Assistant Professor, Faculty of Pharmacy; DIT University Dehradun, India
The AIDS/acquired Immune deficiency syndrome associated with their significance role in the development of HIV infection that later stage lead to broad range of complicated neurological disorder including neuroAIDS. The complication of neuroAIDS involves cognitive impairment, dementia, loss of sensation prominently in legs and arms and behavioral changes. Irrespective of current apprehending clinical pathology as well as availability of anti-retroviral therapy in neuroAIDS, it is still remaining a daunting therapeutic challenge for scientific world. However, the cutting edge technology based on nanomedicine targeting improves the penetration capacity of cargos through blood brain barrier and greatly helpful in eradicating neuroAIDS. The brief review enlightens the nanomedicine advances in the management and therapy of highly devastating neurological AIDS.
The Human Immune deficiency Virus (HIV) infected brain cells through virus or HIV linked oncogenes. The major complication of such infection leads to dementia, peripheral neuropathies, neurosyphilis, meningitis etc. The development of neuroAIDS still remains a topic of debate due to multifaceted symptom, complicated pathology along with lack of precise diagnostic protocol or tool [1-3]. Adversely it was considered that later stage HIV infects brain cells. In the early phase, HIV enters to brain through ‘Trojan horse’ mechanism mediated via phagocytes in response to cytokines and associated proteins. In the early phase of HIV infection in brain leads to modification of cellular integrity of blood brain barrier which induces the leukocytes (normal/infected) throughout blood brain barrier from peripheral circulation and intensifies the infection in different brain cells . The virion and other neurotoxic products stimulate pathological condition in brain cells. The infected monocytes differentiating into macrophages that later induce into astrocytes and other brain cells together evoke inflammation in brain. The inflamed surface area releases tumor necrosis factor, interleukin, reactive oxygen species, and nitric oxide. The resulting release activates chemokine receptors and hence elevates the calcium ion level inside the cells that is related with cell death. The envelop protein (gp120) down regulating glutamate results in neuron damage, nitric acid sythatase induces cell death. The gp120 protein elevates the level of interleukin, TNF-alfa, cytokines in microglial cells thereby prevent proliferation and migration of neuron cells and finally affecting blood brain barrier due to induction of apoptosis in microvascular epithelial cells . The HIV TAT proteins similar to gp120 affect neuron cell in a multiple way such as enhances calcium ion release; NMDA receptor for neurotransmitter release; decrease dopamine level; active nitric oxide and inhibits tyrosine hydroxylase all together elicit to neuronal damage and apoptosis. The HIV infection to brain cells mediated via specific pathway leads to pathological condition which further aggravate and reported in neuroAIDS disease. The recent report supported that synaptic plasticity in brain due to HIV infection showed noteworthy loss of neuron cells, dendrites that is associated with neuronal potentiation and depression genes. The alteration in these genes adversely affects the synapse junction between two neurons, release of neurotransmitter, synaptic density, and loss of white and grey soft matter [6-9].
Current neuroAIDS therapy:
The current therapy relied on antiretroviral therapy, which is comprised of single or combination or medicaments from different classes of anti-retroviral therapy. The continuous treatment with these drugs faces multiple challenges that results in poor patient compliance. The long term medication for eradication of HIV leads to forgetfulness, non-adherence to dosage regimen, feeling sick, and depression at the same time causes the noncompliance and poor outcomes of the therapy . Apart from these, the long doses schedule of anti-retroviral therapy that often results in toxic effect, drug resistance, and genetic diversity in HIV virus. The other complication may be the weakening of immune system, neuro-degeneration, worsening heart condition, liver infection, and other vital organ problems [11, 12].
Therefore, nanomedicine advances from state of art technology investigate the novel nanomaterials as smart drug delivery carrier for potential therapy in neuroAIDS. The preparation of smart nanomaterials for drug targeting requires application of surface chemistry for payload of therapeutics, system biology for machine based learning and optimisation process and pharmacology for suitable drug combination for payloads. Nanomedicine offers nano-enabled formulation, exhibits better therapeutic efficacy and minimise drug related side effect, reduces dose frequency, low variation in pharmacokinetic profile. Despite these on demand release of drug, sustained manner of drug release, specific time release precisely tuned, safe and effective dose can be designed as per the patient profile .
