didanosine	Polymeric nanoparticles	Intranasal for targeting brain	Ratio of didanosine concentration values of the nanoparticles to the solution at 180 min post-intranasal dosing was 2.1 and 1.9 in CSF and brain in rats, respectively	Al-Ghananeem et al. (2010)
	Polymeric nanoparticles	–	Nanoparticles successfully transported didanosine to macrophages in-vitro, causing reduction of dose and minimizing toxicity and side effects	Pattnaik et al. (2012)
	Nanostructured lipid carrier	–	Mixture of Precirol^® ATO 5 and Transcutol^® HP found suitable for production of NLCs of drug instead of single Precirol^® ATO 5	Kasongo et al. (2011b)
Zidovudine	Liposomes	Intravenous	Plasma concentration of drug after intravenous administration of drug loaded liposomes was 2 folds higher compared to plain drug	Jin et al. (2005)
	Liposomes	Transdermal	Biodistribution study indicated 27-folds higher accumulation of drug in lymphoid tissues after transdermal application compared to free drug	Jain et al. (2008)
	Polymeric nanoparticles		Polylactic acid (PLA) nanoparticles were more efficiently phagocytosed than PLA (Polylactic acid)/PEG (poly ethylene glycol) blends	Mainardes and Gremião (2012)
	Solid lipid nanoparticles	–	Two operating variables, polyvinyl alcohol concentration and amount of lipid were found to have significant effect on the particle size and entrapment efficiency (EE) of the SLN. EE of batches with triglycerides were significantly less than that achieved with stearic acid alone.	Singh et al. (2010)
	Niosomes	Bolus intravenous	Prolonged AZT levels in rabbit serum following the treatment with niosomal AZT appeared due to the combined effect of slow in-vivo release and avoidance of extravascular distribution	Gopinath et al. (2001)
Lopinavir	Solid lipid nanoparticles	Intraperitoneal	Appreciable increase in cerebrospinal fluid concentration was detected with solid lipid nanoparticle formulations compared to free drug suspension	Alex et al. (2011)
	Niosomes and ethosomes	Transdermal	Ex-vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes	Patel et al. (2012)
Saquinavir	Polymeric nanoparticles grafted with γ-PGA	–	A higher grafting efficiency and a lower molecular weight of γ-PGA increased the permeability of drug across the blood–brain barrier (BBB) in-vitro	Kuo and Yu (2011a)

Figure 5. Utility of nanoparticles in anti-HIV therapeutics.

Figure 6. A) Solid lipid nanoparticle. B) Nanostructured lipid carrier.

Figure 7. Anti-HIV drug targeting using niosomes.

Figure 8. Targeting of anti-HIV drug by polymeric micelle.

Figure 9. Polymeric dendrimers in anti-HIV drug targeting.

Table VII. List of patents associated with nanosystems used in HIV-AIDS treatment.

Title of patent	Drug	Delivery system	Route of administration	Patent number	Inventors
Liposomes comprising of azidothymidine and lithium for treating HIV/AIDS	Combination of azidothymidine (zidovudine) and lithium	Liposomes	Intravenous/rectal	WIPO Patent Application WO/1998/023276	Gabev and Evgeni Bogomilov (1998)
Micellar colloidal pharmaceutical composition containing a lipophilic active principle	Amprenavir or ritonavir	Micelles	Oral	United States Patent Application 20040052824	Abou Chacra-vernet et al. (2004)
Flexible, polyvalent antiviral dendritic conjugates for the treatment of HIV/AIDS and enveloped viral infection	–	Dendrimers	transdermally, mucosally, nasally, buccally	WIPO Patent Application WO/2009/038605	Subramaniam and Bennett (2009)
Magnetic nanodelivery of therapeutic agents across the blood–brain barrier	5′-triphosphate-azidothymidine (AZT-TP)	Liposomes comprising magnetic nanoparticles bound to therapeutic agent	Intravenous	United States Patent Application 20110213193	Nair and Saiyed (2011)
Composition of lopinavir and ritonavir	Combination of lopinavir and ritonavir	Nanoparticles	Intravenous	WIPO Patent Application WO/2013/034927	Giardiello et al. (2013)

Chiappetta DA, Hocht C, Taira C, Sosnik A. 2010. Efavirenz-loaded polymeric micelles for pediatric anti-HIV pharmacotherapy with significantly higher oral bioavailability [corrected]. Nanomedicine (Lond). 5:11–23.

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