Nanomedicine based neuroAIDS therapy
Magnetically guided nanotherapy: The particle size of cargo for brain delivery through blood brain barrier is the major concern for therapeutic efficacy. However, the receptor based drug targeting decorated with protein, enzymes or biomolecules of magnetically based cargo could achieve better through blood brain barrier. Magneto-liposomes achieved successful delivery via reducing enzymatic decomposition and immobilisation in reticuloendothelial system.
Saiyed and associates developed magnetically guided delivery of AZTTP loaded magnetic nanoparticles for neuroAIDS treatment. Nanoparticle crossed brain barrier and released drug released under the influence of static magnetic field and showed sustained release pattern .
For eradicating the non-adherence issue of HIV infected viruses Jayant and coworkers developed anti-retrovirus loaded novel formulation for potential delivery in brain. The formulation was developed by deposition of multiple polymer layers in between drug molecule over magnetic nanoparticle. The drug release pattern was sustained over 30-fold increase in release time due to 2.8 fold higher drug encapsulation. Further, the developed formulation exhibited improved anti-retroviral efficacy and transmigration capacity across astrocytes compared to plain tenofovir . Jayant et al. fabricated magneto-liposomal nanomedicine with different payloads likewise antiretroviral drugs, latency reactivating agents and drug abuse antagonist to cure CNS HIV infection. Results indicated that sustained drug release for 10 days with reduced HIV-1 infection upto ~40–50 per cent [ 16].
Polymeric micelles with payload of Efavirenz: Chiappetta and collegues fabricated Efavirenz loaded micelles for the treatment of AIDS in children. The nanomedicine has shown improved bioavailability in preclinical study for pediatric application in HIV. The study further extends to intranasal delivery to brain. It was observed that blood brain barrier selectively allow to enter the very small size micelles. Thus, reducing micelles size and increasing the hydrophobicity of nanocarrier the CNS delivery of aforesaid drug can be improved. The intranasal delivery of Efavirenz from polymeric micelles improved four times bioavailability compare to oral delivery and 5-times in case of i.v administration .
Lamivudine loaded PAMAM dendrimers: The amazing results were observed with nanomedicine carrying anti-retroviral agents and genes for neuroAIDS therapy. Dendrimer loaded with lamivudine had indicated 20-time higher cellular uptake compared with free drug solution suggested significant of nanomedicine in BBB drug delivery . Dutta and colleagues developed Tuftsin dendrimers of Efavirenz with intention to specific binding with mononuclear phagocytic cells and observation revealed enhanced phagocytic activity. Further cellular uptake was increased to 34.5 times and cut down viral load by 99 per cent. Continuing with other study reported 12-times of higher cellular uptake of Efavirenz by macrophagic cells compare to drug solution .
Liposomal nanosized formulation:
Liposomes vesicles are good candidate for BBB delivery due to lipophilic and biodegradable nature. Liposomes easily recognised by macrophagic system and HIV infection predominates in such system and therefore, the liposomal payload of anti-retroviral therapy greatly helps in reducing cytotoxicity induced by free drugs both in vitro as well as in vivo. Liposomal foscarnet improved drug level in rat brain by 13-folds compared to foscarnet solution. AZT loaded liposomes showed enhanced anti-viral activity in HIV infected mice. Other showed higher uptake of Zalcitabine from liposomal nanomedicine in anti-cancer study of RAW264.7 and U937 cell line. Ramana et al prepared Nevirapine liposomal nanomedicine and evaluated all the formulation parameters and results expressed potential targeting of drug in brain with reduced toxic effect .
The proper monitoring and management of HIV infection requires diagnosis, therapy, and routine monitoring of viral presence in plasma in time to improve the HIV prevention. The early diagnosis through user friendly techniques more often give precise monitoring of disease. The rapid development of scientific techniques provided cost effective and diagnostic tool for detection of HIV infection. Among therapy in neuroAIDS, the improved nanomedicine developed day-to-day has shown navigation across blood brain barrier for complete eradication of neuroAIDS.
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